Bhide Rajeev S, Cai Zhen-Wei, Zhang Yong-Zheng, Qian Ligang, Wei Donna, Barbosa Stephanie, Lombardo Louis J, Borzilleri Robert M, Zheng Xiaoping, Wu Laurence I, Barrish Joel C, Kim Soong-Hoon, Leavitt Kenneth, Mathur Arvind, Leith Leslie, Chao Sam, Wautlet Barri, Mortillo Steven, Jeyaseelan Robert, Kukral Daniel, Hunt John T, Kamath Amrita, Fura Aberra, Vyas Viral, Marathe Punit, D'Arienzo Celia, Derbin George, Fargnoli Joseph
Bristol-Myers Squibb, Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000, USA.
J Med Chem. 2006 Apr 6;49(7):2143-6. doi: 10.1021/jm051106d.
A series of substituted 4-(4-fluoro-1H-indol-5-yloxy)pyrrolo[2,1-f][1,2,4]triazine-based inhibitors of vascular endothelial growth factor receptor-2 kinase is reported. Structure-activity relationship studies revealed that a methyl group at the 5-position and a substituted alkoxy group at the 6-position of the pyrrolo[2,1-f][1,2,4]triazine core gave potent compounds. Biochemical potency, kinase selectivity, and pharmacokinetics of the series were optimized and in vitro safety liabilities were minimized to afford BMS-540215 (12), which demonstrated robust preclinical in vivo activity in human tumor xenograft models. The l-alanine prodrug of 12, BMS-582664 (21), is currently under evaluation in clinical trials for the treatment of solid tumors.
报道了一系列基于4-(4-氟-1H-吲哚-5-基氧基)吡咯并[2,1-f][1,2,4]三嗪的血管内皮生长因子受体-2激酶抑制剂。构效关系研究表明，吡咯并[2,1-f][1,2,4]三嗪核心结构的5-位甲基和6-位取代烷氧基可得到强效化合物。对该系列化合物的生化活性、激酶选择性和药代动力学进行了优化，并将体外安全性风险降至最低，从而得到了BMS-540215（12），其在人肿瘤异种移植模型中显示出强大的临床前体内活性。12的L-丙氨酸前药BMS-582664（21）目前正在进行治疗实体瘤的临床试验评估。
