1-isoquinolin-5-yl-3-(4-trifluoromethyl-benzyl)-urea and Pain

Topics: Analgesics; Animals; Capsaicin; Humans; Pain; TRPV Cation Channels

Pain is the leading cause of emergency department visits, hospitalizations, and daily suffering in individuals with sickle cell disease (SCD). The pathologic mechanisms leading to the perception of pain during acute RBC sickling episodes and development of chronic pain remain poorly understood and ineffectively treated. We provide the first study that explores nociceptor sensitization mechanisms that contribute to pain behavior in mice with severe SCD. Sickle mice exhibit robust behavioral hypersensitivity to mechanical, cold, and heat stimuli. Mechanical hypersensitivity is further exacerbated when hypoxia is used to induce acute sickling. Behavioral mechanical hypersensitivity is mediated in part by enhanced excitability to mechanical stimuli at both primary afferent peripheral terminal and sensory membrane levels. In the present study, inhibition of the capsaicin receptor transient receptor potential vanilloid 1 (TRPV1) with the selective antagonist A-425619 reversed the mechanical sensitization at both primary afferent terminals and isolated somata, and markedly attenuated mechanical behavioral hypersensitivity. In contrast, inhibition of TRPA1 with HC-030031 had no effect on mechanical sensitivity. These results suggest that the TRPV1 receptor contributes to primary afferent mechanical sensitization and a substantial portion of behavioral mechanical hypersensitivity in SCD mice. Therefore, TRPV1-targeted compounds that lack thermoregulatory side effects may provide relief from pain in patients with SCD.

Topics: Action Potentials; Anemia, Sickle Cell; Animals; Capsaicin; Disease Models, Animal; Female; Humans; Hyperalgesia; Hypoxia; Isoquinolines; Male; Mice; Mice, Inbred Strains; Microelectrodes; Nociceptors; Pain; Pain Measurement; Patch-Clamp Techniques; TRPV Cation Channels; Urea

Evidence implicating Nav1.8 and TRPV1 ion channels in various chronic pain states is extensive. In this study, we used isobolographic analysis to examine the in vivo effects of the combination of the Nav1.8 blocker A-803467 [5-(4-Chloro-phenyl)-furan-2-carboxylic acid (3,5-dimethoxy-phenyl)-amide] with 2 structurally distinct TRPV1 antagonists, A-840257 [1-(1H-Indazol-4-yl)-3-([R]-4-piperidin-1-yl-indan-1-yl)-urea] or A-425619 [1-Isoquinolin-5-yl-3-(4-trifluoromethyl-benzyl)-urea]. The antinociceptive effects of the Nav1.8 blocker alone and in combination with each TRPV1 antagonist were examined in an inflammatory (complete Freund's adjuvant, CFA) and a neuropathic (spinal nerve ligation, SNL) pain model after systemic (intraperitoneal) administration. Alone, A-803467 was efficacious in both CFA and SNL models with ED(50) values of 70 (54.2 to 95.8) mg/kg and 70 (38.1 to 111.9) mg/kg, respectively. The ED(50) values of the TRPV1 antagonists A-840257 and A-425619 alone in the CFA model were 10 (3.6 to 14.9) mg/kg and 43 (24.1 to 62.2) mg/kg, respectively; both were without significant effect in the SNL model. A series of experiments incorporating 1:1, 3:1, or 0.3:1 ED(50) dose-ratio combinations of A-840257 and A-803467, or A-425619 and A-803467 were performed in both pain models, and the effective doses of mixtures that produced 50% antinociception (ED(50, mix)) were determined by isobolographic analysis. The ED(50, mix) in each case was not found to be statistically different than ED(50, add), the theoretical ED(50) calculated assuming additive effects. These data demonstrate that Nav1.8 blockers and TRPV1 antagonists administered in combination produce an additive effect in rat pain models. Using such a combination strategy to produce analgesia may potentially provide an improved therapeutic separation from unwanted in vivo side effects associated with blockade of either Nav1.8 or TRPV1 alone.. In this report, effects of coadministration of TRPV1 antagonists and A-803467, a Nav1.8 blocker, were investigated in preclinical rodent models of neuropathic and inflammatory pain. The 2 classes of novel antinociceptive agents produced an additive interaction in attenuating CFA-induced thermal hyperalgesia, providing a rationale for their use as a combination strategy in the clinic for treating inflammatory pain.

Topics: Analgesics; Aniline Compounds; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Freund's Adjuvant; Furans; Inflammation; Isoquinolines; Male; NAV1.8 Voltage-Gated Sodium Channel; Nerve Tissue Proteins; Pain; Pain Measurement; Pain Threshold; Rats; Rats, Sprague-Dawley; Sodium Channels; Spinal Nerves; Substance-Related Disorders; Treatment Outcome; TRPV Cation Channels; Urea

Vanilloid receptor TRPV1 is a cation channel that can be activated by a wide range of noxious stimuli, including capsaicin, acid, and heat. Blockade of TRPV1 activation by selective antagonists is under investigation by several pharmaceutical companies in an effort to identify novel agents for pain management. Here we report that replacement of substituted benzyl groups by an indan rigid moiety in a previously described N-indazole- N'-benzyl urea series led to a number of TRPV1 antagonists with significantly increased in vitro potency and enhanced drug-like properties. Extensive evaluation of pharmacological, pharmacokinetic, and toxicological properties of synthesized analogs resulted in identification of ( R)-7 ( ABT-102). Both the analgesic activity and drug-like properties of ( R)-7 support its advancement into clinical pain trials.

Topics: Administration, Oral; Analgesics; Animals; Biological Availability; Dogs; Haplorhini; Humans; In Vitro Techniques; Indazoles; Indenes; Microsomes, Liver; Pain; Rats; Stereoisomerism; Structure-Activity Relationship; TRPV Cation Channels; Urea

SAR studies for N-aryl-N'-benzyl urea class of TRPV1 antagonists have been extended to cover alpha-benzyl alkylation. Alkylated compounds showed weaker in vitro potencies in blocking capsaicin activation of TRPV1 receptor, but possessed improved pharmacokinetic properties. Further structural manipulations that included replacement of isoquinoline core with indazole and isolation of single enantiomer led to TRPV1 antagonists like (R)-16a with superior pharmacokinetic properties and greater potency in animal model of inflammatory pain.

Topics: Analgesics; Animals; Inflammation; Methylation; Models, Biological; Pain; Rats; TRPV Cation Channels; Urea

Novel transient receptor potential vanilloid 1 (TRPV1) receptor antagonists with various bicyclic heteroaromatic pharmacophores were synthesized, and their in vitro activity in blocking capsaicin activation of TRPV1 was assessed. On the basis of the contribution of these pharmacophores to the in vitro potency, they were ranked in the order of 5-isoquinoline > 8-quinoline = 8-quinazoline > 8-isoquinoline > or = cinnoline approximately phthalazine approximately quinoxaline approximately 5-quinoline. The 5-isoquinoline-containing compound 14a (hTRPV1 IC50 = 4 nM) exhibited 46% oral bioavailability and in vivo activity in animal models of visceral and inflammatory pain. Pharmacokinetic and pharmacological properties of 14a are substantial improvements over the profile of the high-throughput screening hit 1 (hTRPV1 IC50 = 22 nM), which was not efficacious in animal pain models and was not orally bioavailable.

Topics: Abdominal Pain; Administration, Oral; Analgesics; Animals; Biological Availability; Calcium; Cells, Cultured; Disease Models, Animal; Heterocyclic Compounds, 2-Ring; Humans; Hyperalgesia; Isoquinolines; Models, Molecular; Pain; Quinazolines; Quinolines; Rats; Receptors, Drug; Static Electricity; Structure-Activity Relationship; Urea

The vanilloid receptor 1 (VR1, TRPV1), which is a member of the transient receptor potential (TRP) superfamily, is highly localized on peripheral and central processes of nociceptive afferent fibers. Activation of TRPV1 contributes to the pronociceptive effects of capsaicin, protons, heat, and various endogenous lipid agonists such as anandamide and N-arachidonoyl-dopamine. A-425619 [1-isoquinolin-5-yl-3-(4-trifluoromethyl-benzyl)urea] is a novel potent and selective antagonist at both human and rat TRPV1 receptors. In vivo, A-425619 dose dependently reduced capsaicin-induced mechanical hyperalgesia (ED50 = 45 micromol/kg p.o.). A-425619 was also effective in models of inflammatory pain and postoperative pain. A-425619 potently reduced complete Freund's adjuvant-induced chronic inflammatory pain after oral administration (ED50 = 40 micromol/kg p.o.) and was also effective after either i.t. administration or local injection into the inflamed paw. Furthermore, A-425619 maintained efficacy in the postoperative pain model after twice daily dosing p.o. for 5 days. A-425619 also showed partial efficacy in models of neuropathic pain. A-425619 did not alter motor performance at the highest dose tested (300 micromol/kg p.o.). Taken together, the present data indicate that A-425619, a potent and selective antagonist of TRPV1 receptors, effectively relieves acute and chronic inflammatory pain and postoperative pain.

Topics: Acute Disease; Analgesics; Animals; Capsaicin; Carrageenan; Chronic Disease; Dose-Response Relationship, Drug; Edema; Formaldehyde; Freund's Adjuvant; Hot Temperature; Hyperalgesia; Inflammation; Isoquinolines; Ligation; Male; Motor Activity; Osteoarthritis; Pain; Pain Measurement; Pain, Postoperative; Postural Balance; Rats; Rats, Sprague-Dawley; Receptors, Drug; Sciatic Nerve; Spinal Nerves; Urea