Synthesis and SAR of derivatives based on 2-biarylethylimidazole as bombesin receptor subtype-3 (BRS-3) agonists for the treatment of obesity

作     者：Liu, Jian He, Shuwen Jian, Tianying Dobbelaar, Peter H. Sebhat, Iyassu K. Lin, Linus S. Goodman, Allan Guo, Cheng Guzzo, Peter R. Hadden, Mark Henderson, Alan J. Pattamana, Kevin Ruenz, Megan Sargent, Bruce J. Swenson, Brian Yet, Larry Tamvakopoulos, Constantin Peng, Qianping Pan, Jie Kan, Yanqing Palyha, Oksana Kelly, Theresa M. Guan, Xiao-Ming Howard, Andrew D. Marsh, Donald J. Metzger, Joseph M. Reitman, Marc L. Wyvratt, Matthew J. Nargund, Ravi P. 

作者机构：Merck Res Labs Dept Med Chem Rahway NJ 07065 USA AMRI Albany NY 12212 USA Merck Res Labs Dept Metab Disorders Rahway NJ 07065 USA Merck Res Labs Dept Pharmacol Rahway NJ 07065 USA Merck Res Labs Dept Drug Metab Rahway NJ 07065 USA 

出 版 物：《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 (生物有机化学与医药化学通讯)

年 卷 期：2010年第20卷第7期

页      面：2074-2077页

核心收录：

学科分类：0710[理学-生物学] 1007[医学-药学(可授医学、理学学位)] 071010[理学-生物化学与分子生物学] 081704[工学-应用化学] 07[理学] 08[工学] 0817[工学-化学工程与技术] 0703[理学-化学] 

主　　题：Bombesin receptor subtype-3 (BRS-3) Agonist Obesity 

摘      要：This Letter describes a series of potent and selective BRS-3 agonists containing a biarylethylimidazole pharmacophore. Extensive SAR studies were carried out with different aryl substitutions. This work led to the identification of a compound 2-{2-[4-(pyridin-2-yl) phenyl] ethyl}-5-(2,2-dimethylbutyl)-1H-imidazole 9 with excellent binding affinity (IC(50) = 18 nM, hBRS-3) and functional agonist activity (EC(50) = 47 nM, 99% activation). After oral administration, compound 9 had sufficient exposure in diet induced obese mice to demonstrate efficacy in lowering food intake and body weight via BRS-3 activation. (C) 2010 Elsevier Ltd. All rights reserved.