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

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

  • Bioorg Med Chem Lett. 2010 Apr 1;20(7):2074-7. doi: 10.1016/j.bmcl.2010.02.076.
Jian Liu 1,  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
Affiliations

Affiliation

  • 1 Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA. jian_liu@merck.com
PMID: 20219372 DOI: 10.1016/j.bmcl.2010.02.076
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.

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