Aromatase Inhibitors : Synthesis, Biological Activity, and Structure of 1, 2-Imidazolylmethylcyclopentanol Derivatives

• Published in: Chemical & pharmaceutical bulletin Vol. 43; no. 12; pp. 2152 - 2158
• Main Authors: KATO, Akira, IKEDA, Yuko, SUGITA, Norifumi, NITTA, Toyohiko, ENARI, Hiroyuki, KASHIMA, Akiko, KONNO, Michiko, NIIMURA, Koichi
• Format: Journal Article
• Language: English
• Published: TOKYO The Pharmaceutical Society of Japan 1995; Pharmaceutical Soc Japan; Maruzen
• Subjects: 1, 2-disubstituted imidazolylmethylcyclopentanol; Androstenedione - analogs & derivatives; Androstenedione - pharmacology; Antineoplastic agents; aromatase inhibitor; Aromatase Inhibitors; Biological and medical sciences; Chemistry; Chemistry, Medicinal; Chemistry, Multidisciplinary; Crystallography, X-Ray; Cyclopentanes - chemical synthesis; Cyclopentanes - pharmacology; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacology; Female; General aspects; Humans; In Vitro Techniques; Life Sciences & Biomedicine; Medical sciences; Microsomes - drug effects; Microsomes - enzymology; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Physical Sciences; Placenta - drug effects; Placenta - enzymology; Pregnancy; Science & Technology; X-ray crystallography; 1,2-disubstituted imidazolylmethylcyclopentanol; X-ray crystallography; BREAST-CANCER; FADROZOLE HYDROCHLORIDE; MECHANISM; aromatase inhibitor; Imidazole derivatives; Structure activity relation; Enzyme; Tertiary alcohol; Benzene derivatives; Absolute configuration; Enzyme inhibitor; Estrogen synthase; Chemical synthesis; In vitro; Monocyclic compound
• ISSN: 0009-2363; 1347-5223
• DOI: 10.1248/cpb.43.2152

Two series of 1, 2-disubstituted imidazolylmethylcyclopentanol derivatives (5a-d, 10a-d) were prepared by using easily available metyl 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 4×10-8M. The enantiomers of 10a were separated, and their absolute configurations were determined by X-ray crystallography.