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

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...

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Published in:Journal of medicinal chemistry 2014-05, Vol.57 (10), p.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: Article
Language:English
Subjects:
Animals
Bone Density - drug effects
Clinical Trials as Topic
Drug Discovery
Dyslipidemias - drug therapy
Humans
Male
Mice
Mice, Inbred C57BL
Pyridazines - chemical synthesis
Pyridazines - metabolism
Pyridazines - pharmacology
Pyridazines - therapeutic use
Rats
Rats, Sprague-Dawley
Structure-Activity Relationship
Thyroid Hormone Receptors beta - agonists
Uracil - analogs & derivatives
Uracil - chemical synthesis
Uracil - metabolism
Uracil - pharmacology
Uracil - therapeutic use
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm4019299