We have shown previously that the target of the potent cytotoxic agent 4-[(7-bromo-2-methyl-4-oxo-3H-quinazolin-6-yl)methyl-prop-2-ynylamino]-N-(3-pyridylmethyl)benzamide (CB38065, 1) is nicotinamide phosphoribosyltransferase (Nampt). With its cellular target known we sought to optimize the biochemical and cellular Nampt activity of 1 as well as its cytotoxicity. It was found that a 3-pyridylmethylamide substituent in the A region was critical to cellular Nampt activity and cytotoxicity, although other aromatic substitution did yield compounds with submicromolar enzymatic inhibition. Small unsaturated groups worked best in the D-region of the molecule, with 3,3-dimethylallyl providing optimal potency. The E region required a quinazolin-4-one or 1,2,3-benzotriazin-4-one group for activity, and many substituents were tolerated at C² of the quinazolin-4-one. The best compounds showed subnanomolar inhibition of Nampt and low nanomolar cytotoxicity in cellular assays.

中文翻译：

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4-[（7-溴-2-甲基-4-氧代-3 H-喹唑啉-6-基）甲基丙-2-炔基氨基] -N-（3-吡啶基甲基）苯甲酰胺（CB-30865）的类似物作为有效抑制剂烟酰胺磷酸核糖基转移酶（Nampt）的合成

先前我们已经表明，有效的细胞毒剂的目标是4-[（（7-溴-2-甲基-4-甲基-4-氧代-3 H-喹唑啉-6-基）甲基-丙-2-炔基氨基] -N-（3 -吡啶甲基）苯甲酰胺（CB38065，1）是烟酰胺磷酸（NAMPT）。与其细胞靶已知我们试图优化的生物化学和细胞活性NAMPT 1以及它的细胞毒性。发现在A区域中的3-吡啶基甲基酰胺取代基对细胞Nampt活性和细胞毒性至关重要，尽管其他芳族取代的确产生了具有亚微摩尔酶抑制作用的化合物。小的不饱和基团在分子的D区域效果最佳，而3,3-二甲基烯丙基则提供了最佳的效价。E区需要一个喹唑啉-4-酮基或1,2,3-苯并三嗪-4-酮基团具有活性，并且在喹唑啉-4-酮基的C ²上有许多取代基。最好的化合物在细胞测定中显示出对纳姆普蛋白的亚纳摩尔抑制作用和低纳摩尔细胞毒性。