title: Rational design of novel CYP2A6 inhibitors.
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.
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, POB 1627, 70211 Kuopio, Finland. Electronic address: Niina.Tani@uef.fi.
authors.forename: Niina
authors.initials: N
authors.lastname: Tani
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, POB 1627, 70211 Kuopio, Finland.
authors.forename: Risto O
authors.initials: RO
authors.lastname: Juvonen
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, POB 1627, 70211 Kuopio, Finland.
authors.forename: Hannu
authors.initials: H
authors.lastname: Raunio
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, POB 1627, 70211 Kuopio, Finland.
authors.forename: Muluneh
authors.initials: M
authors.lastname: Fashe
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, POB 1627, 70211 Kuopio, Finland.
authors.forename: Jukka
authors.initials: J
authors.lastname: Leppänen
authors.affiliation: Departments of Pharmacology and Toxicology and Psychiatry, University of Toronto, Campbell Family Mental Health Research Institute, M5S 1A8 Toronto, Ontario, Canada.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhao
authors.affiliation: Departments of Pharmacology and Toxicology and Psychiatry, University of Toronto, Campbell Family Mental Health Research Institute, M5S 1A8 Toronto, Ontario, Canada.
authors.forename: Rachel F
authors.initials: RF
authors.lastname: Tyndale
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, POB 1627, 70211 Kuopio, Finland. Electronic address: Minna.Rahnasto@uef.fi.
authors.forename: Minna
authors.initials: M
authors.lastname: Rahnasto-Rilla
mesh_terms: D065637:Cytochrome P-450 CYP2A6 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016540:Smoking Cessation; D000074606:Smoking Prevention; D013329:Structure-Activity Relationship
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D011725:Pyridines; C446540:thienopyridine; D065637:Cytochrome P-450 CYP2A6
keywords: CYP2A6; Cytochrome P450 (CYP); Inhibition; Nicotine; Smoking reduction therapy