RESUMO
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.
Assuntos
Descoberta de Drogas , Glucocorticoides/síntese química , Metanol/química , Receptores de Glucocorticoides/agonistas , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Artrite/tratamento farmacológico , Sítios de Ligação , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Glucocorticoides/química , Glucocorticoides/farmacologia , Humanos , Concentração Inibidora 50 , Metanol/síntese química , Metanol/farmacologia , Camundongos , Modelos Moleculares , Estrutura Molecular , Prednisolona/química , Prednisolona/farmacologia , Ligação Proteica/efeitos dos fármacos , Ratos , Ratos Sprague-DawleyRESUMO
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.
