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Short Paper | Regular issue | Vol 87, No. 8, 2013, pp.1727-1739
Published online, 17th June, 2013
DOI: 10.3987/COM-13-12744
Synthetic Models Related to Methoxalen – CYP2A6 Interactions. Dimethoxybenzofuran Derivatives as Potent and Selective Inhibitors of CYP2A6

Yuki Yamaguchi, Ichie Akimoto, Kyoko Motegi, Teruki Yoshimura, Keiji Wada, Naozumi Nishizono, and Kazuaki Oda*

*School of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido 061-0293, Japan


The human CYP2A6 enzyme metabolizes several xenobiotics including nicotine, the addictive component in tobacco. Reduced activity of CYP2A6, either for genetic reasons or by administering inhibitors of CYP2A6, reduces tobacco smoking. The reported compound methoxalen had a potent inhibitory effect on activity of CYP2A6 with an IC50 value of 1.27 μM. We selected methoxalen as a lead compound and prepared various dimethoxybenzofuran derivatives that have inhibitory effects on activity of human cytochrome P450 (CYP) 2A6. Synthetic benzofuran derivatives (3,6-dimethoxybenzofuran: IC50=1.92 μM and 3,7-dimethoxybenzofuran: IC50=2.00 μM) also exhibited comparable activities against CYP2A6 and were selective inhibitors of CYP2A6. These compounds can be used as lead compounds in the development of drugs for smoking reduction therapy.