Discovery and Preclinical Profile of ALG-055009, a Potent and Selective Thyroid Hormone Receptor Beta (THR-β) Agonist for the Treatment of MASH,Journal of Medicinal Chemistry

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Discovery and Preclinical Profile of ALG-055009, a Potent and Selective Thyroid Hormone Receptor Beta (THR-β) Agonist for the Treatment of MASH
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-09-02 , DOI: 10.1021/acs.jmedchem.4c01029
Koen Vandyck ₁ , David C McGowan ₁ , Xuan G Luong ₂ , Sarah K Stevens ₂ , Andreas Jekle ₂ , Kusum Gupta ₂ , Dinah L Misner ₂ , Sushmita Chanda ₂ , Vladimir Serebryany ₂ , Michael Welch ₂ , Haiyang Hu ₃ , Zhidan Lv ₃ , Caroline Williams ₂ , Klaus Maskos ₄ , Alfred Lammens ₄ , Antitsa D Stoycheva ₂ , Tse-I Lin ₁ , Lawrence M Blatt ₂ , Leonid N Beigelman ₂ , Julian A Symons ₂ , Pierre Raboisson ₂ , Jerome Deval ₂

Affiliation

Agonists of thyroid hormone receptor β (THR-β) decreased LDL cholesterol (LDL-C) and triglyceride (TG) levels in human clinical trials for patients with dyslipidemia. The authors present the highly potent and selective compound ALG-055009 (14) as a potential best in class THR-β agonist. The high metabolic stability and good permeability translated well in vivo to afford a long in vivo half-life pharmacokinetic profile with limited liability for DDI, and it overcomes certain drawbacks seen in recent clinical candidates.

中文翻译：

ALG-055009 的发现和临床前概况，ALG-055009 是一种用于治疗 MASH 的有效选择性甲状腺激素受体 β (THR-β) 激动剂

在针对血脂异常患者的人体临床试验中，甲状腺激素受体 β (THR-β) 激动剂可降低 LDL 胆固醇 (LDL-C) 和甘油三酯 (TG) 水平。作者提出了高效且选择性的化合物 ALG-055009 ( 14 ) 作为潜在的最佳 THR-β 激动剂。高代谢稳定性和良好的渗透性在体内转化良好，可提供较长的体内半衰期药代动力学特征，且 DDI 的责任有限，并且它克服了最近临床候选药物中发现的某些缺点。

更新日期：2024-09-02

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