RESUMO
The 4-isoxazolyl-dihydropyridines (IDHPs) exhibit inhibition of the multidrug-resistance transporter (MDR-1), and exhibit an SAR distinct from their activity at voltage gated calcium channels (VGCC). Among the four most active IDHPs, three were branched at C-5 of the isoxazole, including the most active analog, 1k.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Dicarbetoxi-Di-Hidrocolidina/análogos & derivados , Di-Hidropiridinas/metabolismo , Isoxazóis/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Células CACO-2 , Canais de Cálcio/química , Canais de Cálcio/metabolismo , Dicarbetoxi-Di-Hidrocolidina/síntese química , Dicarbetoxi-Di-Hidrocolidina/química , Dicarbetoxi-Di-Hidrocolidina/metabolismo , Di-Hidropiridinas/química , Humanos , Isoxazóis/síntese química , Isoxazóis/química , Espectroscopia de Ressonância Magnética , Modelos Químicos , Ligação Proteica , Relação Estrutura-Atividade , TermodinâmicaRESUMO
(E)-3-(2-Carboxy-2-phenylvinyl)-4,6-dichloro-1H-indole-2-carboxylic acid, 1, is a potent and selective antagonist of the glycine site of the N-methyl-d-aspartate (NMDA) receptor. Using 3D comparative molecular field analysis (CoMFA) to guide the synthetic effort, a series of aryl diacid analogues of 1 were synthesized to optimize in vivo potency, duration of action, and binding activity. It was found that the incorporation of a substituted aromatic with an electron withdrawing group or a heterocyclic group at the 2-position of the 3-propenyl moiety of 1 gave compounds with better affinity and potency in the murine stroke model. Ultimately this led to the discovery of 3-[2-(3-aminophenyl)-2-carboxyvinyl]-4,6-dichloro-1H-indole-2-carboxylic acid, 19, as a new potent selective glycine-site NMDA receptor antagonist.
