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 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.
D000818:Animals; D002334:Carnitine O-Palmitoyltransferase / Q000037:antagonists & inhibitors; D004852:Epoxy Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D004988:Ethers, Cyclic / Q000138:chemical synthesis*; D005227:Fatty Acids / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D010084:Oxidation-Reduction; D011422:Propionates / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
D004852:Epoxy Compounds; D004988:Ethers, Cyclic; D005227:Fatty Acids; D007004:Hypoglycemic Agents; D011422:Propionates; C007869:glycidic acid; D002334:Carnitine O-Palmitoyltransferase