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 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.

中文翻译：

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反式-2-（吡啶-3-基）环丙烷羧酸酰胺作为人类烟酰胺磷酸核糖基转移酶（NAMPT）的强抑制剂的基于片段的鉴定

使用基于片段的筛选和基于结构的设计技术，鉴定了人类烟酰胺磷酸核糖基转移酶（NAMPT）的含强反式-2-（吡啶-3-基）环丙烷甲酰胺的抑制剂。从初始片段导联获得了多个晶体结构，并且利用该结构信息来改善相关分子的生化和基于细胞的效力。在体外细胞培养实验中，许多优化的化合物对人肿瘤细胞均表现出纳摩尔的抗增殖活性。在一个关键的例子中，将片段导线（13，K _D = 51μM）制成了有效的NAMPT抑制剂（39，NAMPT IC ₅₀＝ 0.0051μM，A2780细胞培养IC ₅₀ = 0.000 49μM），这在HT-1080小鼠异种移植肿瘤模型中显示出令人鼓舞的体内功效。