鉴定无CYP3A4时间依赖性抑制证据且具有改善的水溶性的烟酰胺磷酸核糖转移酶（NAMPT）抑制剂。
Identification of nicotinamide phosphoribosyltransferase (NAMPT) inhibitors with no evidence of CYP3A4 time-dependent inhibition and improved aqueous solubility.
作者信息
Zak Mark, Liederer Bianca M, Sampath Deepak, Yuen Po-Wai, Bair Kenneth W, Baumeister Timm, Buckmelter Alexandre J, Clodfelter Karl H, Cheng Eric, Crocker Lisa, Fu Bang, Han Bingsong, Li Guangkun, Ho Yen-Ching, Lin Jian, Liu Xiongcai, Ly Justin, O'Brien Thomas, Reynolds Dominic J, Skelton Nicholas, Smith Chase C, Tay Suzanne, Wang Weiru, Wang Zhongguo, Xiao Yang, Zhang Lei, Zhao Guiling, Zheng Xiaozhang, Dragovich Peter S
机构信息
Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
出版信息
Bioorg Med Chem Lett. 2015 Feb 1;25(3):529-41. doi: 10.1016/j.bmcl.2014.12.026. Epub 2014 Dec 17.
Herein we report the optimization efforts to ameliorate the potent CYP3A4 time-dependent inhibition (TDI) and low aqueous solubility exhibited by a previously identified lead compound from our NAMPT inhibitor program (1, GNE-617). Metabolite identification studies pinpointed the imidazopyridine moiety present in 1 as the likely source of the TDI signal, and replacement with other bicyclic systems was found to reduce or eliminate the TDI finding. A strategy of reducing the number of aromatic rings and/or lowering cLogD7.4 was then employed to significantly improve aqueous solubility. These efforts culminated in the discovery of 42, a compound with no evidence of TDI, improved aqueous solubility, and robust efficacy in tumor xenograft studies.
在此，我们报告了优化工作，以改善我们烟酰胺磷酸核糖转移酶（NAMPT）抑制剂项目中先前鉴定的先导化合物（1，GNE-617）所表现出的强效细胞色素P450 3A4（CYP3A4）时间依赖性抑制（TDI）和低水溶性。代谢物鉴定研究确定1中存在的咪唑并吡啶部分可能是TDI信号的来源，发现用其他双环系统取代可减少或消除TDI结果。然后采用减少芳香环数量和/或降低cLogD7.4的策略来显著提高水溶性。这些努力最终发现了化合物42，该化合物在肿瘤异种移植研究中没有TDI证据，水溶性得到改善，且具有强大的疗效。
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