Rational design of novel CYP2A6 inhibitors

Bioorg Med Chem. 2014 Dec 1;22(23):6655-6664. doi: 10.1016/j.bmc.2014.10.001. Epub 2014 Oct 13.

Abstract

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.

Keywords: CYP2A6; Cytochrome P450 (CYP); Inhibition; Nicotine; Smoking reduction therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cytochrome P-450 CYP2A6 / antagonists & inhibitors*
  • Cytochrome P-450 CYP2A6 / metabolism
  • Cytochrome P-450 Enzyme Inhibitors / chemical synthesis
  • Cytochrome P-450 Enzyme Inhibitors / chemistry
  • Cytochrome P-450 Enzyme Inhibitors / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Pyridines / chemical synthesis
  • Pyridines / chemistry
  • Pyridines / pharmacology*
  • Smoking Cessation
  • Smoking Prevention
  • Structure-Activity Relationship

Substances

  • Cytochrome P-450 Enzyme Inhibitors
  • Pyridines
  • thienopyridine
  • Cytochrome P-450 CYP2A6