Fragment-Based Identification of Amides Derived from trans-2-(Pyridin-3-yl)cyclopropanecarboxylic Acid as Potent Inhibitors of Human Nicotinamide Phosphoribosyltransferase (NAMPT)

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• 作者：Anthony M. Giannetti ; 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
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：February 13, 2014
• 年：2014
• 卷：57
• 期：3
• 页码：770-792
• 全文大小：1022K
• ISSN：1520-4804

文摘

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, K_D = 51 渭M) was elaborated into a potent NAMPT inhibitor (39, NAMPT IC₅₀ = 0.0051 渭M, A2780 cell culture IC₅₀ = 0.000鈥?9 渭M) which demonstrated encouraging in vivo efficacy in an HT-1080 mouse xenograft tumor model.