Chem. Pharm. Bull., 55(9),1419-1421, September 2007

Communications to the Editor

Synthetic Models Related to Furanocoumarin-CYP 3A4 Interactions. Comparison of Furanocoumarin, Coumarin, and Benzofuran Dimers as Potent Inhibitors of CYP3A4 Activity

Kazuaki ODA,^* Yuki YAMAGUCHI, Teruki YOSHIMURA, Keiji WADA, and Naozumi NISHIZONO^*

Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido; Ishikari-Tobetsu, Hokkaido 061-0293, Japan. * To whom correspondence should be addressed. e-mail: k-oda@hoku-iryo-u.ac.jp

Furanocoumarin derivatives (dimers and monomers) present in commercially available grapefruit juice have the capacity to inhibit the activity of human CYP3A4. Such interactions are believed to result from the mechanism-based inhibition of CYP3A4 activity in the intestine. The aim of this work was to synthesize and test a series of dimers with a view to determining the relationship between structure and inhibitory activity and determining whether they might make suitable probes of CYP3A4 activity. We prepared a series of furanocoumarin, coumarin, and benzofuran derivatives that have inhibitory effects on the activity of human CYP3A4. A synthetic benzofuran dimer, which is more accessible than furanocoumarin dimers, exhibited activity against CYP3A4 comparable to that of furanocoumarin dimers.

Key words grapefruit juice; furanocoumarin dimer; inhibitor; CYP3A4; benzofuran dimer