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.
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.
Di Fabio
Romano
R
Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline Medicines Research Centre, Via A. Fleming 4, 37135 Verona, Italy. rdf26781@gsk.com
Griffante
Cristiana
C
Alvaro
Giuseppe
G
Pentassuglia
Giorgio
G
Pizzi
Domenica A
DA
Donati
Daniele
D
Rossi
Tino
T
Guercio
Giuseppe
G
Mattioli
Mario
M
Cimarosti
Zadeo
Z
Marchioro
Carla
C
Provera
Stefano
S
Zonzini
Laura
L
Montanari
Dino
D
Melotto
Sergio
S
Gerrard
Philip A
PA
Trist
David G
DG
Ratti
Emiliangelo
E
Corsi
Mauro
M
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
D005464:Fluorobenzenes; D064729:Neurokinin-1 Receptor Antagonists; D010879:Piperazines; D010880:Piperidines; C031503:phenylpiperazine; C534550:vestipitant