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 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 i...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2009-05, Vol.52 (10), p.3238-3247
Main Authors: Di Fabio, Romano, Griffante, Cristiana, Alvaro, Giuseppe, Pentassuglia, Giorgio, Pizzi, Domenica A, Donati, Daniele, Rossi, Tino, Guercio, Giuseppe, Mattioli, Mario, Cimarosti, Zadeo, Marchioro, Carla, Provera, Stefano, Zonzini, Laura, Montanari, Dino, Melotto, Sergio, Gerrard, Philip A, Trist, David G, Ratti, Emiliangelo, Corsi, Mauro
Format: Article
Language:English
Subjects:
Administration, Oral
Animals
Biological and medical sciences
CHO Cells
Cricetinae
Cricetulus
Drug Discovery
Drug Evaluation, Preclinical
Fluorobenzenes
Gerbillinae
Medical sciences
Neurokinin-1 Receptor Antagonists
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems
Pharmacokinetics
Pharmacology. Drug treatments
Piperazines - chemistry
Piperazines - pharmacology
Piperidines - pharmacokinetics
Piperidines - pharmacology
Structure-Activity Relationship
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm900023b