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
MGL-3196 is an oral, liver-targeted selective agonist for the thyroid hormone receptor-ß (THR-ß) that is being developed for the treatment of dyslipidemia. The safety profile and tolerability of THR-ß agonist MGL-3196 was assessed in first-in humans studies, including a single ascending dose study (NCT01367873) in which MGL-3196 appeared safe at all doses tested. A two-week multiple dose study was conducted at doses of 5, 20, 50, 80, 100, and 200 mg per day in healthy subjects with mildly elevated low density lipoprotein (LDL) cholesterol (>110 mg/dL) (NCT01519531). MGL-3196 was well-tolerated at all doses with no dose-related adverse events or liver enzyme, ECG or vital-sign changes. At the highest dose, there was a reversible reduction of â¼20% in the level of pro-hormone, free thyroxine (free T4) that was significantly different from placebo (p < 0.0001) that may be explained by increased hepatic metabolism of T4. There was no change in thyrotropin (TSH) or triiodothyronine (free T3) or other evidence of central thyroid axis dysfunction at any dose. Doses ranging from 50 to 200 mg demonstrated highly statistically significant reductions relative to placebo of up to: 30% for LDL cholesterol (range, p = 0.05-<0.0001); 28% for non- high density lipoprotein (HDL) cholesterol (range, p = 0.027-0.0001); 24% for Apolipoprotein B (range, p = 0.008-0.0004), and statistical trends of up to 60% reduction in triglycerides (TG) (range, p = 0.13-0.016). The near maximal lipid effects were observed at a dose of 80 mg daily. In summary, in a two-week study in healthy volunteers with mild LDL cholesterol elevation, MGL-3196 appeared safe, was well-tolerated and showed a beneficial effect on lipid parameters.
Subject(s)
Hypercholesterolemia/drug therapy , Liver/drug effects , Pyridazines/pharmacokinetics , Thyroid Gland/drug effects , Thyroid Hormone Receptors beta/agonists , Uracil/analogs & derivatives , Adult , Body Mass Index , Cholesterol, LDL/blood , Dose-Response Relationship, Drug , Double-Blind Method , Drug Administration Schedule , Female , Healthy Volunteers , Humans , Liver/metabolism , Male , Middle Aged , Patient Safety , Pyridazines/adverse effects , Pyridazines/chemistry , Thyroid Gland/metabolism , Thyrotropin/blood , Thyroxine/blood , Time Factors , Triiodothyronine/blood , Uracil/adverse effects , Uracil/chemistry , Uracil/pharmacokineticsABSTRACT
The synthesis and optimization of a series of orally bioavailable 1-(1H-indol-4-yl)-3,5-disubstituted benzene analogues as antimitotic agents are described. A functionalized dibromobenzene intermediate was used as a key scaffold, which when modified by sequential Suzuki coupling and Buchwald-Hartwig amination provided a flexible entry to 1,3,5-trisubstituted phenyl compounds. A 1H-indol-4-yl moiety at the 1-position was determined to be a critical feature for optimal potency. The compounds have been shown to induce cell cycle arrest at the G2/M phase and demonstrate efficacy in both cell viability and cell proliferation assays. The primary site of action for these agents is revealed by their colchicine competitive inhibition of tubulin polymerization, and a computational model has been developed for the association of these compounds to tubulin. An optimized lead LP-261 significantly inhibits growth of a human non-small-cell lung tumor (NCI-H522) in a mouse xenograft model.
Subject(s)
Indoles/chemical synthesis , Isonicotinic Acids/chemical synthesis , Sulfonamides/chemical synthesis , Tubulin Modulators/chemical synthesis , Animals , Biological Availability , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Colchicine/chemistry , Drug Screening Assays, Antitumor , G2 Phase , Humans , Indoles/chemistry , Indoles/pharmacology , Isonicotinic Acids/chemistry , Isonicotinic Acids/pharmacology , Mice , Mice, Nude , Models, Molecular , Neoplasm Transplantation , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/pharmacology , Transplantation, Heterologous , Tubulin/chemistry , Tubulin Modulators/chemistry , Tubulin Modulators/pharmacologyABSTRACT
Two new classes of diphenylether inhibitors of p38alpha MAP kinase are described. Both chemical classes are based on a common diphenylether core that is identified by simulated fragment annealing as one of the most favored chemotypes within a prominent hydrophobic pocket of the p38alpha ATP-binding site. In the fully elaborated molecules, the diphenylether moiety acts as an anchor occupying the deep pocket, while polar extensions make specific interactions with either the adenine binding site or the phosphate binding site of ATP. The synthesis, crystallographic analysis, and biological activity of these p38alpha inhibitors are discussed.
