Inhibitors of steroidal cytochrome p450 enzymes as targets for drug development

A simple route for improving the potency of progesterone as a modulator of P-gp-mediated multidrug resistance was established by esterification or etherification of hydroxylated 5α/β-pregnane-3,20-dione or 5β-cholan-3-one precursors. X-ray crystallography of representative 7α-, 11α-, and 17α-(2'R/S)-O-tetrahydropyranyl ether diastereoisomers revealed different combinations of axial-equatorial configurations of the anomeric oxygen. Substantial stimulation of accumulation and chemosensitization was observed on K562/R7 erythroleukemia cells resistant to doxorubicin, especially using 7α,11α-O-disubstituted derivatives of 5α/β-pregnane-3,20-dione, among which the 5β-H-7α-benzoyloxy-11α-(2'R)-O-tetrahydropyranyl ether 22a revealed promising properties (accumulation index , IC50 μM versus and μM for progesterone), slightly overcoming those of verapamil and cyclosporin A. Several 7α,12α-O-disubstituted derivatives of 5β-cholan-3-one proved even more active, especially the 7α-O-methoxymethyl-12α-benzoate 56 (accumulation index , IC50 μM). The panel of modulating effects from different O-substitutions at a same position suggests a structural influence of the substituent completing a simple protection against stimulating effects of hydroxyl groups on P-gp-mediated transport.

Inhibitors of steroidal cytochrome p450 enzymes as targets for drug development

inhibitors of steroidal cytochrome p450 enzymes as targets for drug development

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inhibitors of steroidal cytochrome p450 enzymes as targets for drug developmentinhibitors of steroidal cytochrome p450 enzymes as targets for drug developmentinhibitors of steroidal cytochrome p450 enzymes as targets for drug developmentinhibitors of steroidal cytochrome p450 enzymes as targets for drug developmentinhibitors of steroidal cytochrome p450 enzymes as targets for drug development

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