Rotstein D M, Kertesz D J, Walker K A, Swinney D C
Syntex Research, Palo Alto, California 94304.
J Med Chem. 1992 Jul 24;35(15):2818-25. doi: 10.1021/jm00093a015.
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.
制备了抗真菌剂酮康唑（1）的四种立体异构体，并评估了它们对多种细胞色素P - 450酶的抑制选择性。在抑制参与类固醇生物合成的细胞色素P - 450方面，异构体之间观察到了很大的选择性差异，而在抑制与肝脏药物代谢相关的细胞色素方面，差异很小。顺式 -（2S，4R）异构体2对大鼠羊毛甾醇14α - 脱甲基酶最有效，（2S，4R）-2大于（2R，4S）-4远大于（2R，4R）-3 =（2S，4S）-5，对孕酮17α，20 - 裂解酶也最有效，（2S，4R）-2远大于（2S，4S）-5大于（2R，4R）-3 =（2R，4S）-4；而顺式 -（2R，4S）异构体4对胆固醇7α - 羟化酶更有效，（2R，4S）-4大于（2S，4S）-5大于（2R，4R）-3大于（2S，4R）-2；反式 -（2S，4S）异构体5对芳香化酶最有效，（2S，4R）-5远大于（2R，4R）-3 =（2R，4S）-4大于（2S，4R）-2。顺式 -（2S，4R）和反式 -（2R，4R）异构体2和3在抑制皮质类固醇11β - 羟化酶方面效力相当，且比它们的对映体更有效。在抑制胆固醇侧链裂解或异生素羟化酶方面观察到的选择性很小。这些数据表明，唑类对参与类固醇合成的细胞色素P - 450酶的亲和力高度依赖于整个分子的立体化学，而与药物代谢酶的结合是一个选择性较低的过程。
