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 ß agonist in clinical trials for the treatment of dyslipidemia.
J Med Chem
; 57(10): 3912-23, 2014 May 22.
Article
em En
| MEDLINE
| ID: mdl-24712661
ABSTRACT
The beneficial effects of thyroid hormone (TH) on lipid levels are primarily due to its action at the thyroid hormone receptor ß (THR-ß) 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-ß 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-ß 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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Piridazinas
/
Uracila
/
Receptores beta dos Hormônios Tireóideos
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Dislipidemias
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Descoberta de Drogas
Limite:
Animals
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Humans
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Male
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article