Design, Synthesis, and Local Anti‐Inflammatory Activity of 17β‐Carboxamide Derivatives of Glucocorticoids

Abstract

Molecular docking studies were performed on 18 17β-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 17β-carboxamide steroids with potentially better biological profile than dexamethasone.

Evaluation of Biological Activity and Computer‐Aided Design of New Soft Glucocorticoids

“…Chemical structures, maximal edema inhibition (MEI), and half maximal effective concentrations (EC 50 ) of 17β‐carboxamide steroids tested in this study are presented in Table . Results for HG, PG, MPG, MPA, MPEA, PEA, PP, DF, and dexamethasone were taken from our previously published papers . EC 50 values could not be calculated for HEA, HP, PA, PP, MPEG, MPP, DEA, and DF due to insufficiently steep increase in the ascending part of corresponding edema inhibition versus concentration graph (Supporting Information Figs.…”

“…According to presented results, all tested 17β‐carboxamide steroids possess local anti‐inflammatory activity. This could be expected because derivatives of selected amino acids (L‐glycine, L‐alanine, and L‐phenylalanine) were docked into the ligand binding pocket of the GR similarly to dexamethasone . MPG, MPEA, BG, and BEG have higher, whereas other compounds have similar or slightly lower MEI than dexamethasone.…”

“…Systemic side effects were evaluated on the basis of the thymus and spleen mass decreases after prolonged application (5 days) of selected derivatives in comparison to dexamethasone (Table ). Results for MPEA and dexamethasone were taken from our previously published paper .…”

“…However, ten times higher concentrations of MPEA, BEG, and BG (7.20, 10.10, and 23.90 µM, respectively) did not cause significantly different thymus and spleen mass decreases in comparison to dexamethasone. Lower applied concentrations (due to lower EC 50 values) and expected skin permeability of these derivatives , as well as low predicted glucocorticoid activity of the major expected metabolite of these compounds should significantly contribute to lower systemic side effects of tested 17β‐carboxamide steroids in comparison to dexamethasone.…”

“…Additionally, low systemic side effects of the compound with the best local anti‐inflammatory activity was observed, which could be explained by expected pharmacokinetic (skin permeability) and pharmacodynamic properties of the major predicted metabolite. Therefore, these compounds can be classified as potential soft glucocorticoids . Finally, 15 more derivatives were synthesized.…”