Boyer Serge H, Jiang Hongjian, Jacintho Jason D, Reddy Mali Venkat, Li Haiqing, Li Wenyu, Godwin Jennifer L, Schulz William G, Cable Edward E, Hou Jinzhao, Wu Rongrong, Fujitaki James M, Hecker Scott J, Erion Mark D
Departments of Medicinal Chemistry and Biosciences, Metabasis Therapeutics, Inc., 11119 North Torrey Pines Road, La Jolla, California 92037, USA.
J Med Chem. 2008 Nov 27;51(22):7075-93. doi: 10.1021/jm800824d.
Phosphonic acid (PA) thyroid hormone receptor (TR) agonists were synthesized to exploit the poor distribution of PA-based drugs to extrahepatic tissues and thereby to improve the therapeutic index. Nine PAs showed excellent TR binding affinities (TRbeta(1), K(i) < 10 nM), and most of them demonstrated significant cholesterol lowering effects in a cholesterol-fed rat (CFR) model. Unlike the corresponding carboxylic acid analogue and T(3), PA 22c demonstrated liver-selective effects by inducing maximal mitochondrial glycerol-3-phosphate dehydrogenase activity in rat liver while having no effect in the heart. Because of the low oral bioavailability of PA 22c, a series of prodrugs was synthesized and screened for oral efficacy in the CFR assay. The liver-activated cyclic 1-(3-chlorophenyl)-1,3-propanyl prodrug (MB07811) showed potent lipid lowering activity in the CFR (ED(50) 0.4 mg/kg, po) and good oral bioavailability (40%, rat) and was selected for development for the treatment of hypercholesterolemia.
合成膦酸（PA）甲状腺激素受体（TR）激动剂是为了利用基于PA的药物在肝外组织中分布较少的特点，从而提高治疗指数。九种PA显示出优异的TR结合亲和力（TRβ(1)，K(i) < 10 nM），并且它们中的大多数在高胆固醇喂养大鼠（CFR）模型中表现出显著的降低胆固醇作用。与相应的羧酸类似物和T(3)不同，PA 22c通过诱导大鼠肝脏中最大的线粒体甘油-3-磷酸脱氢酶活性而表现出肝脏选择性作用，而对心脏无影响。由于PA 22c的口服生物利用度较低，合成了一系列前药并在CFR试验中筛选其口服疗效。肝脏激活的环状1-(3-氯苯基)-1,3-丙基前药（MB07811）在CFR中显示出强效的降脂活性（ED(50) 0.4 mg/kg，口服）和良好的口服生物利用度（40%，大鼠），并被选择用于开发治疗高胆固醇血症。
