ABSTRACT
A series of N-(4-hydroxy-3-methylsulfonanilidoethanol)arylglycinamides were prepared and evaluated for their human beta3 adrenergic receptor agonist activity. SAR studies led to the identification of BMS-201620 (39), a potent beta3 full agonist (Ki = 93 nM, 93% activation). Based on its favorable safety profile, BMS-201620 was chosen for clinical evaluation.
Subject(s)
Adrenergic beta-3 Receptor Agonists , Adrenergic beta-Agonists/pharmacology , Glycine/analogs & derivatives , Glycine/pharmacology , Adrenergic beta-Agonists/chemical synthesis , Animals , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Glycine/chemical synthesis , Glycine/chemistry , Haplorhini , Humans , Methylation , Receptors, Adrenergic, beta-3/metabolism , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Screening of the BMS collection identified 4-hydroxy-3-methylsulfonanilidoethanolamines as full beta 3 agonists. Substitution of the ethanolamine nitrogen with a benzyl group bearing a para hydrogen bond acceptor promoted beta(3) selectivity. SAR elucidation established that highly selective beta(3) agonists were generated upon substitution of C(alpha) with either benzyl to form (R)-1,2-diarylethylamines or with aryl to generate 1,1-diarylmethylamines. This latter subset yielded a clinical candidate, BMS-194449 (35).(1)