Discovery of potent and efficacious urea-containing nicotinamide phosphoribosyltransferase (NAMPT) inhibitors with reduced CYP2C9 inhibition properties
| Autor: | Janet Gunzner-Toste, Maureen Caligiuri, Nicholas J. Skelton, Jian Lin, Sophie Mukadam, Weiru Wang, Paul Bauer, Kenneth W. Bair, Xiaozhang Zheng, Karl H. Clodfelter, Bianca M. Liederer, Bang Fu, Thomas O'Brien, Zhongguo Wang, Peter S. Dragovich, Jasleen K. Sodhi, Lei Zhang, Geeta Sharma, Yen-Ching Ho, Chase C. Smith, Dominic J. Reynolds, Bingsong Han, Alexandre J. Buckmelter, Timm Baumeister, Angela Oh, Guiling Zhao, Nikolai Kley, Xiaorong Liang, Yang Xiao, Yuen Po-Wai, Mark Zak |
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| Rok vydání: | 2013 |
| Předmět: |
Gene isoform
Clinical Biochemistry Nicotinamide phosphoribosyltransferase Pharmaceutical Science Pharmacology Biochemistry Mice chemistry.chemical_compound Mouse xenograft Drug Discovery Animals Humans Urea Reversible inhibition Nicotinamide Phosphoribosyltransferase Molecular Biology CYP2C9 IC50 Cytochrome P-450 CYP2C9 Mice Inbred BALB C biology Chemistry Organic Chemistry Cytochrome P450 biology.protein Molecular Medicine Aryl Hydrocarbon Hydroxylases |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 23:3531-3538 |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2013.04.040 |
| Popis: | Potent, reversible inhibition of the cytochrome P450 CYP2C9 isoform was observed in a series of urea-containing nicotinamide phosphoribosyltransferase (NAMPT) inhibitors. This unwanted property was successfully removed from the described inhibitors through a combination of structure-based design and medicinal chemistry activities. An optimized compound which did not inhibit CYP2C9 exhibited potent anti-NAMPT activity (17; BC NAMPT IC50=3 nM; A2780 antiproliferative IC50=70 nM), good mouse PK properties, and was efficacious in an A2780 mouse xenograft model. The crystal structure of this compound in complex with the NAMPT protein is also described. |
| Databáze: | OpenAIRE |
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