Discovery and synthesis of N^2,N^4-substitued-cycloalkyl[d]pyrimidine-2,4-diamine analogs: The first examples of small-molecular FGFR-1 activator  

作　　者：Bao-Li Li Fang Xiao Wen-Chao Lu Yu-Yun Sun Jin Zhu Jian Li 

机构地区：[1]Shanghai Key Laboratory of New Drug Design,School of Pharmacy, East China University of Science and Technology [2]Department of Pharmacy, The Second Hospital of Jilin University [3]China Resources Double-Crane Pharmaceutical Co.,Ltd.

出　　处：《Chinese Chemical Letters》2014年第7期989-994,共6页中国化学快报（英文版）

基　　金：provided by the National Natural Science Foundation of China(Nos.21222211,21372001,91313303);the Program for New Century Excellent Talents in University(No.NCET-12-0853);the Fundamental Research Funds for the Central Universities are gratefully acknowledged

摘　　要：A series of novel, cycloalkyl-modified pazopanib analogs 2 and 3 were designed and synthesized. Their kinase modulatory effects on FGFR-1, VEGFR-2, PDGFR-β and c-KIT were evaluated by the caliper mobility shift assay. Introduction of cycloalkyl into the pyrimidine linker of pazopanib almost abolished the four kinases inhibitory potency of compounds 2 and 3, but surprisingly, resulted in good activation effects on FGFR-1. Compounds 3d and 3g showed double-digit, nanomolar, selective activation effects on FGFR-1, and could be classified as first-generation small molecular activators of FGFR-1 kinase.A series of novel, cycloalkyl-modified pazopanib analogs 2 and 3 were designed and synthesized. Their kinase modulatory effects on FGFR-1, VEGFR-2, PDGFR-β and c-KIT were evaluated by the caliper mobility shift assay. Introduction of cycloalkyl into the pyrimidine linker of pazopanib almost abolished the four kinases inhibitory potency of compounds 2 and 3, but surprisingly, resulted in good activation effects on FGFR-1. Compounds 3d and 3g showed double-digit, nanomolar, selective activation effects on FGFR-1, and could be classified as first-generation small molecular activators of FGFR-1 kinase.

关 键 词：Cycloalkyl[d]pyrimidine derivatives FGFR-1 ACTIVATOR Chemical probe 

分 类 号：TQ460.1[化学工程—制药化工]