Mueller Ralf, Yang Jing, Duan Caiming, Pop Emil, Geoffroy Otto J, Zhang Lian Hao, Huang Tian-Bao, Denisenko Sergey, McCosar Bruce H, Oniciu Daniela C, Bisgaier Charles L, Pape Michael E, Freiman Catherine Delaney, Goetz Brian, Cramer Clay T, Hopson Krista L, Dasseux Jean-Louis H
Alchem Laboratories Corporation, 13305 Rachael Boulevard, Alachua, Florida 32615, USA.
J Med Chem. 2004 Nov 18;47(24):6082-99. doi: 10.1021/jm040006p.
Keto-substituted hydrocarbons with 11-19 methylene and bis-terminal hydroxyl and carboxyl groups have been synthesized and evaluated in both in vivo and in vitro assays for their potential to favorably alter lipid disorders including metabolic syndrome. Compounds were assessed for their effects on the de novo incorporation of radiolabeled acetate into lipids in primary cultures of rat hepatocytes as well as for their effects on lipid and glycemic variables in obese female Zucker fatty rats [Crl:(ZUC)-faBR] following 1 and 2 weeks of oral administration. The most active compounds were found to be symmetrical with four to five methylene groups separating the central ketone functionality and the gem dimethyl or methyl/aryl substituents. Furthermore, biological activity was found to be greatest in both in vivo and in vitro assays for the tetramethyl-substituted keto diacids and diols (e.g., 10c, 10g, 14c), and the least active were shown to be the bis(arylmethyl) derivatives (e.g., 10e, 10f, 14f). Compound 14c dose-dependently elevated HDL-cholesterol, reduced triglycerides, and reduced NEFA, with a minimum effective dose of 30 mg/kg/day. Compound 1 g dose-dependently modified non-HDL-cholesterol, triglycerides, and nonesterified fatty acids, with a minimum effective dose of 10 mg/kg/day. At this dose, compound 10g elevated HDL-cholesterol levels 2-3 times higher than pretreatment levels, and a dose-dependent reduction of fasting insulin and glucose levels was observed.
已合成了具有11至19个亚甲基以及双末端羟基和羧基的酮取代烃，并在体内和体外试验中评估了它们对包括代谢综合征在内的脂质紊乱产生有利改变的潜力。在大鼠肝细胞原代培养物中，评估了这些化合物对放射性标记乙酸从头掺入脂质的影响，以及在肥胖雌性Zucker脂肪大鼠[Crl:(ZUC)-faBR]口服给药1周和2周后，对脂质和血糖变量的影响。发现最具活性的化合物是对称的，中心酮官能团与偕二甲基或甲基/芳基取代基之间有四到五个亚甲基。此外，在体内和体外试验中，发现四甲基取代的酮二酸和二醇（例如10c、10g、14c）的生物活性最高，而双（芳基甲基）衍生物（例如10e、10f、14f）的活性最低。化合物14c剂量依赖性地升高高密度脂蛋白胆固醇、降低甘油三酯和非酯化脂肪酸，最小有效剂量为30mg/kg/天。化合物1g剂量依赖性地改变非高密度脂蛋白胆固醇、甘油三酯和非酯化脂肪酸，最小有效剂量为10mg/kg/天。在此剂量下，化合物10g使高密度脂蛋白胆固醇水平比预处理水平升高2至3倍，并且观察到空腹胰岛素和血糖水平呈剂量依赖性降低。
