ABSTRACT
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.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Dicarbethoxydihydrocollidine/analogs & derivatives , Dihydropyridines/metabolism , Isoxazoles/metabolism , ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors , Caco-2 Cells , Calcium Channels/chemistry , Calcium Channels/metabolism , Dicarbethoxydihydrocollidine/chemical synthesis , Dicarbethoxydihydrocollidine/chemistry , Dicarbethoxydihydrocollidine/metabolism , Dihydropyridines/chemistry , Humans , Isoxazoles/chemical synthesis , Isoxazoles/chemistry , Magnetic Resonance Spectroscopy , Models, Chemical , Protein Binding , Structure-Activity Relationship , ThermodynamicsABSTRACT
(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.