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Identification of amides derived from 1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid as potent inhibitors of human nicotinamide phosphoribosyltransferase (NAMPT)

2013; Elsevier BV; Volume: 23; Issue: 20 Linguagem: Inglês

10.1016/j.bmcl.2013.08.074

1464-3405

Xiaozhang Zheng, Kenneth W. Bair, Paul Bauer, Timm Baumeister, Krista K. Bowman, Alexandre J. Buckmelter, Maureen Caligiuri, Karl H. Clodfelter, Y. Feng, Bingsong Han, Yen‐Ching Ho, Nikolai Kley, Hong Li, Xiaorong Liang, Bianca M. Liederer, Jian Lin, Justin Q. Ly, Thomas O’Brien, Jason Oeh, Angela Oh, Dominic J. Reynolds, Deepak Sampath, Geeta Sharma, Nicholas J. Skelton, Chase C. Smith, Jarrod R. Tremayne, Leslie Wang, Weiru Wang, Zhongguo Wang, Hongxing Wu, Jian Wu, Yang Xiao, Guangxing Yang, Po‐wai Yuen, Mark Zak, Peter S. Dragovich,

Sirtuins and Resveratrol in Medicine

Potent, 1H-pyrazolo[3,4-b]pyridine-containing inhibitors of the human nicotinamide phosphoribosyltransferase (NAMPT) enzyme were identified using structure-based design techniques. Many of these compounds exhibited nanomolar antiproliferation activities against human tumor lines in in vitro cell culture experiments, and a representative example (compound 26) demonstrated encouraging in vivo efficacy in a mouse xenograft tumor model derived from the A2780 cell line. This molecule also exhibited reduced rat retinal exposures relative to a previously studied imidazo-pyridine-containing NAMPT inhibitor. Somewhat surprisingly, compound 26 was only weakly active in vitro against mouse and monkey tumor cell lines even though it was a potent inhibitor of NAMPT enzymes derived from these species. The compound also exhibited only minimal effects on in vivo NAD levels in mice, and these changes were considerably less profound than those produced by an imidazo-pyridine-containing NAMPT inhibitor. The crystal structures of compound 26 and the corresponding PRPP-derived ribose adduct in complex with NAMPT were also obtained.