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. Other Scholarly Work

Denton, Travis T, Srivastava, Pramod, Xia, Zuping et al. (2018). 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. . 61(16), 7065-7086. 10.1021/acs.jmedchem.8b00084

cited authors

  • Denton, Travis T; Srivastava, Pramod; Xia, Zuping; Chen, Gang; Watson, Christy JW; Wynd, Alec; Lazarus, Philip

fiu authors

abstract

  • 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.

publication date

  • August 1, 2018

keywords

  • Cytochrome P-450 CYP2A6
  • Enzyme Inhibitors
  • Humans
  • Methylamines
  • Microsomes, Liver
  • Molecular Structure
  • Pyridines
  • Smoking
  • Tobacco Use Cessation

Digital Object Identifier (DOI)

Medium

  • Print-Electronic

start page

  • 7065

end page

  • 7086

volume

  • 61

issue

  • 16