Minimizing CYP2C9 Inhibition of Exposed-Pyridine NAMPT (Nicotinamide Phosphoribosyltransferase) Inhibitors
| Autor: | Xiongcai Liu, Yuen Po-Wai, Deepak Sampath, Thomas O'Brien, Jasleen K. Sodhi, Lei Zhang, Nicholas J. Skelton, Weiru Wang, Yen-Ching Ho, Jason Oeh, Yang Xiao, Rongbao Hua, Mark Zak, Snahel Patel, Peter S. Dragovich, Kenneth W. Bair, Bianca M. Liederer, Xiaozhang Zheng, Yunli Wang, Guiling Zhao |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Models Molecular Cytochrome P-450 CYP2C9 Inhibitors Pyridines Nicotinamide phosphoribosyltransferase Mice Nude Antineoplastic Agents Pharmacology 03 medical and health sciences chemistry.chemical_compound Mice Cell Line Tumor Neoplasms Pyridine Drug Discovery Potency Animals Humans Mouse tumor Enzyme Inhibitors Nicotinamide Phosphoribosyltransferase CYP2C9 ADME Cytochrome P-450 CYP2C9 030104 developmental biology chemistry Benzyl group Molecular Medicine Female Pharmacophore |
| Zdroj: | Journal of medicinal chemistry. 59(18) |
| ISSN: | 1520-4804 |
| Popis: | NAMPT inhibitors may show potential as therapeutics for oncology. Throughout our NAMPT inhibitor program, we found that exposed pyridines or related heterocyclic systems in the left-hand portion of the inhibitors are necessary pharmacophores for potent cellular NAMPT inhibition. However, when combined with a benzyl group in the center of the inhibitors, such pyridine-like moieties also led to consistent and potent inhibition of CYP2C9. In an attempt to reduce CYP2C9 inhibition, a parallel synthesis approach was used to identify central benzyl group replacements with increased Fsp3. A spirocyclic central motif was thus discovered that was combined with left-hand pyridines (or pyridine-like systems) to provide cellularly potent NAMPT inhibitors with minimal CYP2C9 inhibition. Further optimization of potency and ADME properties led to the discovery of compound 68, a highly potent NAMPT inhibitor with outstanding efficacy in a mouse tumor xenograft model and lacking measurable CYP2C9 inhibition at the concentrations tested. |
| Databáze: | OpenAIRE |
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