Identification of 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-derived ureas as potent inhibitors of human nicotinamide phosphoribosyltransferase (NAMPT)
Identification of 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-derived ureas as potent inhibitors of human nicotinamide phosphoribosyltransferase (NAMPT)
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DOI：
10.1016/j.bmcl.2013.06.090
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发表时间：
2013-09-01
影响因子：
2.7
通讯作者：
Zheng, Xiaozhang
中科院分区：
文献类型：
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作者：
Dragovich, Peter S.;Bair, Kenneth W.;Zheng, Xiaozhang
使用基于结构的设计技术鉴定了含有2，3-二氢-1H-吡咯并[3，4-c]吡啶衍生脲的有效烟酰胺磷酸核糖基转移酶（NAMPT）抑制剂。相对于先前公开的含脲和酰胺的NAMPT抑制剂，新化合物显示出使用高通量溶解度评估确定的改善的水溶解度。优化的2，3-二氢-1H-吡咯并[3，4-c]吡啶衍生化合物显示出有效的抗NAMPT活性（18; BC NAMPT IC 50 = 11 nM; PC-3抗增殖IC 50 = 36 nM）、令人满意的小鼠PK特性，并且在PC-3小鼠异种移植模型中有效。还测定了与NAMPT蛋白复合的另一种优化化合物（29; NAMPT IC 50 = 10 nM; A2780抗增殖IC 50 = 7 nM）的晶体结构。(C)2013爱思唯尔有限公司保留所有权利。
Potent nicotinamide phosphoribosyltransferase (NAMPT) inhibitors containing 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-derived ureas were identified using structure-based design techniques. The new compounds displayed improved aqueous solubilities, determined using a high-throughput solubility assessment, relative to previously disclosed urea and amide-containing NAMPT inhibitors. An optimized 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-derived compound exhibited potent anti-NAMPT activity (18; BC NAMPT IC50 = 11 nM; PC-3 antiproliferative IC50 = 36 nM), satisfactory mouse PK properties, and was efficacious in a PC-3 mouse xenograft model. The crystal structure of another optimized compound (29; NAMPT IC50 = 10 nM; A2780 antiproliferative IC50 = 7 nM) in complex with the NAMPT protein was also determined. (C) 2013 Elsevier Ltd. All rights reserved.