Ho W, Tutwiler G F, Cottrell S C, Morgans D J, Tarhan O, Mohrbacher R J
J Med Chem. 1986 Nov;29(11):2184-90. doi: 10.1021/jm00161a009.
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.
合成了一系列烷基缩水甘油酸类似物和衍生物，并测试了它们在体外抑制长链脂肪酸氧化以及降低大鼠血糖的能力。测定了该系列化合物对肉碱酰基转移酶的抑制程度，肉碱酰基转移酶是线粒体膜上的一种酶，负责将长链脂肪酸转运到线粒体中进行后续的β-氧化。利用大鼠半膈肌中[1-14C]棕榈酸氧化的体外抑制作用建立的构效关系表明，强效活性主要存在于2-烷基（C12-C16）缩水甘油酸酯中。用环丙基、硫杂环丙烷或其他环取代环氧乙烷环会降低活性，在3-位取代缩水甘油酸酯环也是如此。大鼠葡萄糖耐量试验中的体内效力大致与半膈肌试验结果平行。先导化合物2-十四烷基缩水甘油酸甲酯（8）对几种动物口服给药后是一种强效降糖剂。这些降糖类似物通过特异性和不可逆地抑制线粒体肉碱棕榈酰转移酶-A来干扰脂肪酸氧化。
