RESUMO
Molecular docking studies were performed on 18 17ß-carboxamide steroids in order to select compounds with potential local anti-inflammatory activity. These derivatives are amides of cortienic acids (obtained from hydrocortisone, prednisolone, and methylprednisolone) with methyl or ethyl esters of six amino acids. Interactions with the glucocorticoid receptor (GR), binding energies and ligand efficiency values of these compounds were compared with dexamethasone and cortienic acid obtained from prednisolone (inactive metabolite). On the basis of molecular docking studies, seven compounds were selected and their binding affinities for the GR were predicted by use of the exponential model created in this study. Subsequently, selected compounds were synthesized in good yields by use of modified N,N'-dicyclohexylcarbodiimide (DCC)/1-hydroxybenzotriazole (HOBt) coupling procedure. Finally, the local anti-inflammatory activity of the synthesized compounds was examined by use of the croton oil-induced ear edema test. In vivo evaluation of systemic side effects as well as in silico prediction of metabolism were performed on the derivative with the best local anti-inflammatory activity. The combination of molecular docking studies and the exponential model for the GR binding affinity prediction could be used as an in silico tool for the rational design of novel 17ß-carboxamide steroids with potentially better biological profile than dexamethasone.
Assuntos
Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacologia , Desenho de Fármacos , Edema/prevenção & controle , Glucocorticoides/síntese química , Glucocorticoides/farmacologia , Inflamação/prevenção & controle , Animais , Anti-Inflamatórios/metabolismo , Biotransformação , Óleo de Cróton , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Edema/induzido quimicamente , Glucocorticoides/metabolismo , Hidrocortisona/análogos & derivados , Hidrocortisona/síntese química , Hidrocortisona/metabolismo , Hidrocortisona/farmacologia , Inflamação/induzido quimicamente , Ligantes , Metilprednisolona/análogos & derivados , Metilprednisolona/síntese química , Metilprednisolona/metabolismo , Metilprednisolona/farmacologia , Modelos Biológicos , Simulação de Acoplamento Molecular , Estrutura Molecular , Prednisolona/análogos & derivados , Prednisolona/síntese química , Prednisolona/metabolismo , Prednisolona/farmacologia , Ratos , Receptores de Glucocorticoides/efeitos dos fármacos , Receptores de Glucocorticoides/metabolismo , Relação Estrutura-AtividadeRESUMO
The metabolic stability of benzoxazinone derivatives, a potent series of NPY Y5 antagonists, has been investigated. This study resulted in the identification of the structural moieties prone to metabolic transformations and which strongly influenced the in vitro half-life. This provides opportunities to optimize the structure of this new class of NPY Y5 antagonists.