Identification of the 4-position of 3-alkynyl and 3-heteroaromatic substituted pyridine methanamines as a key modification site eliciting increased potency and enhanced selectivity for cytochrome P-450 2A6 inhibition.

摘要

Cigarette smoking causes nearly one in every five deaths in the United States. The development of a specific inhibitor of cytochrome P450 2A6 (CYP2A6), the major nicotine-metabolizing enzyme in humans, which could be prescribed for the cessation of cigarette smoking, has been undertaken. To further refine the structure activity relationship of CYP2A6, previously synthesized 3-alkynyl and 3-heteroaromatic substituted pyridine methanamines were used as lead compounds. Isosteric pyridine replacement and appendage of all available positions around the pyridine ring with a methyl group was performed to identify a modification that would increase CYP2A6 inhibition potency which led to >4g (IC50 = 0.055 mM) as a primary analogue. Potent compounds were evaluated for CYP selectivity, human liver microsomal half-life and compliance with the rules of five. Top compounds (i.e., >6i, IC50 = 0.017 mM, >120 min half-life) are poised for further development as treatments for smoking and tobacco use cessation.