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

• DOI: 10.1016/j.bmcl.2010.02.076
• Publication Date: 2010-02-22T09:12:20Z
• Authors: Jian Liu; Shuwen He; Tianying Jian; Peter H. Dobbelaar; Iyassu K. Sebhat; Linus S. Lin; Allan Goodman; Cheng Guo; Peter R. Guzzo; Mark Hadden; Alan J. Henderson; Kevin Pattamana; Megan Ruenz; Bruce J Sargent; Brian Swenson; Larry Yet; Constantin Tamvak...; Qianping Peng; Jie Pan; Yanqing Kan; Oksana Palyha; Theresa M. Kelly; Xiao-Ming Guan; Andrew D. Howard; Donald J. Marsh; Joseph M. Metzger; Marc L. Reitman; Matthew J. Wyvratt; Ravi P. Nargund
• Keywords: Structure–activity relationship; Imidazole

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.