Stereoisomers of ketoconazole: preparation and biological activity.
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Rotstein DM, Kertesz DJ, Walker KA, Swinney DC
Stereoisomers of ketoconazole: preparation and biological activity.
J Med Chem. 1992 Jul 24;35(15):2818-25.
- PubMed ID
- 1495014 [ View in PubMed]
- Abstract
The four stereoisomers of the antifungal agent ketoconazole (1) were prepared and evaluated for their selectivity in inhibiting a number of cytochrome P-450 enzymes. Large differences in selectivity among the isomers were observed for inhibition of the cytochromes P-450 involved in steroid biosynthesis, whereas little differences was observed for inhibition of those associated with hepatic drug metabolism. The cis-(2S,4R) isomer 2 was the most effective against rat lanosterol 14 alpha-demethylase, (2S,4R)-2 greater than (2R,4S)-4 much greater than (2R,4R)-3 = (2S,4S)-5, and progesterone 17 alpha,20-lyase, (2S,4R)-2 much greater than (2S,4S)-5 greater than (2R,4R)-3 = (2R,4S)-4, whereas the cis-(2R,4S) isomer 4 was more effective against cholesterol 7 alpha-hydroxylase, (2R,4S)-4 greater than (2S,4S)-5 greater than (2R,4R)-3, greater than (2S,4R)-2, and the trans-(2S,4S) isomer 5 was the most effective against aromatase, (2S,4R)-5 much greater than (2R,4R)-3 = (2R,4S)-4 greater than (2S,4R)-2. The cis-(2S,4R) and trans-(2R,4R) isomers 2 and 3 are equipotent in inhibiting corticoid 11 beta-hydroxylase and much more effective than their antipodes. Little selectivity was observed for inhibition of cholesterol side chain cleavage or xenobiotic hydroxylase. These data indicate that the affinity of azoles for cytochrome P-450 enzymes involved in steroid synthesis is highly dependent on the stereochemistry of the entire molecule, whereas binding to drug metabolizing enzymes is a less selective process.
DrugBank Data that Cites this Article
- Drugs
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Levoketoconazole Cholesterol side-chain cleavage enzyme, mitochondrial Protein Humans YesInhibitorDetails Levoketoconazole Cytochrome P450 11B1, mitochondrial Protein Humans YesInhibitorDetails Levoketoconazole Cytochrome P450 11B2, mitochondrial Protein Humans YesInhibitorDetails Levoketoconazole Lanosterol 14-alpha demethylase Protein Humans NoInhibitorDetails Levoketoconazole Steroid 17-alpha-hydroxylase/17,20 lyase Protein Humans YesInhibitorDetails - Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Levoketoconazole Cytochrome P450 19A1 Protein Humans NoInhibitorDetails Levoketoconazole Cytochrome P450 7A1 Protein Humans NoInhibitorDetails Levoketoconazole Steroid 21-hydroxylase Protein Humans NoInhibitorDetails - Binding Properties
Drug Target Property Measurement pH Temperature (°C) Ketoconazole Cytochrome P450 3A4 IC 50 (nM) 1260 N/A N/A Details Ketoconazole Cytochrome P450 3A4 IC 50 (nM) 897 N/A N/A Details Ketoconazole Cytochrome P450 3A4 IC 50 (nM) 570 N/A N/A Details