kb-141 and Dyslipidemias

Topics: Animals; Biomimetic Materials; Dyslipidemias; Humans; Hypothalamo-Hypophyseal System; Organ Specificity; Receptors, Thyroid Hormone; Thyroid Hormones

The aggressive reduction of LDL-cholesterol levels by treatment with statins is a key component of preventive cardiovascular care; however, additional therapies to prevent atherosclerosis and the associated clinical sequelae are still needed. Thyromimetic compounds selective for the liver or for the thyroid hormone receptor isoform beta1 constitute a novel approach for the treatment of dyslipidemia. In preclinical studies, selective thyromimetics significantly reduced plasma cholesterol levels and provided protection from atherosclerosis by upregulating the hepatic LDL receptor and promoting reverse cholesterol transport. Importantly, data from ongoing clinical trials have provided the first evidence that selective thyromimetics may also reduce the levels of plasma cholesterol in humans.

Topics: Acetates; Anilides; Animals; Anticholesteremic Agents; Arteriosclerosis; Atherosclerosis; Biological Transport; Biomimetics; Cholesterol, LDL; Clinical Trials as Topic; Dyslipidemias; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; Lipid Metabolism; Malonates; Molecular Structure; Organophosphonates; Phenols; Phenyl Ethers; Phenylacetates; Propionates; Pyridazines; Receptors, LDL; Thyroid Gland; Thyroid Hormones

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.

Topics: Animals; Bone Density; Clinical Trials as Topic; Drug Discovery; Dyslipidemias; Humans; Male; Mice; Mice, Inbred C57BL; Pyridazines; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; Thyroid Hormone Receptors beta; Uracil