Department of Pharmaceutical Sciences , College of Pharmacy, Washington State University , Spokane , Washington 99202 , United States.
J Med Chem. 2018 Aug 23;61(16):7065-7086. doi: 10.1021/acs.jmedchem.8b00084. Epub 2018 Aug 1.
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 (IC = 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, IC = 0.017 mM, >120 min half-life) are poised for further development as treatments for smoking and tobacco use cessation.
吸烟导致美国近五分之一的人死亡。为了停止吸烟，人们已经开发出一种特定的细胞色素 P450 2A6（CYP2A6）抑制剂，CYP2A6 是人类主要的尼古丁代谢酶。为了进一步完善 CYP2A6 的构效关系，之前合成的 3-炔基和 3-杂芳基取代吡啶甲胺被用作先导化合物。对吡啶环周围所有可用位置的吡啶替代和附加甲基进行等排体替换，以确定能够提高 CYP2A6 抑制效力的修饰，这导致了 4g（IC = 0.055 mM）作为主要类似物。对有潜力的化合物进行 CYP 选择性、人肝微粒体半衰期和符合五规则的评估。顶级化合物（即 6i，IC = 0.017 mM，半衰期 >120 分钟）有望进一步开发成为治疗吸烟和戒烟的药物。
