Fragment-based identification of amides derived from trans-2-(pyridin-3-yl)cyclopropanecarboxylic acid as potent inhibitors of human nicotinamide phosphoribosyltransferase (NAMPT)

J Med Chem. 2014 Feb 13;57(3):770-92. doi: 10.1021/jm4015108.

Anthony M Giannetti ¹, Xiaozhang Zheng, Nicholas J Skelton, Weiru Wang, Brandon J Bravo, Kenneth W Bair, Timm Baumeister, Eric Cheng, Lisa Crocker, Yezhen Feng, Janet Gunzner-Toste, Yen-Ching Ho, Rongbao Hua, Bianca M Liederer, Yongbo Liu, Xiaolei Ma, Thomas O'Brien, Jason Oeh, Deepak Sampath, Youming Shen, Chengcheng Wang, Leslie Wang, Hongxing Wu, Yang Xiao, Po-wai Yuen, Mark Zak, Guiling Zhao, Qiang Zhao, Peter S Dragovich

Affiliations

Affiliation

1 Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.

PMID: 24405419 DOI: 10.1021/jm4015108

Abstract

Potent, trans-2-(pyridin-3-yl)cyclopropanecarboxamide-containing inhibitors of the human nicotinamide phosphoribosyltransferase (NAMPT) Enzyme were identified using fragment-based screening and structure-based design techniques. Multiple crystal structures were obtained of initial fragment leads, and this structural information was utilized to improve the biochemical and cell-based potency of the associated molecules. Many of the optimized compounds exhibited nanomolar antiproliferative activities against human tumor lines in in vitro Cell Culture experiments. In a key example, a fragment lead (13, KD = 51 μM) was elaborated into a potent NAMPT Inhibitor (39, NAMPT IC50 = 0.0051 μM, A2780 Cell Culture IC50 = 0.000 49 μM) which demonstrated encouraging in vivo efficacy in an HT-1080 mouse xenograft tumor model.

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