RESUMEN
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.
Asunto(s)
Agonistas de Receptores Adrenérgicos beta 3 , Agonistas Adrenérgicos beta/farmacología , Glicina/análogos & derivados , Glicina/farmacología , Agonistas Adrenérgicos beta/síntesis química , Animales , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Glicina/síntesis química , Glicina/química , Haplorrinos , Humanos , Metilación , Receptores Adrenérgicos beta 3/metabolismo , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
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)
Asunto(s)
Agonistas de Receptores Adrenérgicos beta 3 , Agonistas Adrenérgicos beta/química , Agonistas Adrenérgicos beta/farmacología , Anilidas/química , Anilidas/farmacología , Etanolamina/química , Etanolamina/farmacología , Administración Oral , Animales , Disponibilidad Biológica , Chlorocebus aethiops , Evaluación Preclínica de Medicamentos , Etanolaminas , Humanos , Ratas , Relación Estructura-ActividadRESUMEN
A series of 4-hydroxy-3-methylsulfonanilido-1,2-diarylethylamines were prepared and evaluated for their human beta(3) adrenergic receptor agonist activity. SAR studies led to the identification of BMS-196085 (25), a potent beta(3) full agonist (K(i)=21 nM, 95% activation) with partial agonist (45%) activity at the beta(1) receptor. Based on its desirable in vitro and in vivo properties, BMS-196085 was chosen for clinical evaluation.