Abstract
A series of 2-(thioalkyl)pentanedioic acids were synthesized and evaluated as inhibitors of glutamate carboxypeptidase II (GCP II, EC 3.4.17.21). The inhibitory potency of these thiol-based compounds against GCP II was found to be dependent on the number of methylene units between the thiol group and pentanedioic acid. A comparison of the SAR of the thiol-based inhibitors to that of the phosphonate-based inhibitors provides insight into the role of each of the two zinc-binding groups in GCP II inhibition. The most potent thiol-based inhibitor, 2-(3-mercaptopropyl)pentanedioic acid (IC(50) = 90 nM), was found to be orally bioavailable in rats and exhibited efficacy in an animal model of neuropathic pain following oral administration.
MeSH terms
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Administration, Oral
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Analgesics / chemical synthesis*
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Analgesics / chemistry
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Analgesics / pharmacology
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Animals
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Biological Availability
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Carboxypeptidases / antagonists & inhibitors*
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Carboxypeptidases / chemistry
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Constriction, Pathologic / complications
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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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Glutarates / chemical synthesis*
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Glutarates / chemistry
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Glutarates / pharmacology
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Hot Temperature
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Hyperalgesia / drug therapy
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Hyperalgesia / etiology
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Male
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Pain / drug therapy
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Pain / etiology
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Peripheral Nervous System Diseases / complications
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Rats
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Rats, Sprague-Dawley
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Sciatic Nerve
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Structure-Activity Relationship
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Sulfhydryl Compounds / chemical synthesis*
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Sulfhydryl Compounds / chemistry
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Sulfhydryl Compounds / pharmacology
Substances
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2-(3-mercaptopropyl)pentanedioic acid
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Analgesics
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Enzyme Inhibitors
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Glutarates
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Sulfhydryl Compounds
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Carboxypeptidases
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Glutamate Carboxypeptidase II