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 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.
Madrigal Pharmaceuticals, Inc. , Fort Washington, Pennsylvania 19034, United States.
Martha J
MJ
Kelly
Sherrie
S
Pietranico-Cole
J Douglas
JD
Larigan
Nancy-Ellen
NE
Haynes
Charles H
CH
Reynolds
Nathan
N
Scott
John
J
Vermeulen
Mark
M
Dvorozniak
Karin
K
Conde-Knape
Kuo-Sen
KS
Huang
Sung-Sau
SS
So
Kshitij
K
Thakkar
Yimin
Y
Qian
Bruce
B
Banner
Frank
F
Mennona
Sara
S
Danzi
Irwin
I
Klein
Rebecca
R
Taub
Jefferson
J
Tilley
D000818:Animals; D015519:Bone Density / Q000187:drug effects; D002986:Clinical Trials as Topic; D055808:Drug Discovery; D050171:Dyslipidemias / Q000188:drug therapy*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011724:Pyridazines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D037042:Thyroid Hormone Receptors beta / Q000819:agonists*; D014498:Uracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use
D011724:Pyridazines; D037042:Thyroid Hormone Receptors beta; D014498:Uracil; C588408:resmetirom