Beta 3 agonists. Part 1: evolution from inception to BMS-194449.

Abstract 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 β 3 selectivity. SAR elucidation established that highly selective β 3 agonists were generated upon substitution of C α 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