Rational design of novel CYP2A6 inhibitors.

Niina Tani, Risto O Juvonen, Hannu Raunio, Muluneh Fashe, Jukka Leppänen, Bin Zhao, Rachel F Tyndale, Minna Rahnasto-Rilla

Bioorganic & medicinal chemistry 2014 Dec 1

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Inhibition of CYP2A6-mediated nicotine metabolism can reduce cigarette smoking. We sought potent and selective CYP2A6 inhibitors to be used as leads for drugs useful in smoking reduction therapy, by evaluating CYP2A6 inhibitory effect of novel formyl, alkyl amine or carbonitrile substituted aromatic core structures. The most potent CYP2A6 inhibitors were thienopyridine-2-carbaldehyde, benzothienophene-3-ylmethanamine, benzofuran-5-carbaldehyde and indole-5-carbaldehyde, with IC50 values below 0.5 μM for coumarin 7-hydroxylation. Nicotine oxidation was effectively inhibited in vitro by two alkyl amine compounds and benzofuran-5-carbonitrile. Some of these molecules could serve as potential lead molecules when designing CYP2A6 inhibitory drugs for smoking reduction therapy. Copyright © 2014 Elsevier Ltd. All rights reserved.

Citation

Niina Tani, Risto O Juvonen, Hannu Raunio, Muluneh Fashe, Jukka Leppänen, Bin Zhao, Rachel F Tyndale, Minna Rahnasto-Rilla. Rational design of novel CYP2A6 inhibitors. Bioorganic & medicinal chemistry. 2014 Dec 1;22(23):6655-64