Discovery and Biological Characterization of (2R,4S)-1′-Acetyl-N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-2-(4-fluoro-2-methylphenyl)-N-methyl-4,4′-bipiperidine-1-carboxamide as a New Potent and Selective Neurokinin 1 (NK1) Receptor Antagonist Clinical Candidate
Discovery and Biological Characterization of (2R,4S)-1′-Acetyl-N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-2-(4-fluoro-2-methylphenyl)-N-methyl-4,4′-bipiperidine-1-carboxamide as a New Potent and Selective Neurokinin 1 (NK1) Receptor Antagonist Clinical Candidate
复制标题
DOI：
10.1021/jm1013264
复制
发表时间：
2011-02-24
影响因子：
7.3
通讯作者：
Corsi, Mauro
中科院分区：
文献类型：
--
作者：
Di Fabio, Romano;Alvaro, Giuseppe;Corsi, Mauro
大量令人信服的临床前证据支持神经激肽（NK）受体拮抗剂在大量中枢神经系统和非中枢神经系统治疗领域的临床应用。在过去的20年里，NK1受体拮抗剂对重度抑郁症的临床疗效的观察使该领域的重大投资达到高潮。此外，阿瑞吡坦（默克）作为一种能够预防化疗引起的恶心和呕吐（CINV）的新药上市。在葛兰素史克（GlaxoSmithKline）发现vestipitant后，一项广泛的药物发现计划启动，旨在确定更多的临床候选药物。新化合物被设计为在NK1受体结合位点上最大化亲和力，同时保留适当的物理化学特性，以确保良好的体内药代动力学和药效学特性。在这里，我们描述了一种新的NK1受体拮抗剂（卡索匹坦）的发现过程，该拮抗剂被选为临床候选药物，并进入临床研究，用于治疗重度抑郁症。
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.