RESUMO
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.
Assuntos
Agonistas Adrenérgicos/química , Agonistas Adrenérgicos/farmacologia , Agonistas de Receptores Adrenérgicos beta 3 , Anilidas/química , Anilidas/farmacologia , Administração Oral , Agonistas de Receptores Adrenérgicos beta 1 , Animais , Glicemia/metabolismo , Chlorocebus aethiops , Avaliação Pré-Clínica de Medicamentos , Ácidos Graxos/sangue , Humanos , Camundongos , Camundongos Obesos , Receptores Adrenérgicos beta 1/metabolismo , Receptores Adrenérgicos beta 3/metabolismo , Relação Estrutura-AtividadeRESUMO
A series of 7,6- and 7,5-fused bicyclic thiazepinones and oxazepinones were generated and incorporated as conformationally restricted dipeptide surrogates in mercaptoacyl dipeptides. These compounds are potent inhibitors of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) both in vitro and in vivo. Compound 1a, a 7,6-fused bicyclic thiazepinone, demonstrated excellent blood pressure lowering in a variety of animal models characterized by various levels of plasma renin activity and significantly potentiated urinary sodium, ANP, and cGMP excretion in a cynomolgus monkey assay. On the basis of its potency and duration of action, compound 1a (BMS-186716) was advanced into clinical development for the treatment of hypertension and congestive heart failure.
