| Literature DB >> 20219372 |
Jian Liu1, 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 Tamvakopoulos, 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.
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 (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. 2010 Elsevier Ltd. All rights reserved.Entities:
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Year: 2010 PMID： 20219372 DOI： 10.1016/j.bmcl.2010.02.076
Source DB: PubMed Journal: Bioorg Med Chem Lett ISSN： 0960-894X Impact factor: 2.823