Objective:To synthesize nNOS PDZ structural domain inhibitors and evaluate their neuroprotective effects. Methods:Multiple-series of dicarboxylic acids and their ester compounds were designed and synthesized based on the structure characteristic of multi-basic groups of the nNOS PDZ ligand binding domain. The neuroprotective effects of the compounds were evaluated by glutamate-induced lactate dehydrogenase (LDH) release model of neurons. Results:Eighteen target compounds were synthesized including N-(2-methoxycarbonylacetyl)-D-valine methyl ester(1),N-(2-carboxylacetyl)-D-valine methyl ester(2),N-(2-methoxycarbony-lacetyl)-L-valine methyl ester(7),N-(2-carboxylacetyl)-L-valine(9) showed potent neuroprotective effect. Conclusion:nNOS PDZ structural domain inhibitors are neuroprotective.