文献类型：期刊文献

中文题名：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

英文题名：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[1];Fang Xiao[2];Wen-Chao Lu[3];Yu-Yun Sun[1];Jin Zhu[1];Jian Li[1]

机构：[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.

年份：2014

卷号：25

期号：7

起止页码：989

中文期刊名：Chinese Chemical Letters

外文期刊名：中国化学快报（英文版）

收录：CSTPCD;;Scopus;CSCD:【CSCD2013_2014】；PubMed;

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

语种：英文

中文关键词：Cycloalkyl[d]pyrimidine derivatives;FGFR-1;Activator;Chemical probe

外文关键词：Cycloalkyl[d]pyrimidine derivatives;FGFR-1;Activator;Chemical probe

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.