烟酰胺磷酸核糖转移酶（NAMPT）非底物异吲哚啉脲抑制剂的构效关系及特性研究
SAR and characterization of non-substrate isoindoline urea inhibitors of nicotinamide phosphoribosyltransferase (NAMPT).
作者信息
Curtin Michael L, Heyman H Robin, Clark Richard F, Sorensen Bryan K, Doherty George A, Hansen T Matthew, Frey Robin R, Sarris Kathy A, Aguirre Ana L, Shrestha Anurupa, Tu Noah, Woller Kevin, Pliushchev Marina A, Sweis Ramzi F, Cheng Min, Wilsbacher Julie L, Kovar Peter J, Guo Jun, Cheng Dong, Longenecker Kenton L, Raich Diana, Korepanova Alla V, Soni Nirupama B, Algire Mikkel A, Richardson Paul L, Marin Violeta L, Badagnani Ilaria, Vasudevan Anil, Buchanan F Greg, Maag David, Chiang Gary G, Tse Chris, Michaelides Michael R
机构信息
AbbVie Inc, 1 North Waukegan Rd., North Chicago, IL 60064, United States.
AbbVie Inc, 1 North Waukegan Rd., North Chicago, IL 60064, United States.
出版信息
Bioorg Med Chem Lett. 2017 Aug 1;27(15):3317-3325. doi: 10.1016/j.bmcl.2017.06.018. Epub 2017 Jun 14.
Herein we disclose SAR studies that led to a series of isoindoline ureas which we recently reported were first-in-class, non-substrate nicotinamide phosphoribosyltransferase (NAMPT) inhibitors. Modification of the isoindoline and/or the terminal functionality of screening hit 5 provided inhibitors such as 52 and 58 with nanomolar antiproliferative activity and preclinical pharmacokinetics properties which enabled potent antitumor activity when dosed orally in mouse xenograft models. X-ray crystal structures of two inhibitors bound in the NAMPT active-site are discussed.
在此，我们披露了一系列异吲哚啉脲的构效关系（SAR）研究，我们最近报道这些异吲哚啉脲是一流的非底物烟酰胺磷酸核糖转移酶（NAMPT）抑制剂。对筛选命中物5的异吲哚啉和/或末端官能团进行修饰，得到了抑制剂52和58，它们具有纳摩尔级的抗增殖活性和临床前药代动力学性质，在小鼠异种移植模型中口服给药时能够产生强效的抗肿瘤活性。文中还讨论了两种抑制剂在NAMPT活性位点结合的X射线晶体结构。
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