telcagepant and Migraine-Disorders

The pivotal role of calcitonin gene-related peptide (CGRP) in migraine pathophysiology was identified over 30 years ago, but the successful clinical development of targeted therapies has only recently been realized. This Perspective traces the decades long evolution of medicinal chemistry required to advance small molecule CGRP receptor antagonists, also called gepants, including the current clinical agents rimegepant, vazegepant, ubrogepant, and atogepant. Providing clinically effective blockade of CGRP signaling required surmounting multiple challenging hurdles, including defeating a sizable ligand with subnanomolar affinity for its receptor, designing antagonists with an extended confirmation and multiple pharmacophores while retaining solubility and oral bioavailability, and achieving circulating free plasma levels that provided near maximal CGRP receptor coverage. The clinical efficacy of oral and intranasal gepants and the injectable CGRP monoclonal antibodies (mAbs) are described, as are recent synthetic developments that have benefited from new structural biology data. The first oral gepant was recently approved and heralds a new era in the treatment of migraine.

Topics: Animals; Calcitonin Gene-Related Peptide; Calcitonin Gene-Related Peptide Receptor Antagonists; Humans; Migraine Disorders; Receptors, Calcitonin Gene-Related Peptide; Signal Transduction

A better understanding of the mechanisms underlying the migraine attack has reinforced the concept that migraine is a complex brain disease, and has paved the way for the development of new migraine specific acute treatments. In recent years, targeting the calcitonin gene-related peptide and its receptors has been one of the most promising pharmacological strategies for both acute and preventive treatment of migraine.. Randomized double-blind placebo-controlled trials have demonstrated the superiority of small molecule calcitonin gene-related peptide receptor antagonists (gepants) over placebo in treating acute migraine attacks measured as the two-hour pain free endpoint. Gepants also improved migraine associated symptoms, such as nausea, photophobia and phonophobia. Two of the class have had their development stopped because of hepatotoxicity, which is emerging as being due to metabolites. Gepants have a good tolerability and can be safely used in patients with stable cardiovascular disease.. Exciting results have been obtained targeting the calcitonin gene-related peptide pathway to abort acute migraine attacks, thus reinforcing the relevance of mechanism-based treatments specific for migraine.

Topics: Azepines; Calcitonin Gene-Related Peptide; Calcitonin Gene-Related Peptide Receptor Antagonists; Clinical Trials, Phase II as Topic; Dipeptides; Drug Delivery Systems; Humans; Imidazoles; Migraine Disorders; Piperazines; Quinazolines; Receptors, Calcitonin Gene-Related Peptide

Although triptans are widely used for treating acute migraine, they are contraindicated or not effective in a large proportion of patients. Hence, alternative treatments are needed. Calcitonin gene-related peptide receptor antagonists, such as telcagepant, have been under investigation as a treatment for acute migraine. A meta-analysis of the efficacy of telcagepant vs. placebo and triptans (zolmitriptan or rizatriptan) was performed. Randomized controlled trials were indentified from databases using the following search terms: migraine; calcitonin gene-related peptide; calcitonin gene-related peptide receptor antagonists; efficacy; safety, and telcagepant. The primary outcome measure was pain freedom 2 hours after first treatment. The secondary outcome measure was pain relief 2 hours after first treatment. Eight trials were included in the meta-analysis (telcagepant = 4011 participants). The difference in pain freedom at 2 hours significantly favored telcagepant over placebo (odds ratio = 2.70, 95% confidence interval = 2.27-3.21, P < 0.001) and triptans over telcagepant (odds ratio = 0.68, 95% confidence interval = 0.56-0.83, P < 0.001). The difference in pain relief at 2 hours significantly favored telcagepant over placebo (odds ratio = 2.48, 95% confidence interval = 2.18-2.81, P < 0.001). The difference in pain relief at 2 hours did not significantly favor telcagepant over triptans or vice versa (odds ratio = 0.76, 95% confidence interval = 0.57-1.01, P = 0.061). These findings indicate that telcagepant can be effective for treating acute migraine. Calcitonin gene-related peptide receptor antagonists represent a potentially important alternative means of treating acute migraine.

Topics: Acute Disease; Azepines; Calcitonin Gene-Related Peptide Receptor Antagonists; Humans; Imidazoles; Migraine Disorders; Oxazolidinones; Serotonin 5-HT1 Receptor Agonists; Treatment Outcome; Triazoles; Tryptamines

Calcitonin gene-related peptide (CGRP) is a potent neuromodulator and vasodilator. It has been implicated in the pathogenesis of migraine by a number of lines of evidence, although its precise role has yet to be fully defined. Compelling evidence for the importance of CGRP in migraine has been provided by clinical trials with multiple small molecule CGRP receptor antagonists. These clinical studies have shown that blockade of the CGRP receptor can produce antimigraine efficacy comparable to that of the gold standard triptan class of drugs with an incidence of adverse events that appears to be relatively low. The present review describes the discovery and development of these new antimigraine agents and highlights the challenges of identifying orally acting drugs that target a family B G-protein-coupled receptor.

Topics: Amino Acid Sequence; Animals; Calcitonin Gene-Related Peptide; Calcitonin Gene-Related Peptide Receptor Antagonists; Clinical Trials as Topic; Drug Discovery; Humans; Migraine Disorders; Molecular Sequence Data; Receptors, Calcitonin Gene-Related Peptide; Structure-Activity Relationship

Migraine is the most prevalent of the neurological disorders and can affect the patient throughout the lifetime. Calcitonin gene-related peptide (CGRP) is a neuropeptide that is expressed in the central and peripheral nervous systems. It is now 2 decades since it was proposed to be involved in migraine pathophysiology. The cranial sensory system contains C-fibers storing CGRP and trigeminal nerve activation and acute migraine attacks result in release of CGRP. The CGRP receptor consists of a complex of calcitonin receptor-like receptor (CLR), receptor activity-modifying protein 1 (RAMP1) and receptor component protein (RCP). At the central synapses in the trigeminal nucleus caudalis, CGRP acts postjunctionally on second-order neurons to transmit pain signals centrally via brainstem and midbrain to thalamus and higher cortical pain regions. CLR and RAMPs are widely expressed throughout the brain, in the trigeminal ganglion and in intracranial arteries. CGRP does not induce neurogenic inflammation or sensitization at peripheral meningeal sites but relays nociceptive information from trigeminal primary afferent neurons to the second-order neurons in the spinal trigeminal nucleus neurons. CGRP receptor antagonists have been developed as novel antimigraine drugs and found to be effective in the treatment of acute migraine attacks. Other ways to stop CGRP activity has been introduced recently through antibodies against CGRP and the CGRP receptor. While the CGRP receptors are expressed both in the CNS and at various places related to the trigeminal system the exact site of action for their therapy effect is still unresolved but the new approaches may resolve this.

Topics: Azepines; Calcitonin Gene-Related Peptide; Calcitonin Gene-Related Peptide Receptor Antagonists; Dipeptides; Humans; Imidazoles; Migraine Disorders; Peptide Fragments; Piperazines; Quinazolines; Receptors, Calcitonin Gene-Related Peptide

We highlight the recent clinical trials for the management of acute and chronic migraine.. In women with menstrual migraine, triptans seem to be well tolerated irrespective of whether or not patients are taking oestrogen-containing contraceptives or have comorbidities that indicate increased cardiovascular risk. The new acute drug, telcagepant, a calcitonin gene-related peptide (CGRP) antagonist, is safe for long-term use (up to 18 months) in migraine patients with stable coronary artery disease in whom the use of triptans is not advisable. From the pooled analysis of the two Phase III Research Evaluating Migraine Prophylaxis Therapy studies of onabotulinumtoxinA (BOTOX) in chronic migraineurs, it clearly emerged that efficacy increases overtime (up to 56 weeks) and paralleled self-perceived improvement in quality of life. Effectiveness was also observed in patients with severely disabling headaches, who met criteria for triptan abuse and were refractory to several prophylactic treatments. Finally, combination of preventive pharmacological agents with different action mechanisms may be the next frontier in therapeutic advancements for treating migraine.. Although triptans are safe and well tolerated, CGRP antagonists may be an option for nonresponsive patients or those in whom the use of triptans is not advisable. New drugs and combinations of old therapeutic options may help patients with severe forms of headache.

Topics: Acute Disease; Azepines; Botulinum Toxins, Type A; Calcitonin Gene-Related Peptide Receptor Antagonists; Chronic Disease; Humans; Imidazoles; Migraine Disorders; Randomized Controlled Trials as Topic; Tryptamines

Migraine afflicts approximately 11% of the population worldwide producing substantial disability, resulting in loss of productivity both at home and at the workplace. Calcitonin gene-related peptide (CGRP) is closely involved in the cascade of molecular events leading to migraine painful crisis.. Acute treatment of migraine is actually based on the use of triptans, class drug which presents a clear limitation due to its cardiovascular side effects. Gepants, a CGRP antagonist class, might offer a new non-vasoconstrictive approach in the acute treatment of migraine. Four chemically unrelated CGRP receptor (CGRP-R) antagonists (olcegepant, telcagepant, MK-3207 and BI 44370 TA) have displayed efficacy in the treatment of migraine.. When compared with triptans, gepants class showed a similar efficacy, moreover corresponding to the best published results for oral triptans. CGRP antagonists are in different phases of their development, and the treatment of migraine could be based on the use of gepants, as class of acute medications. However, CGRP-R antagonists clinical trials seem to be discouraging for their forthcoming use in clinical practice. New CGRP-R antagonists, such as BMS-927711 and BI 44370 TA, are in the pipeline and their developments will outline the future of this drug class.

Topics: Animals; Azepines; Calcitonin Gene-Related Peptide Receptor Antagonists; Dipeptides; Drug Design; Humans; Imidazoles; Migraine Disorders; Piperazines; Quinazolines; Tryptamines

Topics: Analgesics; Azepines; Calcitonin Gene-Related Peptide Receptor Antagonists; Contraindications; Cross-Sectional Studies; Drug Approval; Drug Therapy, Combination; Drugs, Investigational; Germany; Humans; Imidazoles; Migraine Disorders; Nonprescription Drugs; Tryptamines

In 3 randomized clinical trials (n = 1585) the calcitonin gene-related peptide antagonist telcagepant 300 mg orally had an incidence of adverse events similar to placebo when used in the acute treatment of migraine. Telcagepant, thus, has excellent tolerability in migraine. Only a quarter (26%) (334/1307) of patients were, however, pain free after 2 hours, while 56% (729/1297) of patients had pain relief at 2 hours. Telcagepant 300 mg in one randomized clinical trial was equipotent to zolmitriptan 5 mg. Based on results from a meta-analysis, rizatriptan 10 mg (41%) and almotriptan (35%) seem superior to telcagepant (26%) for pain free at 2 hours whereas rizatriptan 10 mg (25%) showed no difference from telcagepant 300 mg (19 %) for sustained pain free (2-24 hours). The introduction of calcitonin gene-related peptide receptor antagonism in the acute treatment of migraine is a major step forward but so far mostly because of its specific mode of action and excellent tolerability.

Topics: Azepines; Calcitonin Gene-Related Peptide Receptor Antagonists; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Headache; Humans; Imidazoles; Migraine Disorders; Randomized Controlled Trials as Topic; Treatment Outcome; Tryptamines

Dose-response curves for headaches relief and adverse events (AEs) are presented for five triptans: sumatriptan, zolmitriptan, naratriptan, almotriptan, and frovatriptan, and the CGRP antagonist telcagepant. The upper part of the efficacy curve of the triptans is generally flat, the so-called ceiling effect; and none of the oral triptans, even in high doses, are as effective as subcutaneous sumatriptan, In contrast, AEs increases with increasing dose without a ceiling effect. The optimal dose for the triptans is mainly determined by tolerability. Telcagepant has an excellent tolerability and can be used in migraine patients with cardiovascular co-morbidity. Based on the literature the triptans and telcagepant are rated in a table for efficacy and tolerability.

Topics: Azepines; Calcitonin Gene-Related Peptide Receptor Antagonists; Humans; Imidazoles; Migraine Disorders; Serotonin 5-HT1 Receptor Agonists; Tryptamines

The calcitonin gene-related peptide (CGRP) receptor antagonists olcegepant and telcagepant are very potent drugs. Both are effective in migraine but in doses much higher than would be predicted from receptor binding and other in vitro results. This could perhaps suggest an effect of CGRP antagonists behind the blood-brain barrier (BBB), i.e. in the central nervous system (CNS).. Comparison of doses needed for CGRP blocking effect in vitro with dose needed in vivo in man and monkeys. Discussion of these doses in relation to doses needed for anti-migraine activity.. In vivo studies in monkeys and man showed that high doses compared to doses needed in vitro are needed to block capsaicin-induced in skin blood flow, a CGRP-mediated reaction. These doses are close to those needed for anti-migraine activity.. The apparently high doses of CGRP receptor antagonists, olcegepant and telcagepant needed for anti-migraine effect are not so high after all. They do not allow a conclusion as to whether CGRP antagonists act on peripheral sites or central sites in migraine.

Topics: Animals; Azepines; Blood-Brain Barrier; Bridged Bicyclo Compounds, Heterocyclic; Calcitonin Gene-Related Peptide Receptor Antagonists; Cerebrovascular Circulation; Dipeptides; Humans; Imidazoles; Migraine Disorders; Piperazines; Quinazolines; Spiro Compounds

This review provides a comprehensive selection of the latest clinical trial results in antimigraine treatment.. The oral calcitonine gene-related peptide antagonist telcagepant is efficacious in acute treatment. Compared to triptans, its efficacy is almost comparable but its tolerance is superior. The same is true for the 5HT-1F agonist lasmiditan, another agent devoid of vascular effects. Triptans, as other drugs, are more efficient if taken early but nonsteroidal anti-inflammatory drugs and analgesics remain useful for acute treatment, according to several meta-analyses. Single-pulse transcranial magnetic stimulation during the aura rendered more patients pain-free (39%) than sham stimulation (22%) in one study. Topiramate could be effective for migrainous vertigo, but it did not prevent transformation to chronic migraine in patients with high attack frequency. Onabotulinumtoxin A was effective for chronic migraine and well tolerated, but the therapeutic gain over placebo was modest; the clinical profile of responders remains to be determined before widespread use. Occipital nerve stimulation was effective in intractable chronic migraine with 39% of responders compared to 6% after sham stimulation. This and other neuromodulation techniques, such as sphenopalatine ganglion stimulation, are promising treatments for medically refractory patients but large controlled trials are necessary. One study suggests that outcome of patent foramen ovale closure in migraine might depend on anatomic and functional characteristics.. Drugs with a better efficacy or side-effect profile than triptans may soon become available for acute treatment. The future may also look brighter for some of the very disabled chronic migraineurs thanks to novel drug and neuromodulation therapies.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Azepines; Biofeedback, Psychology; Calcitonin Gene-Related Peptide Receptor Antagonists; Clinical Trials as Topic; Electric Stimulation; Humans; Imidazoles; Migraine Disorders; Oxalates; Transcranial Magnetic Stimulation; Tryptamines

Telcagepant (MK-0974) is a novel calcitonin gene-related peptide (CGRP) receptor antagonist currently undergoing clinical trials for migraine (http://www.merck.com/research/pipeline/home.html). MK-0974 is currently being studied in phase III clinical trials.

Topics: Animals; Azepines; Biological Availability; Calcitonin Gene-Related Peptide Receptor Antagonists; Cyclic AMP; Humans; Imidazoles; Migraine Disorders; Randomized Controlled Trials as Topic; Tryptamines

Although the triptan drugs provide effective relief from migraine for many patients, a substantial number of affected individuals are unresponsive to these compounds, and such therapy can also lead to a range of adverse effects. Telcagepant represents a new class of antimigraine drug-the calcitonin gene-related peptide receptor blockers. This compound exerts its effects by blocking receptors for the calcitonin-gene-related peptide at several sites in the trigeminal and central nervous systems, resulting in pain relief. Telcagepant does not cause vasoconstriction, a major limitation in the use of triptans. Comparisons with triptans in clinical trials for acute treatment of migraine attacks revealed clinical effects similar to those of triptans but better than those of placebo. Telcagepant might provide hope for those who have a poor response to, or are unable to use, older drugs. In patients who need prophylaxis because of frequent attacks of migraine, topiramate is a first-line drug for migraine prevention in many countries; it is generally safe and reasonably well tolerated. Data suggest that topiramate could aid reversion of chronic migraine to episodic migraine.

Topics: Anticonvulsants; Azepines; Calcitonin Gene-Related Peptide Receptor Antagonists; Fructose; Humans; Imidazoles; Migraine Disorders; Topiramate

Calcitonin gene-related peptide (CGRP) is expressed throughout the central and peripheral nervous systems, consistent with control of vasodilatation, nociception, motor function, secretion, and olfaction. alphaCGRP is prominently localized in primary spinal afferent C and ADelta fibers of sensory ganglia, and betaCGRP is the main isoform in the enteric nervous system. In the CNS there is a wide distribution of CGRP-containing neurons, with the highest levels occurring in striatum, amygdala, colliculi, and cerebellum. The peripheral projections are involved in neurogenic vasodilatation and inflammation, and central release induces hyperalgesia. CGRP is released from trigeminal nerves in migraine. Trigeminal nerve activation results in antidromic release of CGRP to cause non-endothelium-mediated vasodilatation. At the central synapses in the trigeminal nucleus caudalis, CGRP acts postjunctionally on second-order neurons to transmit pain signals centrally via the brainstem and midbrain to the thalamus and higher cortical pain regions. Recently developed CGRP receptor antagonists are effective at aborting acute migraine attacks. They may act both centrally and peripherally to attenuate signaling within the trigeminovascular pathway.

Topics: Animals; Azepines; Calcitonin Gene-Related Peptide; Calcitonin Gene-Related Peptide Receptor Antagonists; Dipeptides; Humans; Imidazoles; Migraine Disorders; Neurotransmitter Agents; Piperazines; Quinazolines

Migraine is a highly prevalent disabling condition, and the current treatment options are not satisfactory. The role of calcitonin gene-related peptide (CGRP) in migraine pathophysiology is well established. CGRP receptor antagonists address this new target and have the potential to improve therapy for both responders and non-responders to previous options.. This review describes CGRP, its receptors and their role in the pathophysiology of migraine. CGRP receptor antagonists are a recent development; all reported antagonists are reported in chronological order. The experimental evidence, as well as all clinical trials since the first proof-of-concept study in 2004, is discussed.. An overview of the CGRP system and why it provides an attractive drug target for headache. The main focus is on the currently presented CGRP receptor antagonists and clinical evidence for this new therapeutic option.. CGRP receptor antagonists will provide an additional and valuable therapeutic option for the treatment of headaches.

Topics: Animals; Azepines; Calcitonin Gene-Related Peptide; Calcitonin Gene-Related Peptide Receptor Antagonists; Clinical Trials as Topic; Dipeptides; Humans; Imidazoles; Indazoles; Migraine Disorders; Piperazines; Quinazolines; Quinazolinones; Treatment Outcome; Trigeminal Nerve

Calcitonin gene related peptide (CGRP) has been proposed to contribute to pain transmission and inflammation and for these reasons to the mechanism of migraine. CGRP is, in fact, expressed in and released from a subset of polymodal primary sensory neurons of the trigeminal ganglion. Release of CGRP in the dorsal spinal cord has been associated to nociceptive transmission, and release from perivascular nerve endings causes neurogenic vasodilatation. CGRP levels increase in the cranial circulation during migraine attacks, and GRP injection in migraineurs results in migraine-like attacks. Most importantly, two chemically unrelated CGRP-receptor antagonists, the parenteral agent, olcegepant, and the orally available telcagepant demonstrated efficacy in the treatment of migraine attacks, thus supporting CGRP as an important mediator in migraine.

Topics: Animals; Azepines; Calcitonin Gene-Related Peptide; Calcitonin Gene-Related Peptide Receptor Antagonists; Dipeptides; Humans; Imidazoles; Migraine Disorders; Neurogenic Inflammation; Piperazines; Quinazolines; Receptors, Calcitonin Gene-Related Peptide

Topics: Animals; Azepines; Calcitonin Gene-Related Peptide Receptor Antagonists; Drug Design; Humans; Imidazoles; Migraine Disorders; Piperazines; Quinazolines; Receptors, Calcitonin Gene-Related Peptide; Species Specificity; Structure-Activity Relationship

Migraine is a complex neurological disorder that affects a significant proportion of the adult population worldwide. It is associated with an increase in plasma calcitonin gene-related peptide (CGRP) level. CGRP, a neuropeptide released from activated trigeminal sensory nerves, dilates intracranial blood vessels and transmits vascular nociception. Therefore, it is proposed that CGRP may have an important role in migraine pathophysiology and inhibition of trigeminal CGRP release or CGRP-induced cranial vasodilatation may abort migraine. The mode of action of CGRP antagonists is inhibition of neurogenic vasodilatation and inflammation, an additional neuronal action cannot be ruled out. Both intravenous applied olcegepant (BIBN 4096) and the oral telcagepant (MK-0974) were tested in clinical trials and showed clinical benefit and excellent tolerability, with recent presentation of phase III data on telcagepant suggesting that proof of concept is positive. CGRP receptor antagonists terminate migraine with efficacy similar to triptans. The results from clinical trials suggest that this new type of drug might offer advantages over existing therapies without vasoconstrictive or vascular side effects.

Topics: Azepines; Calcitonin Gene-Related Peptide; Calcitonin Gene-Related Peptide Receptor Antagonists; Dipeptides; Humans; Imidazoles; Migraine Disorders; Quinazolines; Receptors, Calcitonin Gene-Related Peptide

After the triptans, a calcitonin gene-related peptide blocker (telcagepant) is the first acute medicine that has been developed primarily for treatment of acute migraine. Otherwise, the new drugs have been developed first for other purposes, like anticonvulsants, antihypertensives and antidepressants used for migraine prophylaxis. For acute attacks, a new way to administer a traditional drug like dihydroergotamine is under way, and documentation of efficacy in migraine has been gained for some commonly used painkillers and anti-inflammatory drugs, and for some herbal extracts. Based on insights into the basic pathophysiological mechanisms of the disorder, some drugs have been developed which seem promising in early phase II studies (NOS inhibitors and 5HT1F-receptor agonists). In the future, development and enhancements of existing medicines must be accompanied by increased efforts to develop truly new migraine drugs based on knowledge of the pathophysiology if one wishes to reduce substantially the great burden migraine poses on patients and society.

Topics: Azepines; Calcitonin Gene-Related Peptide Receptor Antagonists; Clinical Trials as Topic; Drug Design; Drug Evaluation, Preclinical; Enzyme Inhibitors; Humans; Imidazoles; Migraine Disorders; Nitric Oxide Synthase; Receptor, Serotonin, 5-HT1F; Receptors, Calcitonin Gene-Related Peptide; Receptors, Serotonin; Serotonin Receptor Agonists

Migraine is a highly prevalent neurovascular disorder that can be provoked by infusion of calcitonin gene-related peptide (CGRP). CGRP, a neuropeptide released from activated trigeminal sensory nerves, dilates intracranial and extracranial blood vessels and centrally modulates vascular nociception. On this basis, it has been proposed that: (i) CGRP may play an important role in the pathophysiology of migraine; and (ii) blockade of CGRP receptors may abort migraine. With the advent of potent and selective CGRP receptor antagonists, the importance of CGRP in the pathophysiology of migraine and the therapeutic principle of CGRP receptor antagonism were clearly established. Indeed, both olcegepant (BIBN4096BS, given intravenously) and telcagepant (MK-0974, given orally) have been shown to be safe, well tolerated and effective acute antimigraine agents in phase I, phase II, and for telcagepant phase III, studies. However, recent data reported elevated liver transaminases when telcagepant was dosed twice daily for three months for the prevention of migraine rather than acutely. The potential for a specific acute antimigraine drug, without producing vasoconstriction or vascular side effects and with an efficacy comparable to triptans, is enormous. The present review will discuss the role of CGRP in the pathophysiology of migraine and the various treatment modalities that are currently available to target this neuropeptide.

Topics: Analgesics; Animals; Azepines; Brain; Calcitonin Gene-Related Peptide; Calcitonin Gene-Related Peptide Receptor Antagonists; Dipeptides; Drug Delivery Systems; Humans; Imidazoles; Migraine Disorders; Piperazines; Quinazolines; Receptors, Calcitonin Gene-Related Peptide

Migraine is a debilitating headache disorder which affects approximately 12% of the general population and is the cause of significant loss of productivity (i.e., lost time from work or school) for those afflicted. The current standard of care, the 5-HT(1B/1D) agonists known as triptans, is contraindicated in patients with cardiovascular disease due to their inherent vasoconstrictive activity; thus, there is a need to develop an alternative therapy for the treatment of the disorder.. This article reviews patent publications related to the use of small molecule calcitonin gene-related peptide (CGRP) receptor antagonists for the treatment of migraine that have appeared in the literature within the past decade. The commentary is supplemented by information presented in journal articles and focuses on the activity of several major pharmaceutical companies in the field.. Two small molecule CGRP receptor antagonists, olcegepant and telcagepant, have been shown to be clinically efficacious in the treatment of migraine, and thus provide validation of this novel therapeutic mechanism.

Topics: Animals; Azepines; Calcitonin Gene-Related Peptide Receptor Antagonists; Dipeptides; Drug Design; Drug Industry; Humans; Imidazoles; Migraine Disorders; Patents as Topic; Piperazines; Quinazolines; Receptors, Calcitonin Gene-Related Peptide

Calcitonin gene-related peptide (CGRP) has a widespread distribution throughout the trigeminovascular system and other brain areas involved in migraine pathogenesis. Serum levels of CGRP are elevated during the migraine attack and return to normal with alleviation of pain. Intravenous injection of CGRP in migraineurs results in delayed headache similar to migraine. Since CGRP receptor antagonists lack direct vasoconstrictor activity, this therapeutic approach may offer advantages over the current mainstay of specific acute migraine treatment with 5-HT1B/1D receptor agonists (triptans), contra-indicated in patients with underlying cardiovascular disease. Intravenous BIBN4096BS (olcegepant) and oral MK-0974 (telcagepant), two CGRP-receptor antagonists, were safe and effective in the treatment of migraine attacks in Phase I and II trials. In a Phase III clinical trial, the efficacy of telcagepant 300 mg was comparable to that of zolmitriptan 5 mg. We intend to review the rationale for the use of CGRP-receptor antagonists, and to outline current developments and future perspectives.

Topics: Azepines; Brain; Calcitonin Gene-Related Peptide; Calcitonin Gene-Related Peptide Receptor Antagonists; Clinical Trials as Topic; Dipeptides; Humans; Imidazoles; Migraine Disorders; Piperazines; Quinazolines

Calcitonin gene-related peptide (CGRP) is linked to migraine and other primary headache disorders. It is found in every location described in migraine genesis and processing, including meninges, trigeminal ganglion, trigeminocervical complex, brainstem nuclei, and cortex. It is released in animal models following stimulation of the CNS similar to that seen in migraine, and triptans inhibit this release. Injection of CGRP into migraineurs results in delayed headache similar to migraine. Elevation of CGRP occurs during migraine, resolving following migraine-specific treatment. Finally, and most importantly, CGRP receptor antagonists terminate migraine with efficacy similar to triptans. Both intravenous olcegepant (BIBN 4096 BS) and oral telcagepant (MK-0974) have been effective, safe, and well tolerated in phase I and II studies. Telcagepant is currently in phase III trials, and preliminary results are favorable. The potential for a migraine-specific medication without vasoconstrictive or vascular side effects is enormous. CGRP receptor blockade may also have applications in other pathologic and pain syndromes.

Topics: Animals; Azepines; Calcitonin Gene-Related Peptide Receptor Antagonists; Clinical Trials as Topic; Dipeptides; Drug Evaluation, Preclinical; Humans; Imidazoles; Migraine Disorders; Piperazines; Quinazolines

The critical role of Calcitonin Gene-Related Peptide (CGRP) in migraine has been validated, with two small molecule CGRP antagonists BIBN4096BS and MK-0974 demonstrating efficacy in the reversal of acute migraine attack. Multiple approaches have been taken to find the ideal agent that most effectively inhibits CGRP's function. Here, we have summarized the progress made in recent years, including the identification and optimization of an orally bioavailable small molecule CGRP receptor antagonist. We also describe other interventions such as scavenging of CGRP itself. The advantages and disadvantages of these distinct approaches are discussed.

Topics: Azepines; Calcitonin Gene-Related Peptide; Calcitonin Gene-Related Peptide Receptor Antagonists; Imidazoles; Migraine Disorders; Piperazines; Quinazolines; Receptors, Calcitonin Gene-Related Peptide; Structure-Activity Relationship; Vasodilation

Primary headaches such as migraine are among the most prevalent neurological disorders, affecting up to one-fifth of the adult population. The scientific work in the last decade has unraveled much of the pathophysiological background of migraine, which is now considered to be a neurovascular disorder. It has been discovered that the trigemino-cerebrovascular system plays a key role in migraine headache pathophysiology by releasing the potent vasodilator calcitonin gene-related peptide (CGRP). This neuropeptide is released in parallel with the pain and its concentration correlates well with the intensity of the headache. The development of drugs of the triptan class has provided relief for the acute attacks but at the cost of, mainly cardiovascular, side effects. Thus, the intention to improve treatment led to the development of small CGRP receptor antagonists such as olcegepant (BIBN4096BS) and MK-0974 that alleviate the acute migraine attack without acute side events. The purpose of this review is to give a short overview of the pathological background of migraine headache and to illustrate the mechanisms behind the actions of triptans and the promising CGRP receptor blockers.

Topics: Animals; Azepines; Calcitonin Gene-Related Peptide; Calcitonin Gene-Related Peptide Receptor Antagonists; Cerebral Arteries; Dipeptides; Humans; Imidazoles; Migraine Disorders; Piperazines; Quinazolines; Receptors, Calcitonin Gene-Related Peptide; Trigeminal Nerve; Tryptamines; Vasodilation

Migraine is a complex, debilitating neurovascular disorder. Although knowledge on the main molecular players is still incomplete, recent preclinical and clinical findings indicate that there is a clear correlation between migraine-associated headache and the release of the neuropeptide calcitonin gene-related peptide (CGRP). BIBN4096 was the first CGRP antagonist to be tested in clinical trials for the treatment of migraine. The proven efficacy of this agent, and also the CGRP antagonist MK-0974, to alleviate acute migraine headache provided significant support for the hypothesis that CGRP has an important role in migraine pathophysiology. Moreover, the recently published results from Phase II trials are encouraging and suggest that this new type of drug might offer advantages over existing therapies for patients suffering from migraine and related headaches.

Topics: Animals; Azepines; Calcitonin Gene-Related Peptide; Clinical Trials as Topic; Dipeptides; Humans; Imidazoles; Migraine Disorders; Models, Biological; Molecular Structure; Quinazolines

The aim of this article is to evaluate the safety and efficacy of perimenstrual telcagepant, a CGRP receptor antagonist, for headache prophylaxis.. We conducted a randomized, double-blind, placebo-controlled, six-month trial in women with migraine for ≥ 3 months who experienced perimenstrual headaches. Women were randomized to telcagepant 140 mg or placebo (2:1 ratio) for seven consecutive days perimenstrually. Safety was assessed by adverse events and laboratory tests. The primary efficacy endpoint was mean monthly headache days in the subset of women reporting perimenstrual migraine (-2 days to +3 days of menses onset) and ≥ 5 moderate or severe migraines per month prior to entering the trial.. Telcagepant was generally well tolerated: 66/2660 (2.5%) on telcagepant and 36/1326 (2.7%) on placebo discontinued because of a clinical adverse event. The percentages of patients with clinical adverse events, laboratory adverse events, or discontinuation because of a laboratory adverse event were also similar between treatments. Alanine aminotransferase elevations ≥ 3x normal occurred in 0.6% of women on telcagepant and 0.4% on placebo. Three women on telcagepant vs none on placebo had alanine aminotransferase elevations ≥ 8× normal. In the efficacy subset there was no significant effect of telcagepant (n = 887) vs placebo (n = 447) in mean monthly headache days (treatment difference -0.5 day (95% CI: -1.1, 0.1)). However, telcagepant was associated with a reduction in on-drug headache days (treatment difference -0.4 day (95% CI: -0.5, -0.2), nominal p < 0.001).. Telcagepant 140 mg taken perimenstrually for seven days was generally well tolerated, but was associated with transaminase elevations. Telcagepant did not reduce monthly headache frequency, but did reduce perimenstrual headaches.

Topics: Adult; Alanine Transaminase; Azepines; Calcitonin Gene-Related Peptide; Calcitonin Gene-Related Peptide Receptor Antagonists; Double-Blind Method; Female; Humans; Imidazoles; Migraine Disorders; Premenstrual Syndrome

To evaluate whether the calcitonin gene-related peptide (CGRP) receptor antagonist telcagepant might be effective for migraine prevention.. In this randomized, double-blind, placebo-controlled, multicenter trial (ClinicalTrials.gov NCT00797667), patients experiencing 3-14 migraine days during a 4-week baseline were randomized to telcagepant 140 mg, telcagepant 280 mg, or placebo twice daily for 12 weeks. Efficacy was assessed by mean monthly headache days and migraine/probable migraine days (headache plus ≥ 1 associated symptom).. The trial was terminated following a recommendation from the Safety Monitoring Board due to hepatotoxicity concerns. At termination, the planned 660 patients had been randomized, 656 had been treated with ≥ 1 dose of study medication, and 14 had completed the trial. The mean treatment duration was 48-50 days. Thirteen patients, all in the telcagepant groups, had an alanine aminotransferase (ALT) elevation ≥ 3 × the upper limit of normal and 7 of these also had an aspartate aminotransferase elevation ≥ 3 × the upper limit of normal. Two patients had very high symptomatic transaminase elevations that occurred within 2-6 weeks of treatment initiation and resolved after treatment discontinuation. The originally planned efficacy analysis over 12 weeks was not performed due to limited data at later time points, but there was evidence that telcagepant resulted in a larger reduction from baseline than placebo for mean monthly headache days (month 1: 140 mg = -2.9, 280 mg = -3.1, placebo = -1.7; p < 0.05) and migraine/probable migraine days (month 1: 140 mg = -2.7, 280 mg = -3.0, placebo = -1.6; p < 0.05).. These data suggest a potential role for CGRP receptor antagonism in migraine prophylaxis. However, the observed aminotransferase elevations do not support the use of telcagepant for daily administration.. This study provides Class II evidence that in patients with migraine, telcagepant taken daily reduces headache days by 1.4 days per month compared to placebo and causes 2.5% of patients to have elevations of serum ALT levels.

Topics: Adult; Alanine Transaminase; Aspartate Aminotransferases; Azepines; Calcitonin Gene-Related Peptide Receptor Antagonists; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Imidazoles; Male; Migraine Disorders; Treatment Outcome

The objective of this article is to assess the effects of sumatriptan monotherapy, telcagepant monotherapy, and their combination on blood pressure (BP) in migraine patients during a headache-free period.. A double-blind, placebo-controlled, four-period, single-dose, randomized crossover study in 24 migraine patients was conducted. In each period, patients received a single oral dose of sumatriptan 100 mg alone, telcagepant 600 mg alone, sumatriptan 100 mg coadministered with telcagepant 600 mg, or placebo. Semi-recumbent BP was measured pre-dose and at seven post-dose time points over a period of six hours. Individual time-weighted averages in mean arterial pressure (MAP) were evaluated using a linear mixed-effects model. The pharmacokinetics of sumatriptan alone and in the presence of telcagepant were also evaluated using limited sampling times.. The mean difference in time-weighted (0-2.5 h) MAP (90% confidence interval) was 1.2 mmHg (-0.2, 2.7) between telcagepant and placebo, 4.0 mmHg (2.5, 5.5) between sumatriptan and placebo, and 1.5 mmHg (0.0, 3.0) between telcagepant with sumatriptan vs sumatriptan alone. When coadministered with telcagepant, the AUC0-6h and C(max) of sumatriptan were increased by 23% and 24%, respectively. The small MAP increases observed after coadministration could possibly be associated with the slight elevations in sumatriptan levels.. Telcagepant does not elevate mean MAP, and coadministration of telcagepant with sumatriptan results in elevations in MAP similar to those observed following administration of sumatriptan alone in migraineurs during the interictal period. When coadministered, telcagepant slightly increases the plasma levels of sumatriptan, but without an apparent clinically meaningful effect.

Topics: Adult; Analgesics; Azepines; Blood Pressure; Calcitonin Gene-Related Peptide Receptor Antagonists; Cross-Over Studies; Double-Blind Method; Drug Interactions; Female; Hemodynamics; Humans; Imidazoles; Male; Middle Aged; Migraine Disorders; Sumatriptan; Young Adult

Calcitonin gene-related peptide (CGRP) is a potent neuropeptide whose agonist interaction with the CGRP receptor (CGRP-R) in the periphery promotes vasodilation, neurogenic inflammation and trigeminovascular sensory activation. This process is implicated in the cause of migraine headaches, and CGRP-R antagonists in clinical development have proven effective in treating migraine-related pain in humans. CGRP-R is expressed on blood vessel smooth muscle and sensory trigeminal neurons and fibers in the periphery as well as in the central nervous system. However, it is not clear what role the inhibition of central CGRP-R plays in migraine pain relief. To this end, the CGRP-R positron emission tomography (PET) tracer [(11)C]MK-4232 (2-[(8R)-8-(3,5-difluorophenyl)-6,8-[6-(11)C]dimethyl-10-oxo-6,9-diazaspiro[4.5]decan-9-yl]-N-[(2R)-2'-oxospiro[1,3-dihydroindene-2,3'-1H-pyrrolo[2,3-b]pyridine]-5-yl]acetamide) was discovered and developed for use in clinical PET studies. In rhesus monkeys and humans, [(11)C]MK-4232 displayed rapid brain uptake and a regional brain distribution consistent with the known distribution of CGRP-R. Monkey PET studies with [(11)C]MK-4232 after intravenous dosing with CGRP-R antagonists validated the ability of [(11)C]MK-4232 to detect changes in CGRP-R occupancy in proportion to drug plasma concentration. Application of [(11)C]MK-4232 in human PET studies revealed that telcagepant achieved only low receptor occupancy at an efficacious dose (140 mg PO). Therefore, it is unlikely that antagonism of central CGRP-R is required for migraine efficacy. However, it is not known whether high central CGRP-R antagonism may provide additional therapeutic benefit.

Topics: Acetanilides; Adult; Analgesics; Animals; Azepines; Brain; Calcitonin Gene-Related Peptide Receptor Antagonists; Carbon Radioisotopes; Female; Humans; Imidazoles; Macaca mulatta; Male; Middle Aged; Migraine Disorders; Molecular Structure; Positron-Emission Tomography; Protein Binding; Radiopharmaceuticals; Species Specificity; Spiro Compounds; Tissue Distribution; Young Adult

To evaluate the efficacy of telcagepant in patients with migraine and coronary artery disease.. Calcitonin gene-related peptide receptor antagonists, such as telcagepant, may be useful for acute migraine treatment in patients with cardiovascular disease, a population for whom triptans are contraindicated.. Randomized, double-blind, two-period (6 weeks per period) crossover study in patients with stable coronary artery disease and migraine. Patients were randomized 1:1 to either: (1) Period 1: telcagepant (280-mg tablet/300-mg capsule), Period 2: acetaminophen (1000-mg); or (2) Period 1: placebo for attack 1 then acetaminophen for subsequent attacks, Period 2: telcagepant. Patients could treat up to 12 migraine attacks per period to assess the tolerability of telcagepant. The primary efficacy analysis evaluated telcagepant vs placebo on 2-hour pain freedom during the first attack of Period 1.. One hundred and sixty-five of the planned 400 patients were enrolled, and 114 took at least one dose of treatment. Telcagepant was not statistically different from placebo for 2-hour pain freedom (25.0% vs 18.9%, odds ratio = 1.62 [95% confidence interval: 0.62, 4.25]). The median number of attacks treated per period was 3. No cardiovascular thrombotic adverse events occurred within 14 days of dosing.. The study was underpowered due to enrollment difficulties and did not demonstrate a significant efficacy difference between telcagepant and placebo for the treatment of a migraine attack in patients with stable coronary artery disease. Telcagepant was generally well tolerated for acute intermittent migraine treatment in these patients.

Topics: Adult; Aged; Azepines; Calcitonin Gene-Related Peptide Receptor Antagonists; Coronary Artery Disease; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Imidazoles; International Cooperation; Male; Middle Aged; Migraine Disorders; Models, Statistical; Severity of Illness Index; Young Adult

Telcagepant is a calcitonin gene-related peptide (CGRP) receptor antagonist being evaluated for acute migraine treatment. CGRP is a potent vasodilator that is elevated after myocardial infarction, and it delays ischemia during treadmill exercise. We tested the hypothesis that CGRP receptor antagonism does not reduce treadmill exercise time (TET). The effects of supratherapeutic doses of telcagepant on TET were assessed in a double-blind, randomized, placebo-controlled, two-period, crossover study in patients with stable angina and reproducible exercise-induced angina. Patients received telcagepant (600 mg, n = 46; and 900 mg, n = 14) or placebo and performed treadmill exercise at T(max) (2.5 h after the dose). The hypothesis that telcagepant does not reduce TET was supported if the lower bound of the two-sided 90% confidence interval (CI) for the mean treatment difference (telcagepant-placebo) in TET was more than -60 s. There were no significant between-treatment differences in TET (mean treatment difference: -6.90 (90% CI: -17.66, 3.86) seconds), maximum exercise heart rate, or time to 1-mm ST-segment depression using pooled data or with stratification for dose.

Topics: Angina, Stable; Azepines; Calcitonin Gene-Related Peptide Receptor Antagonists; Cross-Over Studies; Double-Blind Method; Electrocardiography; Exercise Test; Female; Heart Rate; Humans; Imidazoles; Male; Middle Aged; Migraine Disorders; Vasodilator Agents

Endpoints used to evaluate the efficacy of acute anti-migraine drugs do not measure the tolerability. Sustained pain-free response with no adverse events has been recommended as a composite endpoint which measures the efficacy and tolerability attributes that patients desire.. The aim of this study was to evaluate new composite efficacy-plus-tolerability endpoints based on a post-hoc analysis of patient-level data from a previous randomized, placebo-controlled trial of the calcitonin gene-related peptide (CGRP) receptor antagonist, telcagepant, and zolmitriptan in the acute treatment of migraine. Endpoints were 2-24-hour sustained pain freedom and no adverse events from 0-24 hours (SPF24NAE), 2-24 hour sustained pain relief and no adverse events from 0-24 hours (SPR24NAE), pain freedom at 2 hours and no adverse events from 0-24 hours (PF2NAE), and pain relief at 2 hours and no adverse events from 0-24 hours (PR2NAE).. Compared with placebo, both telcagepant 300 mg and 150 mg achieved nominal superiority (p values <.05) for SPF24NAE, SPR24NAE, PF2NAE and PR2NAE. Zolmitriptan 5 mg showed nominal superiority versus placebo for SPF24NAE, SPR24NAE and PF2NAE, but not PR2NAE. Telcagepant 300 mg showed nominal superiority versus zolmitriptan for SPF24NAE, SPR24NA and PR2NAE.. Composite efficacy-plus-tolerability endpoints may be useful for facilitating comparisons between treatments.

Topics: Adult; Analgesics; Azepines; Calcitonin Gene-Related Peptide Receptor Antagonists; Double-Blind Method; Female; Humans; Imidazoles; Male; Migraine Disorders; Oxazolidinones; Pain; Research Design; Serotonin 5-HT1 Receptor Antagonists; Tryptamines

To evaluate whether the same or different patients respond to triptans and telcagepant.. Telcagepant is an oral calcitonin gene-related peptide receptor antagonist with acute antimigraine efficacy comparable to oral triptans. It is currently unknown whether migraine patients who cannot be adequately helped with triptans might benefit from treatment with telcagepant.. Post-hoc analysis of data from a randomized, controlled trial of telcagepant (150 mg, 300 mg) zolmitriptan 5 mg, or placebo for a moderate/severe migraine. Responder rates were analyzed according to patients' self-reported historical triptan response (HTR): (1) good HTR (N = 660): response in 75-100% of attacks; (2) intermediate HTR (N = 248): response in 25-74% of attacks; (3) poor HTR/no use (N = 407): response in < 25% of attacks, or patient did not take triptans. A limitation of the analysis is that the last subgroup comprised mainly (91%) patients who reported that they did not take triptans, but it was not known whether these patients were triptan-naïve or had previously used triptans and stopped taking them.. For zolmitriptan, 2-hour pain relief rates were higher in the good HTR subgroup (116/162, 72%) than in the intermediate (29/62, 47%) and poor/no use (44/111, 40%) HTR subgroups. The 2-hour pain relief rates were similar across HTR subgroups for telcagepant 150 mg (48-58%), 300 mg (52-58%), and placebo (26-31%). In the poor/no use HTR subgroup, more patients receiving telcagepant 300 mg (56/98, 57.1%) had 2-hour pain relief than those receiving zolmitriptan (44/111, 39.6%; odds ratio = 2.11 [95% CI: 1.20,3.71], P = .009); the percentage for telcagepant 150 mg (57/119, 47.9%) was not significantly different from zolmitriptan (odds ratio = 1.41 [95% CI: 0.82, 2.40], P = .211).. This suggests that different patients may respond to triptans or telcagepant 300 mg. Caution should be exercised in interpreting the results because of the post-hoc nature of the analysis (clinical trial registry: NCT00442936).

Topics: Adult; Azepines; Calcitonin Gene-Related Peptide Receptor Antagonists; Double-Blind Method; Female; Humans; Imidazoles; Male; Migraine Disorders; Oxazolidinones; Pain; Surveys and Questionnaires; Tryptamines

Previous studies have reported health utilities for migraine patients as generally measured between migraine attacks, but health utility data for within a migraine attack are unavailable. We evaluated within-attack health utilities among acute migraine patients experiencing different grades of headache severity.. We examined data for 330 20-65-year-old adults, in good physical health, who had 1-6 moderate/severe migraine attacks per month in the 2 months prior to the screening visit. Data were collected from a multicenter, double-blind study of a treatment for acute migraine in the United States. The EQ-5D system was used to measure generic health status at baseline and 24 h post-treatment within an acute migraine attack, and patients were also asked to rate their pain level at these time points (no, mild, moderate, or severe pain). The D1 time-trade-off scoring algorithm for the U.S. population was applied. Confidence intervals were estimated by bootstrap methods.. The study population was 88% women and 78% white ethnicity, with 60% of subjects over age 40. The disutility of mild migraine pain was estimated to be 0.140 (95% CI: 0.0848, 0.1940), with a disutility for moderate migraine pain of 0.186 (95% CI: 0.1645, 0.2053) and for severe migraine pain of 0.493 (95% CI: 0.4100, 0.5654).. Within-attack disutilities estimated for migraine in this study are much greater than those reported for migraine when evaluated as a chronic health condition (e.g., valuations collected at random time points). These data can be of value in adapting results from clinical trials of migraine interventions to cost-utility policy analyses.

Topics: Adult; Aged; Azepines; Female; Humans; Imidazoles; Male; Middle Aged; Migraine Disorders; Patients; Quality of Life; Surveys and Questionnaires; United States; Young Adult

To evaluate the long-term tolerability of telcagepant for acute treatment of intermittent migraine attacks. Background.- Telcagepant is a calcitonin gene-related peptide (CGRP) receptor antagonist being investigated for the acute treatment of migraine.. Migraine patients were randomized 2:1 to double-blind treatment with telcagepant 280/300 mg or rizatriptan 10 mg for an acute mild, moderate, or severe migraine. Patients could administer a second dose within 2-24 hours for nonresponse or migraine recurrence. Patients could treat up to 8 attacks per month for up to 18 months. Safety assessments included spontaneous reports of adverse events and collection of vital signs, electrocardiograms, and laboratory assessments. The primary endpoint was the percentage of patients with ≥ 1 triptan-related adverse events in the 14-day period post dose.. Of 1068 patients randomized, 641 (90%) patients treated ≥ 1 attack with telcagepant and 313 (88%) treated ≥ 1 attack with rizatriptan. A total of 19,820 attacks were treated with telcagepant (mean per patient = 31) and 10,981 with rizatriptan (mean per patient = 35). Fewer triptan-related adverse events (difference: -6.2%; 95% CI -10.4, -2.6; P < .001) and drug-related adverse events (difference: -15.6%; 95% CI -22.2, -9.0) were reported for telcagepant vs rizatriptan. The most common adverse events appeared to have generally similar incidence proportions between the treatment groups. Those with an incidence > 5% in the telcagepant group were dry mouth (9.7%, rizatriptan = 13.7%), somnolence (9.2%, rizatriptan = 16.6%), dizziness (8.9%, rizatriptan = 10.2%), and nausea (9.0%, rizatriptan = 6.4%).. Telcagepant was generally well tolerated when administered for the acute intermittent treatment of migraine for up to 18 months. The incidences of triptan-related and drug-related adverse events favored telcagepant over rizatriptan.

Topics: Adult; Aged; Azepines; Calcitonin Gene-Related Peptide Receptor Antagonists; Double-Blind Method; Endpoint Determination; Female; Humans; Imidazoles; Male; Middle Aged; Migraine Disorders; Triazoles; Tryptamines

To evaluate the efficacy and tolerability of telcagepant when co-administered with ibuprofen or acetaminophen for the acute treatment of migraine.. Telcagepant is an oral calcitonin gene-related peptide receptor antagonist which is being evaluated for the acute treatment of migraine. Combining telcagepant with analgesics that have a different mechanism of action could produce greater efficacy.. Randomized, double-blind, placebo-controlled study. Patients were randomized to treat a moderate or severe migraine headache with either telcagepant 280 mg + ibuprofen 400 mg (N = 171), telcagepant 280 mg + acetaminophen 1000 mg (N = 171), telcagepant 280 mg (N =170), or placebo (N = 171). The primary efficacy endpoint was 2-hour pain freedom. The study had approximately 88% power to detect an additive effect of at least 15 percentage points (telcagepant combination vs telcagepant monotherapy) and 48% power to detect an additive effect of at least 10 percentage points. Safety and tolerability were assessed by adverse events and laboratory tests.. The percentages of patients with 2-hour pain freedom were greater in each active treatment group compared to placebo (P < .001): telcagepant + ibuprofen = 35.2%, telcagepant + acetaminophen = 38.3%, telcagepant = 31.2%, placebo = 10.9%. No significant differences were seen for either of the combination groups vs telcagepant monotherapy, but both were numerically larger than telcagepant monotherapy. All the active treatments were generally well tolerated. The percentage of patients reporting any adverse event within 48 hours was higher in the active treatment groups than placebo: telcagepant + ibuprofen = 30.3%, telcagepant + acetaminophen = 31.6%, telcagepant = 24.8%, placebo = 18.2%. The most common adverse events reported by ≥ 4 patients in one or more of the treatment groups that included telcagepant were fatigue, nausea, dizziness, somnolence, dry mouth, and tremor.. The combination of telcagepant 280 mg with either ibuprofen 400 mg or acetaminophen 1000 mg did not show a statistically significant difference from telcagepant alone. Numerically greater treatment effects in the combination treatment groups over the telcagepant 280 mg monotherapy suggest that telcagepant combination treatments may merit further evaluation in studies powered to detect smaller additive benefits. (Clinicaltrials.gov; NCT00758836).

Topics: Acetaminophen; Adult; Analgesics; Anti-Inflammatory Agents, Non-Steroidal; Azepines; Calcitonin Gene-Related Peptide Receptor Antagonists; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Ibuprofen; Imidazoles; Male; Middle Aged; Migraine Disorders; Receptors, Calcitonin Gene-Related Peptide

The primary purpose of the study was to explore the safety and tolerability of telcagepant in patients with stable coronary artery disease.. Triptans are effective acute anti-migraine drugs whose vasoconstrictive effects limit their use in patients at risk for adverse cardiovascular events. Telcagepant, a calcitonin gene-related peptide receptor antagonist, is being developed for the acute treatment of migraine. Antagonism of calcitonin gene-related peptide, which does not appear to cause vasoconstriction, may allow for treatment of migraine in patients with coronary artery disease.. In this randomized, double-blind, placebo-controlled, crossover study, patients with documented stable coronary artery disease were assigned to 1 of 2 treatment sequences: telcagepant then placebo, or placebo then telcagepant. In each treatment period, patients received 2 doses of telcagepant 300-mg or placebo 2 hours apart. They remained in the research center for 24 hours after receiving the first dose of each period, during which time continuous 12-lead ambulatory electrocardiographic (Holter) monitoring was performed.. Twenty-eight patients were enrolled; all patients completed the study and were included in all analyses. Telcagepant was generally well tolerated. No laboratory or serious adverse experiences were reported, and no patient discontinued due to an adverse experience. There were no consistent treatment-related changes in laboratory, vital signs or electrocardiogram safety parameters. Three patients (2 after receiving placebo and 1 after receiving telcagepant) experienced ST segment depression during the study; none of these patients reported chest pain.. Two doses of 300-mg telcagepant, administered 2 hours apart, did not appear to exacerbate spontaneous ischemia and were generally well tolerated in a small cohort of patients with stable coronary artery disease. Results of this study support further evaluation of telcagepant in patients with stable coronary artery disease.

Topics: Adult; Aged; Azepines; Cross-Over Studies; Double-Blind Method; Female; Humans; Imidazoles; Male; Middle Aged; Migraine Disorders; Myocardial Ischemia

Telcagepant is a novel, orally active, and selective calcitonin gene-related peptide receptor antagonist being developed for acute treatment of migraine with and without aura. Three separate clinical studies were conducted to evaluate the pharmacokinetics and tolerability of telcagepant following single oral doses in healthy young and elderly men and women and multiple oral doses in men. Telcagepant was rapidly absorbed with a time to maximum concentration of approximately 1.5 hours. The terminal half-life was approximately 6 hours. A greater than dose-proportional increase was observed in the area under the plasma concentration versus time curve from zero to infinity. Following twice-daily dosing, with each dose separated by 2 hours, steady state was achieved in approximately 3 to 4 days with an accumulation ratio of approximately 2. There were no clinically meaningful pharmacokinetic differences when compared across age and gender. Telcagepant was generally well tolerated up to single doses of 1200 mg and multiple doses of 400 mg twice daily.

Topics: Adolescent; Adult; Aged; Aging; Azepines; Calcitonin Gene-Related Peptide Receptor Antagonists; Dose-Response Relationship, Drug; Female; Half-Life; Humans; Imidazoles; Intestinal Absorption; Male; Middle Aged; Migraine Disorders; Sex Characteristics; Young Adult

This study evaluated the calcitonin gene-related peptide (CGRP) receptor antagonist telcagepant (tablet formulation) for treatment of a migraine attack and across four attacks. Adults with migraine were randomized, double-blind, to telcagepant 140 mg, telcagepant 280 mg, or control treatment sequences to treat four moderate-to-severe migraine attacks. Control patients received placebo for three attacks and telcagepant 140 mg for one attack. Efficacy for the first attack (Attack 1) and consistency of efficacy over multiple attacks were assessed. For an individual patient, consistent efficacy was defined as ≥ 3 successes, and lack of consistent efficacy was defined as ≥ 2 failures, in treatment response. A total of 1677 patients treated ≥ 1 attack and 1263 treated all four attacks.. Based on Attack 1 data, telcagepant 140 mg and 280 mg were significantly (p < .001) more effective than placebo for 2-hour pain freedom, 2-hour pain relief, 2-hour absence of migraine-associated symptoms (phonophobia, photophobia, nausea), and 2-24 hours sustained pain freedom. The percentage of patients with 2-hour pain freedom consistency and 2-hour pain relief consistency was significantly (p < .001) higher for both telcagepant treatment sequences versus control. Adverse events within 48 hours for telcagepant with an incidence ≥ 2% and twice that of placebo were somnolence (placebo = 2.3%, 140 mg = 5.9%, 280 mg = 5.7%) and vomiting (placebo = 1.4%, 140 mg = 1.0%, 280 mg = 2.9%).. Telcagepant 140 mg and 280 mg were effective for treatment of a migraine attack and were more consistently effective than control for intermittent treatment of up to four migraine attacks. Telcagepant was generally well tolerated. (Clinicaltrials.gov; NCT00483704).

Topics: Adult; Analgesics; Azepines; Double-Blind Method; Female; Humans; Imidazoles; Male; Migraine Disorders

The neuropeptide calcitonin gene-related peptide (CGRP) plays a key role in migraine pathophysiology. In this large phase 3 clinical trial, we sought to confirm the efficacy of telcagepant, the first orally bioavailable CGRP receptor antagonist.. Adults with migraine with or without aura (International Headache Society criteria) treated a moderate or severe attack with oral telcagepant 50 mg (n = 177), 150 mg (n = 381), 300 mg (n = 371), or placebo (n = 365) in a randomized, double-blind trial. The 5 co-primary endpoints were pain freedom, pain relief, and absence of photophobia, absence of phonophobia, and absence of nausea, all at 2 hours postdose. The key secondary endpoint was 2-24 hour sustained pain freedom. The prespecified primary efficacy analyses evaluated the 150 mg and 300 mg groups; the 50-mg group was included on an exploratory basis to further characterize the dose response but was not prespecified for analysis. Tolerability was assessed by adverse experience reports.. Telcagepant 300 mg was more effective (p

Topics: Acute Disease; Adult; Azepines; Calcitonin Gene-Related Peptide; Calcitonin Gene-Related Peptide Receptor Antagonists; Dose-Response Relationship, Drug; Double-Blind Method; Endpoint Determination; Female; Humans; Hyperacusis; Imidazoles; Male; Middle Aged; Migraine Disorders; Nausea; Outcome Assessment, Health Care; Pain Measurement; Photophobia; Placebos; Quality of Life; Receptors, Calcitonin Gene-Related Peptide; Surveys and Questionnaires; Treatment Outcome

Calcitonin gene-related peptide (CGRP) probably has a role in migraine pathophysiology, and antagonism of its receptors might provide treatment without the vasoconstrictor effects of triptans. We aimed to assess the clinical profile of MK-0974 (telcagepant), an orally bioavailable antagonist of CGRP receptor.. In a randomised, parallel-treatment, placebo-controlled, double-blind, trial at 81 sites in the Europe and the USA, adults with migraine diagnosed by International Headache Society criteria treated moderate or severe attacks with either oral telcagepant 150 mg or 300 mg, zolmitriptan 5 mg, or placebo. The five co-primary endpoints were pain freedom, pain relief, or absence of photophobia, phonophobia, or nausea at 2 h after treatment. Analysis was by the full analysis set and multiplicity was controlled for with a step-down closed-testing procedure. This trial is registered with ClinicalTrials.gov, number NCT00442936.. 1380 patients were randomly assigned to receive telcagepant 150 mg (n=333) or 300 mg (354), zolmitriptan (345), or placebo (348). Telcagepant 300 mg was more effective than placebo for pain freedom (95 [27%] of 353 patients vs 33 [10%] of 343 [p<0.0001]), pain relief (194 [55%] of 353 vs 95 [28%] of 343 [p<0.0001]), and absences of phonophobia (204 [58%] of 353 vs 126 [37%] of 342 [p<0.0001]), photophobia (180 [51%] of 353 vs 99 [29%] of 342 [p<0.0001]), and nausea (229 [65%] of 352 vs 189 [55%] of 342 [p=0.0061]). Efficacy of telcagepant 300 mg and zolmitriptan 5 mg were much the same, and both were more effective than telcagepant 150 mg. Adverse events were recorded for 31% taking telcagepant 150 mg, 37% taking telcagepant 300 mg, 51% taking zolmitriptan 5 mg, and 32% taking placebo.. Telcagepant 300 mg is effective as an acute treatment for migraine with efficacy comparable to that of zolmitriptan 5 mg, but with fewer associated adverse effects.. Merck Research Laboratories.

Topics: Adult; Azepines; Calcitonin Gene-Related Peptide; Calcitonin Gene-Related Peptide Receptor Antagonists; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Imidazoles; Male; Migraine Disorders; Oxazolidinones; Serotonin Receptor Agonists; Severity of Illness Index; Tryptamines

To determine an effective and tolerable dose of a novel oral calcitonin gene-related peptide (CGRP) receptor antagonist, MK-0974, for the acute treatment of migraine.. Randomized, double-blind, parallel-group, clinical trial with a two-stage, adaptive, dose-ranging design. Patients were allocated to treat a moderate or severe migraine attack with MK-0974 (25, 50, 100, 200, 300, 400, or 600 mg), rizatriptan 10 mg, or placebo taken orally. The primary endpoint was pain relief (reduction to mild or none) 2 hours after dosing. Secondary endpoints included pain freedom at 2 hours and sustained pain relief at 24 hours. A prespecified, blinded, automated interim analysis was used to discontinue randomization to less effective doses.. Per the adaptive study design, the four lowest MK-0974 groups (25, 50, 100, 200 mg) were discontinued due to insufficient efficacy. For the remaining treatment groups, the estimated pain relief proportions at 2 hours were 300 mg (n = 38) 68.1%, 400 mg (n = 45) 48.2%, 600 mg (n = 40) 67.5%, rizatriptan 10 mg (n = 34) 69.5%, and placebo (n = 115) 46.3%. The prespecified primary efficacy hypothesis test, which compared the average 2-hour pain relief response proportion of the combined 300, 400, and 600 mg MK-0974 groups to placebo, was significant (P = 0.015). A generally similar efficacy pattern was seen for other endpoints. MK-0974 was generally well tolerated and there did not appear to be an increase in adverse events with increasing dose.. The novel, orally administered calcitonin gene-related peptide (CGRP) receptor antagonist, MK-0974, was effective and generally well tolerated for the acute treatment of migraine.

Topics: Administration, Oral; Adult; Azepines; Calcitonin Gene-Related Peptide Receptor Antagonists; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Imidazoles; Male; Migraine Disorders; Receptors, Calcitonin Gene-Related Peptide; Time Factors

The clinical efficacy of migraine therapeutic agents directed towards the calcitonin-gene related peptide (CGRP) pathway has confirmed the key role of this axis in migraine pathogenesis. Three antibodies against CGRP - fremanezumab, galcanezumab and eptinezumab - and one antibody against the CGRP receptor, erenumab, are clinically approved therapeutics for the prevention of migraine. In addition, two small molecule CGRP receptor antagonists, ubrogepant and rimegepant, are approved for acute migraine treatment. Targeting either the CGRP ligand or receptor is efficacious for migraine treatment; however, a comparison of the mechanism of action of these therapeutic agents is lacking in the literature.. To gain insights into the potential differences between these CGRP pathway therapeutics, we compared the effect of a CGRP ligand antibody (fremanezumab), a CGRP receptor antibody (erenumab) and a CGRP receptor small molecule antagonist (telcagepant) using a combination of binding, functional and imaging assays.. Erenumab and telcagepant antagonized CGRP, adrenomedullin and intermedin cAMP signaling at the canonical human CGRP receptor. In contrast, fremanezumab only antagonized CGRP-induced cAMP signaling at the human CGRP receptor. In addition, erenumab, but not fremanezumab, bound and internalized at the canonical human CGRP receptor. Interestingly, erenumab also bound and internalized at the human AMY. The therapeutic effect of agents targeting the CGRP ligand versus receptor for migraine prevention (antibodies) or acute treatment (gepants) may involve distinct mechanisms of action. These findings suggest that differing mechanisms could affect efficacy, safety, and/or tolerability in migraine patients.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Azepines; Calcitonin Gene-Related Peptide; Calcitonin Gene-Related Peptide Receptor Antagonists; Humans; Imidazoles; Islet Amyloid Polypeptide; Migraine Disorders; Receptors, Calcitonin Gene-Related Peptide

Calcitonin gene-related peptide (CGRP) has been implicated in acute migraine pathogenesis. In an effort to identify novel CGRP receptor antagonists for the treatment of migraine, we have discovered thiazolidinone 49, a potent (Ki=30 pM, IC50=1 nM), orally bioavailable, CNS-penetrant CGRP antagonist with good pharmacokinetic properties.

Topics: Animals; Azepines; Calcitonin Gene-Related Peptide; Dipeptides; Humans; Imidazoles; Inhibitory Concentration 50; Migraine Disorders; Molecular Structure; Molecular Weight; Piperazines; Protein Binding; Quinazolines; Quinazolinones; Rats; Receptors, Calcitonin Gene-Related Peptide; Thiazolidinediones; Urea

Topics: Azepines; Calcitonin Gene-Related Peptide Receptor Antagonists; Female; Humans; Imidazoles; Male; Migraine Disorders

Calcitonin gene-related peptide (CGRP) receptor antagonists have been shown to be efficacious as abortive migraine therapeutics with the absence of cardiovascular liabilities that are associated with triptans. Herein, we report the discovery of a highly potent CGRP receptor antagonist, BMS-742413, with the potential to provide rapid onset of action through intranasal delivery. The compound displays excellent aqueous solubility, oxidative stability, and toxicological profile. BMS-742413 has good intranasal bioavailability in the rabbit and shows a robust, dose-dependent inhibition of CGRP-induced increases in marmoset facial blood flow.

Topics: Administration, Intranasal; Amides; Animals; Caco-2 Cells; Calcitonin Gene-Related Peptide Receptor Antagonists; Callithrix; Coronary Vessels; Drug Evaluation, Preclinical; Face; Humans; Indazoles; Migraine Disorders; Quinolones; Rabbits; Rats; Receptors, Calcitonin Gene-Related Peptide; Respiratory Mucosa

Rational modification of the clinically tested CGRP receptor antagonist MK-3207 (3) afforded an analogue with increased unbound fraction in rat plasma and enhanced aqueous solubility, 2-[(8R)-8-(3,5-difluorophenyl)-8-methyl-10-oxo-6,9-diazaspiro[4.5]dec-9-yl]-N-[(6S)-2'-oxo-1',2',5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b]pyridin]-3-yl]acetamide (MK-8825) (6). Compound 6 maintained similar affinity to 3 at the human and rat CGRP receptors but possessed significantly improved in vivo potency in a rat pharmacodynamic model. The overall profile of 6 indicates it should find utility as a rat tool to investigate effects of CGRP receptor blockade in vivo.

Topics: Administration, Oral; Analgesics; Animals; Biological Availability; Calcitonin Gene-Related Peptide Receptor Antagonists; Disease Models, Animal; Dogs; Humans; Macaca mulatta; Mice; Migraine Disorders; Pyridines; Rats; Receptors, Calcitonin Gene-Related Peptide; Species Specificity; Spiro Compounds

In our ongoing efforts to develop CGRP receptor antagonists for the treatment of migraine, we aimed to improve upon telecagepant by targeting a compound with a lower projected clinical dose. Imidazoazepanes were identified as potent caprolactam replacements and SAR of the imidazole yielded the tertiary methyl ether as an optimal substituent for potency and hERG selectivity. Combination with the azabenzoxazinone spiropiperidine ultimately led to preclinical candidate 30 (MK-2918).

Topics: Analgesics, Non-Narcotic; Animals; Azepines; Biological Availability; Calcitonin Gene-Related Peptide Receptor Antagonists; Caprolactam; Cells, Cultured; Dogs; Humans; Imidazoles; Inhibitory Concentration 50; Macaca mulatta; Migraine Disorders; Molecular Structure; Rats; Structure-Activity Relationship

Topics: Azepines; Botulinum Toxins, Type A; Calcitonin Gene-Related Peptide Receptor Antagonists; Cerebrovascular Disorders; Humans; Imidazoles; Migraine Disorders; Neuromuscular Agents; Photophobia

Topics: Azepines; Clinical Trials as Topic; Humans; Imidazoles; Migraine Disorders; Pain; Treatment Outcome

Studies were conducted in human isolated coronary arteries to explore the vascular effects of the calcitonin gene-related peptide (CGRP) receptor antagonist telcagepant and to compare its coronary vasoconstrictive potential to that of zolmitriptan. KCl precontracted coronary vessels were shown to relax to human alphaCGRP, with the CGRP-mediated vasorelaxation completely blocked with 30 microM telcagepant. In coronary vessels at basal tone, zolmitriptan caused a concentration-dependent contraction (pEC50 = 6.9 +/- 0.1; slope 0.94), with the greatest contraction obtained between 1 and 10 microM in most tissues. In contrast, telcagepant at concentrations up to 30 microM evoked no change in contractile tone. These findings suggest the potential for CGRP receptor antagonists to exert antimigraine efficacy in the absence of adverse effects on coronary tone.

Topics: Adult; Azepines; Calcitonin Gene-Related Peptide Receptor Antagonists; Coronary Vessels; Dose-Response Relationship, Drug; Humans; Imidazoles; In Vitro Techniques; Middle Aged; Migraine Disorders; Oxazolidinones; Tryptamines; Vasoconstriction; Vasodilation; Vasodilator Agents

The calcitonin receptor-like receptor (CLR) associates with the accessory protein RAMP1 to form a receptor for the neuropeptide calcitonin gene-related peptide (CGRP). Multiple lines of evidence have implicated CGRP in the pathophysiology of migraine headache making the CGRP receptor an attractive target for development of small-molecule antagonists as a novel treatment for this debilitating condition. The CGRP receptor antagonists telcagepant and olcegepant (BIBN4096BS) have demonstrated clinical efficacy in the treatment of migraine and there is now a need to better understand how these molecules interact with the receptor. Previous work has shown the extracellular portion of RAMP1 to be important for binding of these antagonists, with tryptophan-74 being a key interaction site. The crystal structure of the extracellular portion of human RAMP1 placed tryptophan-74 in a hydrophobic patch hypothesized to interact with CGRP receptor ligands and also identified nearby residues that may be important for ligand binding. In this study we explored the role played by these residues of RAMP1 using an alanine replacement strategy. We confirmed a role for tryptophan-74 in antagonist binding and also identified arginine-67 as being important for binding of telcagepant but not compound 3, a close analog of BIBN4096BS. We also identified tryptophan-84 as being critical for both high-affinity binding of the non-peptide antagonists as well as the peptides CGRP and CGRP(8-37). These data for the first time pinpoint a specific RAMP1 residue important for both antagonist and agonist potency and are consistent with the N-terminal domain of RAMP1 forming the binding pocket interface with CLR.

Topics: Azepines; Calcitonin Gene-Related Peptide Receptor Antagonists; Calcitonin Receptor-Like Protein; Crystallography, X-Ray; Dipeptides; Humans; Imidazoles; Intracellular Signaling Peptides and Proteins; Ligands; Membrane Proteins; Migraine Disorders; Piperazines; Protein Interaction Domains and Motifs; Protein Interaction Mapping; Quinazolines; Receptor Activity-Modifying Protein 1; Receptor Activity-Modifying Proteins; Receptors, Calcitonin; Receptors, Calcitonin Gene-Related Peptide; Tryptophan

Topics: Azepines; Calcitonin Gene-Related Peptide Receptor Antagonists; Humans; Imidazoles; Migraine Disorders; Randomized Controlled Trials as Topic

Based on preclinical and clinical studies, the neuropeptide calcitonin gene-related peptide (CGRP) is proposed to play a central role in the underlying pathology of migraine. CGRP and its receptor are widely expressed in both the peripheral and central nervous systems by multiple cell types involved in the regulation of inflammatory and nociceptive responses. Peripheral release of CGRP from trigeminal nerve fibres within the dura and from the cell body of trigeminal ganglion neurons is likely to contribute to peripheral sensitization of trigeminal nociceptors. Similarly, the release of CGRP within the trigeminal nucleus caudalis can facilitate activation of nociceptive second-order neurons and glial cells. Thus, CGRP is involved in the development and maintenance of persistent pain, central sensitization and allodynia, events characteristic of migraine pathology. In contrast, CGRP release within the brain is likely to function in an anti-nociceptive capacity. Given the role of CGRP in migraine pathology, the potential of CGRP receptor antagonists in the treatment of migraine has been investigated. Towards this end, the non-peptide CGRP receptor antagonists olcegepant and telcagepant have been shown to be effective in the acute treatment of migraine. While telcagepant is being pursued as a frontline abortive migraine drug in a phase III clinical trial, an oral formulation of a novel CGRP receptor antagonist, BI 44370, is currently in phase II clinical trials. Encouragingly, data from clinical studies on these compounds have clearly demonstrated the potential therapeutic benefit of this class of drugs and support the future development of CGRP receptor antagonists to treat migraine and possibly other types of chronic pain.

Topics: Azepines; Calcitonin Gene-Related Peptide; Calcitonin Gene-Related Peptide Receptor Antagonists; Clinical Trials as Topic; Dipeptides; Humans; Imidazoles; Migraine Disorders; Piperazines; Quinazolines; Treatment Outcome

A highly efficient, asymmetric synthesis of telcagepant (1), a CGRP receptor antagonist for the treatment of migraine, is described. This synthesis features the first application of iminium organocatalysis on an industrial scale. The key to the success of this organocatalytic transformation was the identification of a dual acid cocatalyst system, which allowed striking a balance of the reaction efficiency and product stability effectively. As such, via an iminium species, the necessnary C-6 stereogenicity was practically established in one operation in >95% ee. Furthermore, we enlisted an unprecedented Doebner-Knoevenagel coupling, which was also via an iminium species, to efficiently construct the C3-C4 bond with desired functionality. In order to prepare telcagepant (1) in high quality, a practical new protocol was discovered to suppress the formation of desfluoro impurities formed under hydrogenation conditions to <0.2%. An efficient lactamization facilitated by t-BuCOCl followed by a dynamic epimerization-crystallization resulted in the isolation of caprolactam acetamide with the desired C3 (R) and C6 (S) configuration cleanly. Isolating only three intermediates, the overall yield of this cost-effective synthesis was up to 27%. This environmentally responsible synthesis contains all of the elements required for a manufacturing process and prepares telcagepant (1) with the high quality required for pharmaceutical use.

Topics: Azepines; Calcitonin Gene-Related Peptide Receptor Antagonists; Catalysis; Imidazoles; Migraine Disorders; Molecular Structure

Calcitonin gene-related peptide (CGRP) is a neuropeptide that plays a key role in the pathophysiology of migraine headache. MK-0974 (telcagepant) is a potent and selective antagonist of the human and rhesus CGRP receptors and is currently in Phase III clinical studies for the acute treatment of migraine. The pharmacology of MK-0974 has been studied extensively, but there has not been a thorough characterization of its binding properties. Here, we characterize the binding of a tritiated analog of MK-0974 on human neuroblastoma (SK-N-MC) membranes and rhesus cerebellum. [(3)H]MK-0974 displayed reversible and saturable binding to both SK-N-MC membranes and rhesus cerebellum with a K(D) of 1.9 nM and 1.3 nM, respectively. Agonists and antagonists of the CGRP receptor displaced [(3)H]MK-0974 in a concentration-dependent manner in competition binding experiments. Both CGRP and adrenomedullin demonstrated biphasic competition while MK-0974 and the peptide antagonist CGRP(8-37) displaced [(3)H]MK-0974 in a monophasic fashion. In competitive binding studies with [(3)H]MK-0974 and CGRP, the fraction of high-affinity binding was reduced significantly by incubating the membranes with GTPgammaS. In kinetic binding experiments, the off-rate of [(3)H]MK-0974 was determined to be 0.51 min(-1) with a half-life of 1.3 min. In conclusion, the radioligand [(3)H]MK-0974 has proven to be a useful tool for studying the binding characteristics of MK-0974 and has broadened our understanding of this promising molecule.

Topics: Animals; Azepines; Binding, Competitive; Calcitonin Gene-Related Peptide Receptor Antagonists; Humans; Imidazoles; Kinetics; Macaca mulatta; Migraine Disorders; Protein Binding; Receptors, Calcitonin Gene-Related Peptide; Tritium

Topics: Adult; Aged; Animals; Azepines; Calcitonin Gene-Related Peptide; Calcitonin Gene-Related Peptide Receptor Antagonists; Double-Blind Method; Humans; Imidazoles; Middle Aged; Migraine Disorders; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Treatment Outcome; Young Adult

Topics: Azepines; Calcitonin Gene-Related Peptide Receptor Antagonists; Humans; Imidazoles; Migraine Disorders; Oxazolidinones; Randomized Controlled Trials as Topic; Tryptamines

Telcagepant (MK-0974) is a novel oral calcitonin gene-related peptide (CGRP) receptor antagonist and is currently under clinical development. Results from phases II and III clinical trials have suggested that telcagepant is effective for migraine treatment. A reliable and high throughput protein precipitation (PPT) method for determination of telcagepant in human plasma using liquid chromatography coupled with atmospheric pressure chemical ionization (APCI) tandem mass spectrometry has been developed. Clinical samples, internal standard (IS) and acetonitrile are transferred into 96-well plates using a robotic liquid handling system. An aliquot of 10 microL supernatant is directly injected into the LC-MS/MS system where separation is performed on a FluoPhase RP (150 x 2.1mm, 5 microm) column with an isocratic mobile phase (60% acetonitrile with 0.1% formic acid and 40% water with 0.1% formic acid) at 0.2 mL/min. The interfering 3S-diastereomer of telcagepant, which is observed in clinical samples, is chromatographically resolved from telcagepant. The PPT procedure significantly reduces the time required for sample processing and the assay is sufficiently sensitive for detection using both API 4000 and API 3000 mass spectrometers. The linear calibration range is 5-5000 nM using 200 microL of plasma. Assay intraday validation was conducted using six calibration curves derived from six lots of human control plasma. Calibration standard accuracy did not deviate by more than 3% and 6% of nominal values, and precision did not exceed 4% coefficient of variation (CV) and 10% CV, respectively on the API 4000 and API 3000. Several clinical phases IIb and III studies have been successfully supported with this assay.

Topics: Azepines; Chromatography, High Pressure Liquid; Humans; Imidazoles; Migraine Disorders; Tandem Mass Spectrometry

To eliminate the diastereomer interference on Telcagepant (MK-0974) determination during clinical study support, on-line high turbulent-flow liquid chromatography (HTLC) methods, HTLC-A and HTLC-B that covered dynamic range of 0.5-500 nM and 5-5000 nM, respectively, were developed. To meet the requirement of rapid assay transfer among multiple laboratories and analysts, a solid-phase extraction (SPE) assay was derived from the existing HTLC-B assay under the same dynamic range. The on-line HTLC assays were achieved through direct injection of plasma samples, extraction of analyte with a Cohesive C18 column (50 mm x 0.5 mm, 50 microm), followed by HPLC separation on a FluoPhase RP column (100 mm x 2.1 mm, 5 microm) and MS/MS detection. The off-line SPE assay used Waters Oasis HLB microElution plate to extract the analytes from plasma matrix before injecting on a FluoPhase RP column (150 mm x 2.1 mm, 5 microm) for LC-MS/MS analysis. Under both on-line and off-line assay conditions, the diastereomer 1c was chromatographically separated from MK-0974. Cross-validation with the pooled samples demonstrated that both on-line and off-line assays provided comparable data with a difference of < 2.6%. The assays were proved to be specific, accurate and reliable, and have been used to support multiple clinical studies. The pros and cons of on-line and off-line assays with regard to man power involved in sample preparation, total analysis time, carryover, cost efficiency, and the requirement for assay transfer are discussed.

Topics: Azepines; Chromatography, Liquid; Flow Injection Analysis; Humans; Imidazoles; Mass Spectrometry; Migraine Disorders; Solid Phase Extraction; Tandem Mass Spectrometry

Topics: Azepines; Calcitonin Gene-Related Peptide Receptor Antagonists; Clinical Trials as Topic; Humans; Imidazoles; Migraine Disorders

Telcagepant is an oral calcitonin-gene related peptide (CGRP) receptor antagonist that is being developed by Merck & Co Inc for the treatment of migraine. This compound blocks CGRP receptors and may block the dilation of dural vessels and reduce neurotransmission in the CNS, resulting in pain relief. Telcagepant does not cause vasoconstriction, one of the major limitations in the use of triptans, which are considered to be the standard of care for migraine. Data from phase II and III clinical trials suggest that the use of telcagepant for the acute treatment of migraine was comparable with the use of triptan compounds and was superior to placebo in all primary endpoints, including pain relief and freedom from pain at 2 h. However, recent data reported elevated transaminase levels when telcagepant was dosed daily rather than acutely. It was concluded that, if these hepatic toxicities are not observed in ongoing/future trials of the acute use of telcagepant, then this agent may offer an alternative to triptan therapy for the treatment of migraine.

Topics: Analgesics, Non-Narcotic; Azepines; Calcitonin Gene-Related Peptide Receptor Antagonists; Clinical Trials as Topic; Drugs, Investigational; Humans; Imidazoles; Migraine Disorders; Molecular Structure; Patents as Topic; Structure-Activity Relationship

Calcitonin gene-related peptide (CGRP) receptor antagonists are a new treatment principle in acute migraine attacks. Intravenous olcegepant 2.5 mg resulted in 66% headache relief after 2 h, whereas subcutaneous sumatriptan resulted in 81-92% headache relief after 2 h. The intrinsic activity of a parenteral triptan, a 5HT(1B/1D) receptor agonist, is thus higher than the maximum effect of the parenteral CGRP receptor antagonist olcegepant. For the orally bioavailable CGRP antagonist telcagepant 300 mg, the headache relief was only 55% in one phase III study. These results indicate that CGRP receptor antagonism results in success in the acute treatment of migraine in only a certain fraction of the patients.

Topics: Azepines; Calcitonin Gene-Related Peptide; Calcitonin Gene-Related Peptide Receptor Antagonists; Cerebral Arteries; Clinical Trials as Topic; Dipeptides; Humans; Imidazoles; Migraine Disorders; Piperazines; Quinazolines; Receptors, Calcitonin Gene-Related Peptide; Serotonin Receptor Agonists; Treatment Failure; Tryptamines

Topics: Azepines; Calcitonin Gene-Related Peptide Receptor Antagonists; Clinical Trials as Topic; Dipeptides; Drug Administration Schedule; Endpoint Determination; Humans; Imidazoles; Migraine Disorders; Piperazines; Quinazolines; Receptors, Calcitonin Gene-Related Peptide; Serotonin Receptor Agonists; Time Factors; Treatment Outcome; Tryptamines

Topics: Azepines; Calcitonin Gene-Related Peptide Receptor Antagonists; Dipeptides; Female; Humans; Imidazoles; Migraine Disorders; Migraine with Aura; Myocardial Infarction; Piperazines; Quinazolines; Risk Factors; Stroke; Tryptamines

Topics: Animals; Azepines; Calcitonin Gene-Related Peptide; Calcitonin Gene-Related Peptide Receptor Antagonists; Cerebrovascular Circulation; Humans; Imidazoles; Migraine Disorders; Oxazolidinones; Serotonin Receptor Agonists; Tryptamines

Calcitonin gene-related peptide (CGRP) is a potent neuropeptide that plays a key role in the pathophysiology of migraine headache. CGRP levels in the cranial circulation are increased during a migraine attack, and CGRP itself has been shown to trigger migraine-like headache. The correlation between CGRP release and migraine headache points to the potential utility of CGRP receptor antagonists as novel therapeutics in the treatment of migraine. Indeed, clinical proof-of-concept in the acute treatment of migraine was demonstrated with an intravenous formulation of the CGRP receptor antagonist BIBN4096BS (olcegepant). Here we report on the pharmacological characterization of the first orally bioavailable CGRP receptor antagonist in clinical development, MK-0974 [N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide]. In vitro, MK-0974 is a potent antagonist of the human (K(i) = 0.77 nM) and rhesus (K(i) = 1.2 nM) CGRP receptors but displays >1500-fold lower affinity for the canine and rat receptors as determined via (125)I-human CGRP competition binding assays. A rhesus pharmacodynamic assay measuring capsaicin-induced changes in forearm dermal blood flow via laser Doppler imaging was utilized to determine the in vivo activity of CGRP receptor antagonism. MK-0974 produced a concentration-dependent inhibition of dermal vasodilation, generated by capsaicin-induced release of endogenous CGRP, with plasma concentrations of 127 and 994 nM required to block 50 and 90% of the blood flow increase, respectively. In conclusion, MK-0974 is a highly potent, selective, and orally bioavailable CGRP receptor antagonist, which may be valuable in the acute treatment of migraine.

Topics: Administration, Oral; Animals; Azepines; Calcitonin Gene-Related Peptide Receptor Antagonists; Cell Line; Dogs; Dose-Response Relationship, Drug; Female; Humans; Imidazoles; Macaca mulatta; Male; Migraine Disorders; Protein Binding; Rats; Receptors, Calcitonin Gene-Related Peptide

Topics: Azepines; Calcitonin Gene-Related Peptide; Humans; Imidazoles; Migraine Disorders; Piperazines; Quinazolines; Serotonin Receptor Agonists; Treatment Outcome; Triazoles; Tryptamines; Vasodilator Agents

Calcitonin gene-related peptide (CGRP) has been implicated in the pathogenesis of migraine. Herein we describe optimization of CGRP receptor antagonists based on an earlier lead structure containing a (3R)-amino-(6S)-phenylcaprolactam core. Replacement of the phenylimidazolinone with an azabenzimidazolone gave stable derivatives with lowered serum shifts. Extensive SAR studies of the C-6 aryl moiety revealed the potency-enhancing effect of the 2,3-difluorophenyl group, and trifluoroethylation of the N-1 amide position resulted in improved oral bioavailabilities, ultimately leading to clinical candidate 38 (MK-0974).

Topics: Administration, Oral; Animals; Azepines; Biological Availability; Caco-2 Cells; Calcitonin Gene-Related Peptide Receptor Antagonists; Cell Membrane Permeability; Dogs; Humans; Imidazoles; Macaca mulatta; Migraine Disorders; Rats; Regional Blood Flow; Skin; Stereoisomerism; Structure-Activity Relationship