title: Discovery and biological characterization of (2R,4S)-1'-acetyl-N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-2-(4-fluoro-2-methylphenyl)-N-methyl-4,4'-bipiperidine-1-carboxamide as a new potent and selective neurokinin 1 (NK1) receptor antagonist clinical candidate.
abstract: 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.
authors.affiliation: GlaxoSmithKline Medicines Research Centre, Via A. Fleming 4, 37135 Verona, Italy. romano.difabio@aptuit.com
authors.forename: Romano
authors.initials: R
authors.lastname: Di Fabio
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Alvaro
authors.forename: Cristiana
authors.initials: C
authors.lastname: Griffante
authors.forename: Domenica A
authors.initials: DA
authors.lastname: Pizzi
authors.forename: Daniele
authors.initials: D
authors.lastname: Donati
authors.forename: Mario
authors.initials: M
authors.lastname: Mattioli
authors.forename: Zadeo
authors.initials: Z
authors.lastname: Cimarosti
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Guercio
authors.forename: Carla
authors.initials: C
authors.lastname: Marchioro
authors.forename: Stefano
authors.initials: S
authors.lastname: Provera
authors.forename: Laura
authors.initials: L
authors.lastname: Zonzini
authors.forename: Dino
authors.initials: D
authors.lastname: Montanari
authors.forename: Sergio
authors.initials: S
authors.lastname: Melotto
authors.forename: Philip A
authors.initials: PA
authors.lastname: Gerrard
authors.forename: David G
authors.initials: DG
authors.lastname: Trist
authors.forename: Emiliangelo
authors.initials: E
authors.lastname: Ratti
authors.forename: Mauro
authors.initials: M
authors.lastname: Corsi
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D003866:Depressive Disorder / Q000188:drug therapy* / Q000378:metabolism; D055808:Drug Discovery; D005849:Gerbillinae; D006207:Half-Life; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D064729:Neurokinin-1 Receptor Antagonists; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D012044:Regression Analysis; D021241:Spectrometry, Mass, Electrospray Ionization; D013055:Spectrophotometry, Infrared; D013237:Stereoisomerism; D014508:Urea
chemical_list: D064729:Neurokinin-1 Receptor Antagonists; D010879:Piperazines; D010880:Piperidines; C531951:casopitant; D014508:Urea