Forma Therapeutics, Inc., 500 Arsenal Street, Watertown, Massachusetts 02472, USA.
J Med Chem. 2013 Jun 27;56(12):4921-37. doi: 10.1021/jm400186h. Epub 2013 Jun 13.
Nicotinamide phosphoribosyltransferase (Nampt) is a promising anticancer target. Virtual screening identified a thiourea analogue, compound 5, as a novel highly potent Nampt inhibitor. Guided by the cocrystal structure of 5, SAR exploration revealed that the corresponding urea compound 7 exhibited similar potency with an improved solubility profile. These studies also indicated that a 3-pyridyl group was the preferred substituent at one inhibitor terminus and also identified a urea moiety as the optimal linker to the remainder of the inhibitor structure. Further SAR optimization of the other inhibitor terminus ultimately yielded compound 50 as a urea-containing Nampt inhibitor which exhibited excellent biochemical and cellular potency (enzyme IC50 = 0.007 μM; A2780 IC50 = 0.032 μM). Compound 50 also showed excellent in vivo antitumor efficacy when dosed orally in an A2780 ovarian tumor xenograft model (TGI of 97% was observed on day 17).
烟酰胺磷酸核糖基转移酶（Nampt）是一种很有前途的抗癌靶点。虚拟筛选发现一种硫脲类似物，化合物 5，是一种新型的高活性 Nampt 抑制剂。根据 5 的共晶结构，SAR 研究揭示了相应的脲类化合物 7 具有相似的活性，且溶解度得到改善。这些研究还表明，一个抑制剂末端的 3-吡啶基是首选取代基，同时也确定了脲基作为与抑制剂结构其余部分的最佳连接基团。另一个抑制剂末端的进一步 SAR 优化最终得到了含有脲基的 Nampt 抑制剂 50，其具有优异的生化和细胞活性（酶 IC50=0.007 μM；A2780 IC50=0.032 μM）。化合物 50 在 A2780 卵巢肿瘤异种移植模型中口服给药时也表现出优异的体内抗肿瘤疗效（第 17 天观察到 97%的肿瘤生长抑制率）。
