Aromatase inhibitors: synthesis, biological activity, and structure of 1,2-imidazolylmethylcyclopentanol derivatives.
Two series of 1,2-disubstituted imidazolylmethylcyclopentanol derivatives (5a-d, 10a-d) were prepared by using easily available methyl 2-oxocyclopentanecarboxylate as the starting material. Evaluation of the aromatase inhibitory activities in vitro was performed. Their activities were compared with those of a steroidal aromatase inhibitor, Formestane, and a non-steroidal inhibitor, Fadrozole. Among these compounds, the aromatase inhibitory activities of 5d, 10a, 10b, 10c, 11a, 15a, and 15b were more potent than Formestane. One compound, 1-(4-chlorobenzyl)-cis-2-(1H-imidazol-1-ylmethyl)cyclopentanol+  ++ (10a) was in particular identified as a potent aromatase inhibitor in vitro, exhibiting an IC50 value of 4 x 10(-8)M. The enantiomers of 10a were separated, and their absolute configuration were determined by X-ray crystallography.
Kato
A
A
Biomedical Research Laboratories, Kureha Chemical Industry Co. Ltd., Tokyo, Japan.
Ikeda
Y
Y
Sugita
N
N
Nitta
T
T
Enari
H
H
Kashima
A
A
Konno
M
M
Niimura
K
K
D000735:Androstenedione / Q000031:analogs & derivatives / Q000494:pharmacology; D047072:Aromatase Inhibitors; D018360:Crystallography, X-Ray; D003517:Cyclopentanes / Q000138:chemical synthesis* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D010920:Placenta / Q000187:drug effects / Q000201:enzymology; D011247:Pregnancy
D047072:Aromatase Inhibitors; D003517:Cyclopentanes; D004791:Enzyme Inhibitors; D000735:Androstenedione; C014594:formestane