RESUMO
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)
Assuntos
Agonistas de Receptores Adrenérgicos beta 3 , Agonistas Adrenérgicos beta/química , Agonistas Adrenérgicos beta/farmacologia , Anilidas/química , Anilidas/farmacologia , Etanolamina/química , Etanolamina/farmacologia , Administração Oral , Animais , Disponibilidade Biológica , Chlorocebus aethiops , Avaliação Pré-Clínica de Medicamentos , Etanolaminas , Humanos , Ratos , Relação Estrutura-AtividadeRESUMO
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
Treatment of obese (ob/ob) mice with the beta 3-adrenergic receptor (beta 3-AR) agonist BRL-35135 (1 mg.kg body wt-1.day-1 for 20 days) normalized plasma glucose levels and significantly decreased plasma insulin and nonesterified fatty acid levels. The time frame for the hypoglycemic effect, which reached a maximum after 10 days of treatment, paralleled an increase in brown adipose tissue DNA and protein content. The basal level of mRNA for the beta 3-AR and mitochondrial uncoupling protein was found to be markedly decreased in the ob/ob animals relative to the lean group. Chronic treatment of ob/ob mice for 20 days resulted in a twofold increase in beta 3-AR mRNA and a fivefold increase in uncoupling protein mRNA in brown adipose tissue relative to the placebo group. These findings indicate that chronic treatment of ob/ob animals with a beta 3-AR agonist results in proliferation of brown adipose tissue, with an upregulation of the beta 3-AR, which is associated with a decrease in plasma glucose, insulin, and nonesterified fatty acid levels.
