Discovery of (3-(4-(2-Oxa-6-azaspiro[3.3]heptan-6-ylmethyl)phenoxy)azetidin-1-yl)(5-(4-methoxyphenyl)-1,3,4-oxadiazol-2-yl)methanone (AZD1979), a Melanin Concentrating Hormone Receptor 1 (MCHr1) Antagonist with Favorable Physicochemical Properties

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• 作者：Anders Johansson ; Christian Löfberg ; Madeleine Antonsson ; Sverker von Unge ; Martin A. Hayes ; Robert Judkins ; Karolina Ploj ; Lambertus Benthem ; Daniel Lindén ; Peter Brodin ; Marie Wennerberg ; Marléne Fredenwall ; Lanna Li ; Joachim Persson ; Rolf Bergman ; Anna Pettersen ; Peter Gennemark ; Anders Hogner
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：March 24, 2016
• 年：2016
• 卷：59
• 期：6
• 页码：2497-2511
• 全文大小：829K
• ISSN：1520-4804

文摘

A novel series of melanin concentrating hormone receptor 1 (MCHr1) antagonists were the starting point for a drug discovery program that culminated in the discovery of 103 (AZD1979). The lead optimization program was conducted with a focus on reducing lipophilicity and understanding the physicochemical properties governing CNS exposure and undesired off-target pharmacology such as hERG interactions. An integrated approach was taken where the key assay was ex vivo receptor occupancy in mice. The candidate compound 103 displayed appropriate lipophilicity for a CNS indication and showed excellent permeability with no efflux. Preclinical GLP toxicology and safety pharmacology studies were without major findings and 103 was taken into clinical trials.