ABSTRACT
SAR around non-peptidic potent bombesin receptor subtype-3 (BRS-3) agonist lead 2 is presented. Attempts to replace the carboxylic acid with heterocyclic isosteres to improve oral bioavailability and brain penetration are described.
Subject(s)
Anti-Obesity Agents/chemical synthesis , Imidazoles/chemistry , Receptors, Bombesin/agonists , Administration, Oral , Animals , Anti-Obesity Agents/chemistry , Anti-Obesity Agents/therapeutic use , Brain/metabolism , Humans , Imidazoles/chemical synthesis , Imidazoles/therapeutic use , Mice , Obesity/drug therapy , Rats , Receptors, Bombesin/metabolism , Structure-Activity RelationshipABSTRACT
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.
