Erion Mark D, Cable Edward E, Ito Bruce R, Jiang Hongjian, Fujitaki James M, Finn Patricia D, Zhang Bao-Hong, Hou Jinzhao, Boyer Serge H, van Poelje Paul D, Linemeyer David L
Metabasis Therapeutics, Inc., 11119 North Torrey Pines Road, La Jolla, CA 92037, USA.
Proc Natl Acad Sci U S A. 2007 Sep 25;104(39):15490-5. doi: 10.1073/pnas.0702759104. Epub 2007 Sep 18.
Despite efforts spanning four decades, the therapeutic potential of thyroid hormone receptor (TR) agonists as lipid-lowering and anti-obesity agents remains largely unexplored in humans because of dose-limiting cardiac effects and effects on the thyroid hormone axis (THA), muscle metabolism, and bone turnover. TR agonists selective for the TRbeta isoform exhibit modest cardiac sparing in rodents and primates but are unable to lower lipids without inducing TRbeta-mediated suppression of the THA. Herein, we describe a cytochrome P450-activated prodrug of a phosphonate-containing TR agonist that exhibits increased TR activation in the liver relative to extrahepatic tissues and an improved therapeutic index. Pharmacokinetic studies in rats demonstrated that the prodrug (2R,4S)-4-(3-chlorophenyl)-2-[(3,5-dimethyl-4-(4'-hydroxy-3'-isopropylbenzyl)phenoxy)methyl]-2-oxido-[1,3,2]-dioxaphosphonane (MB07811) undergoes first-pass hepatic extraction and that cleavage of the prodrug generates the negatively charged TR agonist (3,5-dimethyl-4-(4'-hydroxy-3'-isopropylbenzyl)phenoxy)methylphosphonic acid (MB07344), which distributes poorly into most tissues and is rapidly eliminated in the bile. Enhanced liver targeting was further demonstrated by comparing the effects of MB07811 with 3,5,3'-triiodo-l-thyronine (T(3)) and a non-liver-targeted TR agonist, 3,5-dichloro-4-(4-hydroxy-3-isopropylphenoxy)phenylacetic acid (KB-141) on the expression of TR agonist-responsive genes in the liver and six extrahepatic tissues. The pharmacologic effects of liver targeting were evident in the normal rat, where MB07811 exhibited increased cardiac sparing, and in the diet-induced obese mouse, where, unlike KB-141, MB07811 reduced cholesterol and both serum and hepatic triglycerides at doses devoid of effects on body weight, glycemia, and the THA. These results indicate that targeting TR agonists to the liver has the potential to lower both cholesterol and triglyceride levels with an acceptable safety profile.
尽管历经四十年的努力，但由于存在剂量限制的心脏效应以及对甲状腺激素轴（THA）、肌肉代谢和骨转换的影响，甲状腺激素受体（TR）激动剂作为降脂和抗肥胖药物在人类中的治疗潜力仍 largely 未被探索。对TRβ亚型具有选择性的TR激动剂在啮齿动物和灵长类动物中表现出适度的心脏保护作用，但在不诱导TRβ介导的THA抑制的情况下无法降低血脂。在此，我们描述了一种含膦酸酯的TR激动剂的细胞色素P450激活前药，其在肝脏中相对于肝外组织表现出增强的TR激活以及改善的治疗指数。大鼠的药代动力学研究表明，前药(2R,4S)-4-(3-氯苯基)-2-[(3,5-二甲基-4-(4'-羟基-3'-异丙基苄基)苯氧基)甲基]-2-氧化-[1,3,2]-二氧杂磷烷（MB07811）经历首过肝提取，并且前药的裂解产生带负电荷的TR激动剂(3,5-二甲基-4-(4'-羟基-3'-异丙基苄基)苯氧基)甲基膦酸（MB07344），其在大多数组织中分布不佳并在胆汁中迅速消除。通过比较MB07811与3,5,3'-三碘-L-甲状腺原氨酸（T(3)）以及一种非肝脏靶向的TR激动剂3,5-二氯-4-(4-羟基-3-异丙基苯氧基)苯乙酸（KB-141）对肝脏和六个肝外组织中TR激动剂反应性基因表达的影响，进一步证明了增强的肝脏靶向性。肝脏靶向的药理作用在正常大鼠中很明显，其中MB07811表现出增强的心脏保护作用，在饮食诱导的肥胖小鼠中也很明显，与KB-141不同，MB07811在不影响体重、血糖和THA的剂量下降低了胆固醇以及血清和肝脏甘油三酯。这些结果表明，将TR激动剂靶向肝脏有可能在可接受的安全性范围内降低胆固醇和甘油三酯水平。
