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

J Liu, S He, T Jian, PH Dobbelaar, IK Sebhat…

Index: 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. Bioorganic and Medicinal Chemistry Letters, 2010 , vol. 20, # 7 p. 2074 - 2077

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Citation Number: 20

Abstract

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 (IC50= 18nM, hBRS-3) and functional agonist activity (EC50= 47nM, 99% activation). After oral ...