920509-16-6Relevant articles and documents
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
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
, p. 3912 - 3923 (2014/06/09)
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.
