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

被引：43

作者：

Di Fabio, Romano ^{[1
]}

Griffante, Cristiana ^{[1
]}

Alvaro, Giuseppe ^{[1
]}

Pentassuglia, Giorgio ^{[1
]}

Pizzi, Domenica A. ^{[1
]}

Donati, Daniele ^{[1
]}

Rossi, Tino ^{[1
]}

Guercio, Giuseppe

Mattioli, Mario

Cimarosti, Zadeo

Marchioro, Carla

Provera, Stefano

Zonzini, Laura ^{[1
]}

Montanari, Dino ^{[1
]}

Melotto, Sergio ^{[1
]}

Gerrard, Philip A. ^{[1
]}

Trist, David G. ^{[1
]}

Ratti, Emiliangeto ^{[1
]}

Corsi, Mauro ^{[1
]}

机构：

[1] GlaxoSmithKline Med Res Ctr, Neurosci Ctr Excellence Drug Discovery, I-37135 Verona, Italy

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2009年 / 52卷 / 10期

关键词：

SUBSTANCE-P; DEPRESSION; INHIBITION; EFFICACY; TARGETS; ANXIETY;

D O I：

10.1021/jm900023b

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

In an effort to discover novel druglike NK1 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 NK1 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.

引用

页码：3238 / 3247

页数：10

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