RESUMO
We have previously disclosed the selective ET(A) receptor antagonist N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide (1, BMS-193884) as a clinical development candidate. Additional SAR studies at the 2'-position of 1 led to the identification of several analogues with improved binding affinity as well as selectivity for the ET(A) receptor. Following the discovery that a 3-amino-isoxazole group displays significantly improved metabolic stability in comparison to its 5-regioisomer, the 3-amino-isoxazole group was combined with the optimal 2'-substituent leading to 16a (BMS-207940). Compound 16a is an extremely potent (ET(A) K(i) = 10 pM) and selective (80,000-fold for ET(A) vs ET(B)) antagonist. It is also 150-fold more potent and >6-fold more selective than 1. The bioavailability of 16a was 100% in rats and the systemic clearance and volume of distribution are higher than that of 1. In rats, intravenous 16a blocks big ET pressor responses with 30-fold greater potency than 1. After oral dosing at 3 micromol/kg, 16a displays enhanced duration relative to 1.
Assuntos
Antagonistas dos Receptores de Endotelina , Oxazóis/síntese química , Sulfonamidas/síntese química , Administração Oral , Animais , Pressão Sanguínea/efeitos dos fármacos , Células CHO , Células CACO-2 , Artérias Carótidas/efeitos dos fármacos , Artérias Carótidas/fisiologia , Cricetinae , Humanos , Técnicas In Vitro , Isoxazóis/síntese química , Isoxazóis/farmacocinética , Isoxazóis/farmacologia , Macaca fascicularis , Masculino , Contração Muscular/efeitos dos fármacos , Oxazóis/farmacocinética , Oxazóis/farmacologia , Coelhos , Ratos , Ratos Sprague-Dawley , Receptor de Endotelina A , Receptor de Endotelina B , Relação Estrutura-Atividade , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologiaRESUMO
The ET(A) receptor antagonist (2) (N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)-[1,1'-biphenyl]-2-sulfonamide, BMS-193884) shares the same biphenyl core as a large number of AT(1) receptor antagonists, including irbesartan (3). Thus, it was hypothesized that merging the structural elements of 2 with those of the biphenyl AT(1) antagonists (e.g., irbesartan) would yield a compound with dual activity for both receptors. This strategy led to the design, synthesis, and discovery of (15) (4'-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-N-(3,4-dimethyl-5-isoxazolyl)-2'-[(3,3-dimethyl-2-oxo-1-pyrrolidinyl)methyl]-[1,1'-biphenyl]-2-sulfonamide, BMS-248360) as a potent and orally active dual antagonist of both AT(1) and ET(A) receptors. Compound 15 represents a new approach to treating hypertension.
Assuntos
Angiotensina II/metabolismo , Antagonistas de Receptores de Angiotensina , Antagonistas dos Receptores de Endotelina , Isoxazóis/síntese química , Sulfonamidas/síntese química , Animais , Anti-Hipertensivos/síntese química , Anti-Hipertensivos/química , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Células CHO , Cricetinae , Cristalografia por Raios X , Isoxazóis/química , Isoxazóis/farmacologia , Estrutura Molecular , Ensaio Radioligante , Ratos , Receptor Tipo 1 de Angiotensina , Receptor de Endotelina A , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologiaRESUMO
A number of 4'-heterocyclic biphenylsulfonamide derivatives, formally derived from BMS-193884 (1) by replacing the oxazole ring with other heterocyclic rings, are potent and selective endothelin A (ET(A)) receptor antagonists. Among the analogues examined, the pyrimidine derivative 18 is the most potent (K(i)=0.9 nM) and selective for the ET(A) receptor, approximately equivalent to 1.
