Discovery and Biological Characterization of (2R,4S)-1鈥?Acetyl-N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-2-(4-fluoro-2-methylphenyl)-N-methyl-4,4鈥?bipiperidin

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• 作者：Romano Di Fabio ; Giuseppe Alvaro ; Cristiana Griffante ; Domenica A. Pizzi ; Daniele Donati ; Mario Mattioli ; Zadeo Cimarosti ; Giuseppe Guercio ; Carla Marchioro ; Stefano Provera ; Laura Zonzini ; Dino Montanari ; Sergio Melotto ; Philip A. Gerrard ; David G. Trist ; Emiliangelo Ratti ; Mauro Corsi
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：February 24, 2011
• 年：2011
• 卷：54
• 期：4
• 页码：1071-1079
• 全文大小：859K
• 年卷期：v.54,no.4(February 24, 2011)
• ISSN：1520-4804

文摘

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 NK₁ 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 NK₁ 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 NK₁ receptor antagonist (casopitant) selected as clinical candidate and progressed into clinical studies to treat major depression disorders.