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
| Autor: | Gang Chen, Zuping Xia, Pramod Kumar Srivastava, Christy J. W. Watson, Travis T. Denton, Alec Wynd, Philip Lazarus |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cytochrome Pyridines Stereochemistry Article Cytochrome P-450 CYP2A6 Methylamines 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Drug Discovery Pyridine Humans Potency Structure–activity relationship Enzyme Inhibitors CYP2A6 IC50 Tobacco Use Cessation chemistry.chemical_classification Molecular Structure biology Smoking 030104 developmental biology Enzyme chemistry Microsomes Liver biology.protein Microsome Molecular Medicine 030217 neurology & neurosurgery |
| Zdroj: | Journal of Medicinal Chemistry. 61:7065-7086 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.8b00084 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|