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

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.

Thyromimetics as emerging therapeutic agents for nonalcoholic steatohepatitis: rationale for the development of resmetirom (MGL-3196)

“…Resmetirom is an orally active agonist of THR that is liverdirected with a 28-fold more selectivity than triiodothyronine (T3) for THR-β than THR-α [12]. A recent phase 2b trial randomized patients with biopsy-proven NASH to resmetirom (n = 84) or placebo (n = 41) in a 2:1 ratio [13].…”

Molecular functions and clinical impact of thyroid hormone-triggered autophagy in liver-related diseases

“…More recently, two liver-directed THRB selective agonists, MGL-3196 and VK2809, have been developed [160,161]. Results from phase II trials showed preventive effects on NAFLD accompanied by a decrease in serum levels of LDL cholesterol and triglycerides as well as hepatic lipids with none of the side-effects of the thyroid hormone axis.…”

Review article: the impact of liver‐directed therapies on the atherogenic risk profile in non‐alcoholic steatohepatitis

“…Resmetirom (MGL-3196) is a highly selective thyroid hormone receptor β (THRβ) agonist. 157 THRβ-selective agonism is hypothesised to elicit the beneficial effects on dyslipidaemia without eliciting the adverse effects of thyroid hormone receptor α agonism in heart and bone. In a Phase 1 study, MGL-3196 dosed at 50 mg per day or higher for 2 weeks significantly reduced LDL-C by 30% and showed a trend for decreased TG.…”