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Discovery of potent and efficacious urea-containing nicotinamide phosphoribosyltransferase (NAMPT) inhibitors with reduced CYP2C9 inhibition properties

2013; Elsevier BV; Volume: 23; Issue: 12 Linguagem: Inglês

10.1016/j.bmcl.2013.04.040

1464-3405

Janet Gunzner-Toste, Gui‐Ling 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 J. Skelton, Chase C. Smith, Jasleen K. Sodhi, Weiru Wang, Zhongguo Wang, Yang Xiao, Po‐wai Yuen, Mark Zak, Lei Zhang, Xiaozhang Zheng, Kenneth W. Bair, Peter S. Dragovich,

PARP inhibition in cancer therapy

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.