Gribble A D, Ife R J, Shaw A, McNair D, Novelli C E, Bakewell S, Shah V P, Dolle R E, Groot P H, Pearce N, Yates J, Tew D, Boyd H, Ashman S, Eggleston D S, Haltiwanger R C, Okafo G
Departments of Medicinal Chemistry, SmithKline Beecham Pharmaceuticals Ltd, New Frontiers Science Park (North), Third Avenue, Harlow, Essex CM19 5AW, UK.
J Med Chem. 1998 Sep 10;41(19):3582-95. doi: 10.1021/jm980091z.
A series of (3R,5S)-omega-substituted-3-carboxy-3, 5-dihydroxyalkanoic acids have been synthesized and evaluated as inhibitors of the recombinant human form of ATP-citrate lyase. The best of these have Ki's in the 200-1000 nM range. As the corresponding thermodynamically favored gamma-lactone prodrugs, a number of compounds are able to inhibit cholesterol and fatty acid synthesis in HepG2 cells and reduce plasma triglyceride levels in vivo. The best of these, compound 77, is able to induce clear hypocholesterolemic and hypotriglyceridaemic responses when administered orally to rat and dog. These results provide evidence to support the hypothesis that compounds which inhibit ATP-citrate lyase have the potential to be a novel class of hypolipidemic agent, which possess combined hypocholesterolemic and hypotriglyceridemic activities.
一系列(3R,5S)-ω-取代-3-羧基-3,5-二羟基链烷酸已被合成并作为重组人ATP-柠檬酸裂解酶的抑制剂进行了评估。其中最佳的化合物的抑制常数（Ki）在200-1000 nM范围内。作为相应的热力学上有利的γ-内酯前药，许多化合物能够抑制HepG2细胞中的胆固醇和脂肪酸合成，并在体内降低血浆甘油三酯水平。其中最佳的化合物77，口服给予大鼠和狗时能够诱导明显的降胆固醇和降甘油三酯反应。这些结果提供了证据支持以下假设：抑制ATP-柠檬酸裂解酶的化合物有可能成为一类新型的降血脂药物，具有联合降胆固醇和降甘油三酯活性。
