| Literature DB >> 23668988 |
Janet Gunzner-Toste1, Guiling Zhao, Paul Bauer, Timm Baumeister, Alexandre J Buckmelter, Maureen Caligiuri, Karl H Clodfelter, Bang Fu, Bingsong Han, Yen-Ching Ho, Nikolai Kley, Xiaorong Liang, Bianca M Liederer, Jian Lin, Sophie Mukadam, Thomas O'Brien, Angela Oh, Dominic J Reynolds, Geeta Sharma, Nicholas Skelton, Chase C Smith, Jasleen Sodhi, Weiru Wang, Zhongguo Wang, Yang Xiao, Po-wai Yuen, Mark Zak, Lei Zhang, Xiaozhang Zheng, Kenneth W Bair, Peter S Dragovich.
Abstract
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.Entities:
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Year: 2013 PMID： 23668988 DOI： 10.1016/j.bmcl.2013.04.040
Source DB: PubMed Journal: Bioorg Med Chem Lett ISSN： 0960-894X Impact factor: 2.823