Fragment-based design of 3-aminopyridine-derived amides as potent inhibitors of human nicotinamide phosphoribosyltransferase (NAMPT)

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• 作者：Peter S. Dragovich ; Guiling Zhao ; Timm Baumeister ; Br ; on Bravo ; Anthony M. Giannetti ; Yen-Ching Ho ; Rongbao Hua ; Guangkun Li ; Xiaorong Liang ; Xiaolei Ma ; Thomas O鈥橞rien ; Angela Oh ; Nicholas J. Skelton ; Chengcheng Wang ; Weiru Wang ; Yunli Wang ; Yang Xiao ; Po-wai Yuen ; Mark Zak ; Qiang Zhao ; Xiaozhang Zheng ; et al.
• 关键词：Nicotinamide phosphoribosyltransferase ; NAMPT ; Fragment-based design ; Structure-based design ; X-ray crystal structure ; Surface plasmon resonance
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：1 February, 2014
• 年：2014
• 卷：24
• 期：3
• 页码：954-962
• 全文大小：4506 K

文摘

The fragment-based identification of two novel and potent biochemical inhibitors of the nicotinamide phosphoribosyltransferase (NAMPT) enzyme is described. These compounds (ong class="boldFont">51ong> and ong class="boldFont">63ong>) incorporate an amide moiety derived from 3-aminopyridine, and are thus structurally distinct from other known anti-NAMPT agents. Each exhibits potent inhibition of NAMPT biochemical activity (IC₅₀ = 19 and 15 nM, respectively) as well as robust antiproliferative properties in A2780 cell culture experiments (IC₅₀ = 121 and 99 nM, respectively). However, additional biological studies indicate that only inhibitor ong class="boldFont">51ong> exerts its A2780 cell culture effects via a NAMPT-mediated mechanism. The crystal structures of both ong class="boldFont">51ong> and ong class="boldFont">63ong> in complex with NAMPT are also independently described.