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
Through high throughput screening and subsequent hit identification and optimization, we synthesized a series of 1-arylcarbonyl-6,7-dimethoxyisoquinoline derivatives as the first reported potent and reversible GFAT inhibitors. SAR studies of this class of compounds indicated significant impact on GFAT inhibition potency by substitutions on the A-ring and C-ring. The ketone group was found to be necessary for high potency. Compound 28 (RO0509347) demonstrated potent GFAT inhibition (IC(50)=1µM) with a desirable pharmacokinetic profile in rats, and showed significant efficacy in reducing the glucose excursion in an OGTT test in ob/ob mice.
Subject(s)
Drug Discovery , Enzyme Inhibitors/pharmacology , Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing)/antagonists & inhibitors , Isoquinolines/pharmacology , Inhibitory Concentration 50ABSTRACT
A series of N-benzoyl-4-[(2,6-dichlorobenzoyl)amino]-L-phenylalanine derivatives was prepared in order to optimize the substitution on the N-benzoyl moiety for VCAM/VLA-4 antagonist activity. Disubstitution in the 2- and 6-positions is favored and a range of small alkyl and halogen are tolerated. A model of the bioactive conformation of these compounds is proposed.
