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

  • J Med Chem. 2024 Sep 12;67(17):14840-14851. 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
Affiliations
  • 1. Aligos Belgium BV, Gaston Geenslaan 1, 3001 Leuven, Belgium.
  • 2. Aligos Therapeutics, Incorporated, 1 Corporate Drive, South San Francisco, California 94080, United States.
  • 3. Pharmaron, 6 Taihe Road, BDA, Beijing, 100176, P. R. China.
  • 4. Proteros Biostructures GmbH, Bunsenstraße 7a, 82152 Planegg-Martinsried, Germany.
PMID: 39221768 DOI: 10.1021/acs.jmedchem.4c01029
Abstract

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.

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