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

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.

• 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 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
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 20 Issue 7 Pg. 2074-7 (Apr 01 2010) ISSN: 1464-3405 [Electronic] England
• PMID: 20219372 (Publication Type: Journal Article)
• Copyright: 2010 Elsevier Ltd. All rights reserved.

Chemical References

• 2-(2-(4-(pyridin-2-yl)phenyl)ethyl)-5-(2,2-dimethylbutyl)-1H-imidazole
• Imidazoles
• Receptors, Bombesin
• bombesin receptor subtype 3

Topics

• Animals
• Body Weight (drug effects)
• Eating (drug effects)
• Humans
• Imidazoles (chemistry, pharmacokinetics, therapeutic use)
• Mice
• Obesity (drug therapy)
• Rats
• Receptors, Bombesin (agonists, metabolism)
• Structure-Activity Relationship