Alkylglycidic acids: potential new hypoglycemic agents

A series of alkylglycidic acid analogues and derivatives were synthesized and tested for their ability to inhibit long-chain fatty acid oxidation in vitro and to lower blood sugar in rats. The extent of inhibition of carnitine acyl transferase, the enzyme at the mitochondrial membrane necessary to t...

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Bibliographic Details
Published in:	Journal of medicinal chemistry Vol. 29; no. 11; pp. 2184 - 2190
Main Authors:	Ho, Winston, Tutwiler, Gene F, Cottrell, Sandra C, Morgans, Dave J, Tarhan, Okan, Mohrbacher, Richard J
Format:	Journal Article
Language:	English
Published:	Washington, DC American Chemical Society 01-11-1986
Subjects:	Animals Carnitine O-Palmitoyltransferase - antagonists & inhibitors Chemistry Epoxy Compounds - chemical synthesis Epoxy Compounds - pharmacology Ethers, Cyclic - chemical synthesis Exact sciences and technology Fatty Acids - metabolism Heterocyclic compounds Heterocyclic compounds with o, s, se, te hetero atom and condensed derivatives Hypoglycemic Agents - chemical synthesis Hypoglycemic Agents - pharmacology Organic chemistry Oxidation-Reduction Preparations and properties Propionates - chemical synthesis Propionates - pharmacology Rats Structure-Activity Relationship Three membered ring Hypoglycemic agent Oxygen heterocycle Aliphatic compound Biological activity
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Summary:	A series of alkylglycidic acid analogues and derivatives were synthesized and tested for their ability to inhibit long-chain fatty acid oxidation in vitro and to lower blood sugar in rats. The extent of inhibition of carnitine acyl transferase, the enzyme at the mitochondrial membrane necessary to transport long-chain fatty acids into the mitochondria for subsequent beta-oxidation, was determined for the series. Structure-activity relationships using in vitro inhibition of [1-14C]palmitic acid oxidation in rat hemidiaphragm muscle indicate that potent activity resides mainly in 2-alkyl (C12-C16) glycidates. Replacement of the oxirane ring with cyclopropyl, thiirane, or other rings diminishes activity, as does substitution of the glycidate ring at the 3-position. In vivo potency in the rat glucose tolerance test roughly parallels the hemidiaphragm results. The lead compound, methyl 2-tetradecylglycidate (8), is a potent hypoglycemic agent following oral administration to several animal species. The hypoglycemic analogues interfere with fatty acid oxidation by specific and irreversible inhibition of mitochondrial carnitine palmitoyl transferase-A.
Bibliography:	ark:/67375/TPS-CBVCDGHF-R istex:9818614A9A12E64B5C9A23C2B60627539CF3CDAD ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0022-2623 1520-4804
DOI:	10.1021/jm00161a009