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

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.