ABSTRACT
A series of triaryl pyrazoles were identified as potent pan antagonists for the retinoic acid receptors (RARs) α, ß and γ. X-ray crystallography and structure-based drug design were used to improve selectivity for RARγ by targeting residue differences in the ligand binding pockets of these receptors. This resulted in the discovery of novel antagonists which maintained RARγ potency but were greater than 500-fold selective versus RARα and RARß. The potent and selective RARγ antagonist LY2955303 demonstrated good pharmacokinetic properties and was efficacious in the MIA model of osteoarthritis-like joint pain. This compound demonstrated an improved margin to RARα-mediated adverse effects.
Subject(s)
Drug Design , Osteoarthritis/drug therapy , Pain/drug therapy , Piperazines/pharmacology , Pyrazoles/pharmacology , Receptors, Retinoic Acid/antagonists & inhibitors , Dose-Response Relationship, Drug , Humans , Models, Molecular , Molecular Structure , Piperazines/chemical synthesis , Piperazines/chemistry , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Structure-Activity Relationship , Retinoic Acid Receptor gammaABSTRACT
The design, synthesis, and structure activity relationships for a novel series of indoles as potent, selective, thyroid hormone receptor ß (TRß) agonists is described. Compounds with >50× binding selectivity for TRß over TRα were generated and evaluation of compound 1c from this series in a model of dyslipidemia demonstrated positive effects on plasma lipid endpoints in vivo.
Subject(s)
Acetates/pharmacology , Drug Design , Indoles/pharmacology , Thyroid Hormone Receptors beta/agonists , Acetates/chemical synthesis , Acetates/chemistry , Dose-Response Relationship, Drug , Humans , Indoles/chemical synthesis , Indoles/chemistry , Models, Molecular , Molecular Structure , Structure-Activity RelationshipABSTRACT
The matrix metalloproteinase enzyme MMP-13 plays a key role in the degradation of type II collagen in cartilage and bone in osteoarthritis (OA). An effective MMP-13 inhibitor would therefore be a novel disease modifying therapy for the treatment of arthritis. Our efforts have resulted in the discovery of a series of carboxylic acid inhibitors of MMP-13 that do not significantly inhibit the related MMP-1 (collagenase-1) or tumor necrosis factor-alpha (TNF-alpha) converting enzyme (TACE). It has previously been suggested (but not proven) that inhibition of the latter two enzymes could lead to side effects. A promising carboxylic acid lead 9 was identified and a convergent synthesis developed. This paper describes the optimization of 9 and the identification of a compound 24f for further development. Compound 24f is a subnanomolar inhibitor of MMP-13 (IC(50) value 0.5 nM and K(i) of 0.19 nM) having no activity against MMP-1 or TACE (IC(50) of >10000 nM). Furthermore, in a rat model of MMP-13-induced cartilage degradation, 24f significantly reduced proteoglycan release following oral dosing at 30 mg/kg (75% inhibition, p < 0.05) and at 10 mg/kg (40% inhibition, p < 0.05).
Subject(s)
Cartilage/drug effects , Matrix Metalloproteinase Inhibitors , Piperidines/pharmacology , Protease Inhibitors/chemical synthesis , Sulfonamides/pharmacology , Animals , Cartilage/metabolism , Cattle , Collagen Type II/metabolism , Crystallography, X-Ray , Inhibitory Concentration 50 , Piperidines/administration & dosage , Piperidines/chemical synthesis , Piperidines/pharmacokinetics , Protease Inhibitors/administration & dosage , Protease Inhibitors/pharmacokinetics , Protease Inhibitors/pharmacology , Proteoglycans/metabolism , Rats , Structure-Activity Relationship , Sulfonamides/administration & dosage , Sulfonamides/chemical synthesis , Sulfonamides/pharmacokineticsABSTRACT
Syntheses and SAR studies of 3,3-bisaryloxindole analogues provided potent mineralocorticoid receptor (MR) antagonists that were selective over other steroid nuclear hormone receptors.
