Design and pharmacological activity of phosphinic acid based NAALADase inhibitors

A novel series of phosphinic acid based inhibitors of the neuropeptidase NA ALADase are described in this work. This series of compounds is the most po tent series of inhibitors of the enzyme described to date. In addition, we have shown that these compounds are protective in animal models of neurodeg eneration. Compound 34 significantly prevented neurodegeneration in a middl e cerebral artery occlusion model of cerebral ischemia. In addition, in the chronic constrictive mc del of neuropathic pain, compound 34 significantly attenuated the hypersensitivity observed with saline-treated animals. Thes e data suggest that NAALADase inhibition may provide a new approach for the treatment of both neurodegenerative disorders and peripheral neuropathies.