Journal of Medicinal Chemistry p. 2818 - 2825 (1992)
Update date:2022-08-03
Topics:
Rotstein
Kertesz
Walker
Swinney
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 14α-demethylase, (2S,4R)-2 > (2R,4S)-4 >> (2R,4R)-3 = (2S,4S)-5, and progesterone 17α,20-lyase, (2S,4R)-2 >> (2S,4S)-5 > (2R,4R)-3 = (2R,4S)-4, whereas the cis-(2R,4S) isomer 4 was more effective against cholesterol 7α-hydroxylase, (2R,4S)-4 > (2S,4S)-5 > (2R,4R)-3 > (2S,4R)-2, and the trans-(2S,4S) isomer 5 was the most effective against aromatase, (2S,4R)-5 >> (2R,4R)-3 = (2R,4S)-4 > (2S,4R)-2. The cis- (2S,4R) and trans-(2R,4R) isomers 2 and 3 are equipotent in inhibiting corticoid 11β-hydroxylase and much more effective than their antipodes. Little selectivity was observed for inhibition of cholesterol side chain cleavage or xenobiotic hydroxylases. 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.
View MoreWuhan Sunrise Pharmaceutical Technology Co., Ltd
Contact:+86-27-83314682
Address:Room 340, New material Industrial base No.17, Gu Tian Five Lu , Qiaokou District, Wuhan , China
website:http://www.shengmaochem.com
Contact:86-27-82853423, 82819281
Address:Rm 202, A Unit Huaqiao Building No. 2, Lihuangpi Road, Wuhan, China
MedicalChem(Yancheng)Manuf.Co.,Ltd.
Contact:+86-515-84383366
Address:Touzeng BinHai, YanCheng City, JiangSu Province, China
Contact:0086-357-6662688
Address:Zhaocheng town, Hongtong County, Linfen City, Shanxi Province
Ningbo Hi-tech Zone Nice-Synth Chemical Industry Ltd.
Contact:+86-(574)-81110986
Address:No. 1210, Building 3, Wante Business Centre, Hi-tech Zone, Ningbo
Doi:10.1002/chem.201202345
(2012)Doi:10.3762/bjoc.8.220
(2012)Doi:10.1021/jm301677r
(2013)Doi:10.1021/ol400099h
(2013)Doi:10.1021/ol303497q
(2013)Doi:10.1016/j.bmc.2011.05.064
(2011)