Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10591709 | Bioorganic & Medicinal Chemistry Letters | 2013 | 8 Pages |
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 IC50Â =Â 3Â nM; A2780 antiproliferative IC50Â =Â 70Â 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.
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Authors
Janet Gunzner-Toste, 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,