Discovery of 2-[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yloxy)phenyl]-3,5-dioxo-2,3,4,5-tetrahydro[1,2,4]triazine-6-carbonitrile (MGL-3196), a Highly Selective Thyroid Hormone Receptor β agonist in clinical trials for the treatment of dyslipidemia

  • J Med Chem. 2014 May 22;57(10):3912-23. doi: 10.1021/jm4019299.
Martha J Kelly  1 ,  Sherrie Pietranico-Cole ,  J Douglas Larigan ,  Nancy-Ellen Haynes ,  Charles H Reynolds ,  Nathan Scott ,  John Vermeulen ,  Mark Dvorozniak ,  Karin Conde-Knape ,  Kuo-Sen Huang ,  Sung-Sau So ,  Kshitij Thakkar ,  Yimin Qian ,  Bruce Banner ,  Frank Mennona ,  Sara Danzi ,  Irwin Klein ,  Rebecca Taub ,  Jefferson Tilley
Affiliations
  • 1. Madrigal Pharmaceuticals, Inc. , Fort Washington, Pennsylvania 19034, United States.
PMID: 24712661 DOI: 10.1021/jm4019299
Abstract

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.

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