Deems R O, Anderson R C, Foley J E
Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936, USA.
Am J Physiol. 1998 Feb;274(2):R524-8. doi: 10.1152/ajpregu.1998.274.2.R524.
Increased fatty acid oxidation contributes to hyperglycemia in patients with non-insulin-dependent diabetes mellitus. To improve glucose homeostasis in these patients, we have designed a novel, reversible inhibitor of carnitine palmitoyl-transferase I (CPT I) that potently inhibits fatty acid oxidation. SDZ-CPI-975 significantly lowered glucose levels in normal 18-h-fasted nonhuman primates and rats. In rats, glucose lowering required fatty acid oxidation inhibition of > or = 70%, as measured by beta-hydroxybutyrate levels, the end product of beta-oxidation. In cynomolgus monkeys, comparable glucose lowering was achieved with more modest lowering of beta-hydroxybutyrate levels. SDZ-CPI-975 did not increase glucose utilization by heart muscle, suggesting that CPT I inhibition with SDZ-CPI-975 would not induce cardiac hypertrophy. This was in contrast to the irreversible CPT I inhibitor etomoxir. These results demonstrate that SDZ-CPI-975 effectively inhibited fatty acid oxidation and lowered blood glucose levels in two species. Thus reversible inhibitors of CPT I represent a class of novel hypoglycemic agents that inhibit fatty acid oxidation without inducing cardiac hypertrophy.
脂肪酸氧化增加在非胰岛素依赖型糖尿病患者的高血糖症中起作用。为改善这些患者的葡萄糖稳态，我们设计了一种新型的、可逆的肉碱棕榈酰转移酶I（CPT I）抑制剂，它能有效抑制脂肪酸氧化。SDZ-CPI-975可显著降低正常禁食18小时的非人类灵长类动物和大鼠的血糖水平。在大鼠中，通过β氧化的终产物β-羟基丁酸水平测定，血糖降低需要脂肪酸氧化抑制≥70%。在食蟹猴中，通过更适度地降低β-羟基丁酸水平也实现了类似的血糖降低。SDZ-CPI-975不会增加心肌对葡萄糖的利用，这表明用SDZ-CPI-975抑制CPT I不会诱发心脏肥大。这与不可逆的CPT I抑制剂依托莫昔不同。这些结果表明，SDZ-CPI-975在两个物种中均有效抑制脂肪酸氧化并降低血糖水平。因此，CPT I的可逆抑制剂代表了一类新型的降血糖药物，它们抑制脂肪酸氧化而不诱发心脏肥大。
