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Discovery of potent and efficacious urea-containing nicotinamide phosphoribosyltransferase (NAMPT) inhibitors with reduced CYP2C9 inhibition properties.
|Title||Discovery of potent and efficacious urea-containing nicotinamide phosphoribosyltransferase (NAMPT) inhibitors with reduced CYP2C9 inhibition properties.|
|Publication Type||Journal Article|
|Year of Publication||2013|
|Authors||Gunzner-Toste J, Zhao G, Bauer P, Baumeister T, Buckmelter AJ, Caligiuri M, Clodfelter KH, Fu B, Han B, Ho Y-C, Kley N, Liang X, Liederer BM, Lin J, Mukadam S, O'Brien T, Oh A, Reynolds DJ, Sharma G, Skelton N, Smith CC, Sodhi J, Wang W, Wang Z, Xiao Y, Yuen P-W, Zak M, Zhang L, Zheng X, Bair KW, Dragovich PS|
|Journal||Bioorganic & medicinal chemistry letters|
|Date Published||2013 Jun 15|
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.
|Alternate Journal||Bioorg. Med. Chem. Lett.|