Structural modifications of a 3-methoxy-2-aminopyridine compound to reduce potential for mutagenicity and time-dependent drug–drug interaction
| Autor: | Kephart Susan Elizabeth, Annette John-Baptiste, Deal Judith G, Danlin Gu, Shubha Bagrodia, Cui Jingrong Jean, Shinji Yamazaki, Djamal Bouzida, Pairish Mason Alan, Evan Smith, Chuangxing Guo, Robert Steven Kania, Dong Liming, Angelica Linton, Indrawan James Mcalpine, Cynthia Louise Palmer |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
Time Factors
Stereochemistry Metabolite Clinical Biochemistry Aminopyridines Pharmaceutical Science Electrons Biochemistry Dependent drug chemistry.chemical_compound Drug Discovery Humans Molecular Biology ADME Ligand efficiency Molecular Structure Mutagenicity Tests Kinase Organic Chemistry Drug interaction chemistry Reactive metabolite Toxicity Microsomes Liver Molecular Medicine Oxidation-Reduction |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 22:7605-7609 |
| ISSN: | 0960-894X |
| Popis: | ( S )-1-((4-(3-(6-Amino-5-methoxypyridin-3-yl)-1-isopropyl-1 H -pyrazol-4-yl)pyrimidin-2-yl)amino)propan-2-ol, 1 , was recently identified as a potent inhibitor of the oncogenic kinase bRAF. Compounds containing 3-methoxy-2-aminopyridine, as in 1 , comprised a promising lead series because of their high ligand efficiency and excellent ADME profile. However, following metabolic oxidation, compounds in this series also demonstrated two significant safety risks: mutagenic potential and time-dependent drug–drug interaction (TDI). Metabolite identification studies revealed formation of a reactive metabolite. We hypothesized that minimizing or blocking the formation of such a metabolite would mitigate the safety liabilities. Our investigation demonstrated that structural modifications which either reduced the electron density of the 3-methoxy-2-aminopyridine ring or blocked the reactive site following metabolic oxidation were successful in reducing TDI and AMES mutagenicity. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect