ABSTRACT
Synthesis and structure-activity relationship (SAR) of a series of alkyl and cycloalkyl containing non-steroidal dissociated glucocorticoid receptor (GR) agonists is reported. This series of compounds was identified as part of an effort to replace the CF3 group in a scaffold represented by 1a. The study culminated in the identification of compound 14, a t-butyl containing derivative, which has shown potent activity for GR, selectivity against the progesterone receptor (PR) and the mineralocorticoid receptor (MR), in vitro anti-inflammatory activity in an IL-6 transrepression assay, and dissociation in a MMTV transactivation counter-screen. In a collagen-induced arthritis mouse model, 14 displayed prednisolone-like efficacy, and lower impact on body fat and free fatty acids than prednisolone at an equivalent anti-inflammatory dose.
Subject(s)
Drug Discovery , Glucocorticoids/chemical synthesis , Methanol/chemistry , Receptors, Glucocorticoid/agonists , Animals , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Arthritis/drug therapy , Binding Sites , Disease Models, Animal , Dose-Response Relationship, Drug , Glucocorticoids/chemistry , Glucocorticoids/pharmacology , Humans , Inhibitory Concentration 50 , Methanol/chemical synthesis , Methanol/pharmacology , Mice , Models, Molecular , Molecular Structure , Prednisolone/chemistry , Prednisolone/pharmacology , Protein Binding/drug effects , Rats , Rats, Sprague-DawleyABSTRACT
Integration of computational methods, X-ray crystallography, and structure-activity relationships will be disclosed, which lead to a new class of p38 inhibitors that bind to p38 MAP kinase in a Phe out conformation.