Reversible inhibition of human placental microsomal aromatase by CGS 18320B and other non-steroidal compounds.
The effect of bis-(p-cyanophenyl)imidazo-1-yl-methane hemisuccinate (CGS 18320B) and other non-steroidal compounds on the aromatization of androstenedione by human placental microsomal aromatase was studied. CGS 18320B exhibited competitive inhibition with an apparent Ki of 0.16 nM, a 90 and 3800-fold increase in affinity compared to 4-hydroxyandrostenedione and amino-glutethimide, respectively. The inhibition is not time-dependent, indicating that the active site interaction is reversible. CGS 18230B showed a two-fold increased affinity as compared to 4-(5,6,7,8-tetrahydroimidazo[1,5a]pyridin-5-yl)benzonitrile (CGS 16949A) and cis-1-[(4-[(1-imidazoyl)methyl]cyclohexyl)methyl]-imidazole succinate (CGS 14796C) which showed Ki values of 0.35 and 0.39 4M, respectively. 1-[2-[1-(4-carboxyphenyl)-3-ureido]ethyl]-2-(4-pyridyl)-2-imidazoline monohydrochloride (CGP 15720A) showed negligible inhibition.
Bullion
K A
KA
Endocrine Biochemistry Department, Medical Foundation of Buffalo, Inc., New York 14203.
Osawa
Y
Y
Braun
D G
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D000735:Androstenedione / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D047072:Aromatase Inhibitors; D001665:Binding Sites; D001667:Binding, Competitive; D017316:Fadrozole; D005260:Female; D005984:Glutethimide / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007700:Kinetics; D008861:Microsomes / Q000201:enzymology; D015394:Molecular Structure; D009570:Nitriles / Q000494:pharmacology; D010920:Placenta / Q000201:enzymology* / Q000648:ultrastructure; D011247:Pregnancy
D047072:Aromatase Inhibitors; D007093:Imidazoles; D009570:Nitriles; C064306:CGS 18320B; D000735:Androstenedione; D005984:Glutethimide; D017316:Fadrozole; C014594:formestane