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

摘要

(E)-3-(2-Carboxy-2-phenylvinyl)-4,6-dichloro-lH-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-lH-indole-2-carboxylic acid,19,as a new potent selective glycine-site NMDA receptor antagonist.