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

• Published in: Journal of medicinal chemistry Vol. 57; no. 10; pp. 3912 - 3923
• Main Authors: Kelly, Martha J, Pietranico-Cole, Sherrie, Larigan, J. Douglas, Haynes, Nancy-Ellen, Reynolds, Charles H, Scott, Nathan, Vermeulen, John, Dvorozniak, Mark, Conde-Knape, Karin, Huang, Kuo-Sen, So, Sung-Sau, Thakkar, Kshitij, Qian, Yimin, Banner, Bruce, Mennona, Frank, Danzi, Sara, Klein, Irwin, Taub, Rebecca, Tilley, Jefferson
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 22.05.2014; Amer Chemical Soc
• Subjects: Animals; Bone Density - drug effects; Chemistry, Medicinal; Clinical Trials as Topic; Drug Discovery; Dyslipidemias - drug therapy; Humans; Life Sciences & Biomedicine; Male; Mice; Mice, Inbred C57BL; Pharmacology & Pharmacy; Pyridazines - chemical synthesis; Pyridazines - metabolism; Pyridazines - pharmacology; Pyridazines - therapeutic use; Rats; Rats, Sprague-Dawley; Science & Technology; Structure-Activity Relationship; Thyroid Hormone Receptors beta - agonists; Uracil - analogs & derivatives; Uracil - chemical synthesis; Uracil - metabolism; Uracil - pharmacology; Uracil - therapeutic use; LIPOPROTEIN; ACID; SERIES; CHOLESTEROL; LIGANDS; AFFINITY; ANALOGS; DISEASE; DERIVATIVES; THYROMIMETICS
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm4019299

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.