Abstract
A novel series of phosphinic acid based inhibitors of the neuropeptidase NAALADase are described in this work. This series of compounds is the most potent series of inhibitors of the enzyme described to date. In addition, we have shown that these compounds are protective in animal models of neurodegeneration. Compound 34 significantly prevented neurodegeneration in a middle cerebral artery occlusion model of cerebral ischemia. In addition, in the chronic constrictive model of neuropathic pain, compound 34 significantly attenuated the hypersensitivity observed with saline-treated animals. These data suggest that NAALADase inhibition may provide a new approach for the treatment of both neurodegenerative disorders and peripheral neuropathies.
MeSH terms
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Animals
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Arterial Occlusive Diseases / prevention & control
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Carboxypeptidases / antagonists & inhibitors*
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Drug Design
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology
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Glutamate Carboxypeptidase II
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Middle Cerebral Artery
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Neuroprotective Agents / chemical synthesis*
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Neuroprotective Agents / chemistry
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Neuroprotective Agents / pharmacology
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Pain Measurement
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Peripheral Nervous System Diseases / drug therapy
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Peripheral Nervous System Diseases / physiopathology
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Phosphinic Acids / chemical synthesis*
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Phosphinic Acids / chemistry
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Phosphinic Acids / pharmacology
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Rats
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Structure-Activity Relationship
Substances
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Enzyme Inhibitors
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Neuroprotective Agents
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Phosphinic Acids
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Carboxypeptidases
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Glutamate Carboxypeptidase II