Discovery and synthesis of N2,N4-substitued-cycloalkyl[d]pyrimidine 2,4-diamine analogs： The first examples of small-molecular FGFR-1 activator

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 abolishe...

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Bibliographic Details
Published inChinese chemical letters Vol. 25; no. 7; pp. 989 - 994
Main Authors Li, Bao-Li, Xiao, Fang, Lu, Wen-Chao, Sun, Yu-Yun, Zhu, Jin, Li, Jian
Format Journal Article
LanguageEnglish
Published Elsevier B.V 01.07.2014
Subjects
Activator
Chemical probe
Cycloalkyl[d]pyrimidine derivatives
FGFR-1
个例
合成
嘧啶
小分子
激活作用
环烷基
类似物
Cycloalkyl[d]pyrimidine derivatives
Chemical probe
Activator
FGFR-1
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Summary: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.
Bibliography:Cycloalkyl[d]pyrimidine derivatives;FGFR-1;Activator;Chemical probe
11-2710/O6
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.
ISSN:1001-8417
1878-5964
DOI:10.1016/j.cclet.2014.06.010