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.
Subject(s)
Drug Discovery , Dyslipidemias/drug therapy , Pyridazines/chemical synthesis , Thyroid Hormone Receptors beta/agonists , Uracil/analogs & derivatives , Animals , Bone Density/drug effects , Clinical Trials as Topic , Humans , Male , Mice , Mice, Inbred C57BL , Pyridazines/metabolism , Pyridazines/pharmacology , Pyridazines/therapeutic use , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Uracil/chemical synthesis , Uracil/metabolism , Uracil/pharmacology , Uracil/therapeutic useABSTRACT
High throughput screening of the Roche compound collection led to the identification of diaminopyrroloquinazoline series as a novel class of PTP1B inhibitors. Structural modification of diaminopyrroloquinazoline series resulted in pyrido[2,3-d]pyrimidine-2,4-diamine series which was further optimized to give compounds 5 and 24 as potent, selective (except T-cell phosphatase) PTP1B inhibitors with good mouse PK properties.
Subject(s)
Diamines/pharmacology , Enzyme Inhibitors/pharmacology , Protein Tyrosine Phosphatase, Non-Receptor Type 1/antagonists & inhibitors , Pyrimidines/pharmacology , Animals , Diamines/chemical synthesis , Diamines/chemistry , Dose-Response Relationship, Drug , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemistry , Humans , Mice , Mice, Inbred C57BL , Molecular Structure , Protein Tyrosine Phosphatase, Non-Receptor Type 1/metabolism , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Structure-Activity RelationshipABSTRACT
This paper describes the lead optimization of a new series of potent, selective, orally bioavailable, brain-penetrant MCH-1 receptor antagonists. A major focus of the work was to achieve a selectivity profile appropriate for in vivo efficacy studies and safety.
