vestipitant and casopitant

The difference in location between the receptor occupancy curve of an agonist and its functional response has been described as receptor reserve. This "reserve" for a specific receptor has been found to differ from tissue to tissue and between agonists acting on the same tissue. Recently, two structurally different neurokinin 1 (NK1) receptor antagonists were taken into human and both were tested as antidepressants and for insomnia. Vestipitant and Casopitant both have high affinity for the human NK1 receptor (pKi = 9.4 and 10.2, respectively). In human, at the chosen clinical doses, receptor occupancy was measured in the frontal cortex, at 24 hours post administration, as ∼90% for vestipitant (15 mg) and ∼100% for casopitant (30 mg). In patients with moderate to severe major depression, vestipitant given at 15 mg for 8 weeks showed no statistical significant benefit as measured by change in baseline in HAM-D total score; whereas casopitant at 80 mg achieved statistically significant improvement versus placebo at week 8 (LOCF HAMD17 = -2.7, p = 0.023). A lower dose of 30 mg showed a clear but not significant separation from placebo. However, in acute studies in insomnia, both vestipitant and casopitant at 15 mg and 30 mg, respectively, significantly reduced latency to persistent sleep, wakenings after sleep onset and increased total sleep time by similar amounts. These clinical results suggest that for major depression the receptor occupancy of an NK1 antagonist needs to be very high (almost 100%), whereas, for insomnia a lower occupation is sufficient to give clinical effect.

Topics: Antidepressive Agents; Depressive Disorder, Major; Fluorobenzenes; Humans; Neurokinin-1 Receptor Antagonists; Piperazines; Piperidines; Receptors, Neurokinin-1; Sleep Initiation and Maintenance Disorders; Tissue Distribution

The last two decades have provided a large weight of preclinical data implicating the neurokinin-1 receptor (NK1) and its cognate ligand substance P (SP) in a broad range of both central and peripheral disease conditions. However, to date, only the NK1 receptor antagonist aprepitant has been approved as a therapeutic and this is to prevent chemotherapy-induced nausea & vomiting (CINV). The belief remained that the full therapeutic potential of NK1 receptor antagonists had yet to be realized; therefore clinical evidence that NK1 receptor antagonists may be effective in major depression disorder, resulted in a significant further investment in discovering novel CNS penetrant druggable NK1 receptor antagonists to address this condition. At GlaxoSmithKline after the discovery of casopitant, that went on to demonstrate efficacy as a novel antidepressant in the clinic, additional novel analogues of this NK1 receptor antagonist were designed to further enhance its drug developability characteristics. Herein, we therefore describe the discovery process and the vivo pharmacological and pharmacokinetic profile of the new NK1 receptor antagonist 3a (also called orvepitant), selected as clinical candidate and further progressed into clinical studies for major depressive disorder. Moreover, molecular modeling studies enabled us to improve the pharmacophore model of the NK1 receptor antagonists with the identification of a region able to accommodate a variety of heterocycle moieties.

Topics: Animals; Antidepressive Agents; Behavior, Animal; Bridged Bicyclo Compounds, Heterocyclic; CHO Cells; Cricetinae; Cricetulus; Dogs; Female; Gerbillinae; Half-Life; Humans; Male; Models, Molecular; Molecular Conformation; Neurokinin-1 Receptor Antagonists; Piperazines; Piperidines; Protein Binding; Rats; Receptors, Neurokinin-1

A large body of compelling preclinical evidence supports the clinical use of neurokinin (NK) receptor antagonists in a plethora of CNS and non-CNS therapeutic areas. The significant investment made in this area over the past 2 decades culminated with the observation that NK(1) receptor antagonists elicited clinical efficacy in major depression disorders. In addition, aprepitant (Merck) was launched as a new drug able to prevent chemotherapy-induced nausea and vomiting (CINV). After the discovery by GlaxoSmithKline of vestipitant, a wide drug discovery program was launched aimed at identifying additional clinical candidates. New compounds were designed to maximize affinity at the NK(1) receptor binding site while retaining suitable physicochemical characteristics to ensure excellent pharmacokinetic and pharmacodynamic properties in vivo. Herein we describe the discovery process of a new NK(1) receptor antagonist (casopitant) selected as clinical candidate and progressed into clinical studies to treat major depression disorders.

Topics: Animals; Behavior, Animal; Brain; CHO Cells; Cricetinae; Cricetulus; Depressive Disorder; Drug Discovery; Gerbillinae; Half-Life; Humans; Magnetic Resonance Spectroscopy; Neurokinin-1 Receptor Antagonists; Piperazines; Piperidines; Regression Analysis; Spectrometry, Mass, Electrospray Ionization; Spectrophotometry, Infrared; Stereoisomerism