CoMFA, Synthesis, and Pharmacological Evaluation of (<i>E</i>)-3-(2-Carboxy-2-arylvinyl)-4,6-dichloro-1<i>H</i>-indole-2-carboxylic Acids:  3-[2-(3-Aminophenyl)-2-carboxyvinyl]-4,6-dichloro-1<i>H</i>-indole-2-carboxylic Acid, a Potent Selective Glycine-Site NMDA Receptor Antagonist

Abstract

(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.