title: Discovery process and pharmacological characterization of 2-(S)-(4-fluoro-2-methylphenyl)piperazine-1-carboxylic acid [1-(R)-(3,5-bis-trifluoromethylphenyl)ethyl]methylamide (vestipitant) as a potent, selective, and orally active NK1 receptor antagonist.
abstract: In an effort to discover novel druglike NK(1) receptor antagonists a new series of suitably substituted C-phenylpiperazine derivatives was identified by an appropriate chemical exploration of related N-phenylpiperazine analogues, with the specific aim to maximize their in vitro affinity and optimize in parallel their pharmacokinetic profile. Among the compounds synthesized, 2-(S)-(4-fluoro-2-methylphenyl)piperazine-1-carboxylic acid [1-(R)-(3,5-bis-trifluoromethylphenyl)ethyl]methylamide (vestipitant) was identified as one of the most in vitro potent and selective NK(1) receptor antagonists ever discovered, showing appropriate pharmacokinetic properties and in vivo activity. On the basis of its preclinical profile, this compound was selected as a drug candidate.
authors.affiliation: Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline Medicines Research Centre, Via A. Fleming 4, 37135 Verona, Italy. rdf26781@gsk.com
authors.forename: Romano
authors.initials: R
authors.lastname: Di Fabio
authors.forename: Cristiana
authors.initials: C
authors.lastname: Griffante
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Alvaro
authors.forename: Giorgio
authors.initials: G
authors.lastname: Pentassuglia
authors.forename: Domenica A
authors.initials: DA
authors.lastname: Pizzi
authors.forename: Daniele
authors.initials: D
authors.lastname: Donati
authors.forename: Tino
authors.initials: T
authors.lastname: Rossi
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Guercio
authors.forename: Mario
authors.initials: M
authors.lastname: Mattioli
authors.forename: Zadeo
authors.initials: Z
authors.lastname: Cimarosti
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: D000284:Administration, Oral; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D005464:Fluorobenzenes; D005849:Gerbillinae; D064729:Neurokinin-1 Receptor Antagonists; D010599:Pharmacokinetics; D010879:Piperazines / Q000737:chemistry* / Q000494:pharmacology; D010880:Piperidines / Q000493:pharmacokinetics / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D005464:Fluorobenzenes; D064729:Neurokinin-1 Receptor Antagonists; D010879:Piperazines; D010880:Piperidines; C031503:phenylpiperazine; C534550:vestipitant