The beneficial effects of thyroid hormone (TH) on lipid levels are primarily due to its action at the thyroid hormone receptor β (THR-β) in the liver, while adverse effects, including cardiac effects, are mediated by thyroid hormone receptor α (THR-α). A pyridazinone series has been identified that is significantly more THR-β selective than earlier analogues. Optimization of this series by the addition of a cyanoazauracil substituent improved both the potency and selectivity and led to MGL-3196 (53), which is 28-fold selective for THR-β over THR-α in a functional assay. Compound 53 showed outstanding safety in a rat heart model and was efficacious in a preclinical model at doses that showed no impact on the central thyroid axis. In reported studies in healthy volunteers, 53 exhibited an excellent safety profile and decreased LDL cholesterol (LDL-C) and triglycerides (TG) at once daily oral doses of 50 mg or higher given for 2 weeks.

中文翻译：

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发现2- [3,5-二氯-4-（5-异丙基-6-氧代-1,6-二氢哒嗪-3-基氧基）苯基] -3,5-二氧代-2,3,4,5-四氢[1,2,4]三嗪-6-腈（MGL-3196）是一种用于治疗血脂异常的高选择性甲状腺激素受体β激动剂。

甲状腺激素（TH）对脂质水平的有益作用主要是由于其对肝脏中甲状腺激素受体β（THR-β）的作用，而不良反应（包括心脏作用）是由甲状腺激素受体α（THR）介导的-α）。已鉴定出比以前的类似物显着更高的THR-β选择性的哒嗪酮系列。通过添加氰基氮脲嘧啶取代基对该系列进行优化可提高效能和选择性，并导致MGL-3196（53），在功能测定中，其对THR-β的选择性是对THR-α的28倍。化合物53在大鼠心脏模型中显示出出色的安全性，并且在临床前模型中以对甲状腺中央轴无影响的剂量有效。在针对健康志愿者的报道研究中，