Department of Medicinal Chemistry, Myrexis, Inc., Salt Lake City, Utah 84108, USA.
J Med Chem. 2010 Dec 23;53(24):8734-46. doi: 10.1021/jm101145b. Epub 2010 Nov 16.
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.
我们之前已经表明，强效细胞毒性试剂 4-[(7-溴-2-甲基-4-氧代-3H-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）的靶标是烟酰胺磷酸核糖转移酶（Nampt）。既然已经知道了它的细胞靶标，我们就试图优化 1 的生化和细胞 Nampt 活性及其细胞毒性。研究发现，A 区域中的 3-吡啶甲基酰胺取代基对于细胞 Nampt 活性和细胞毒性至关重要，尽管其他芳香取代基也能产生具有亚毫摩尔酶抑制作用的化合物。小分子不饱和基团在分子的 D 区域效果最佳，其中 3,3-二甲基烯丙基提供最佳的效力。E 区域需要喹唑啉-4-酮或 1,2,3-苯并三嗪-4-酮基团才能发挥作用，并且喹唑啉-4-酮的 C² 上可以容忍许多取代基。最好的化合物在细胞测定中显示出对 Nampt 的亚纳摩尔抑制作用和低纳摩尔级别的细胞毒性。
