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
  • 1. Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA. [email protected]
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.