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

Citation: Bao-Li Li, Fang Xiao, Wen-Chao Lu, Yu-Yun Sun, Jin Zhu, Jian Li. Discovery and synthesis of N²,N⁴-substitued-cycloalkyl[d] pyrimidine-2,4-diamine analogs：The first examples of small-molecular FGFR-1 activator[J]. Chinese Chemical Letters, 2014, 25(7): 989-994. doi: 10.1016/j.cclet.2014.06.010 shu

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

Bao-Li Li ^a, ,
Fang Xiao ^{b,
,} ,
Wen-Chao Lu ^c, ,
Yu-Yun Sun ^a, ,
Jin Zhu ^a, ,
Jian Li ^{a,
,}

通讯作者: Fang Xiao,
Jian Li,

基金项目:
Financial support of this research provided by the National Natural Science Foundation of China (Nos. 21222211, 21372001, 91313303) (Nos. 21222211, 21372001, 91313303)

the Program for New Century Excellent Talents in University (No. NCET-12-0853) (No. NCET-12-0853)

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.

关键词:

English

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

Bao-Li Li ^a, ,
Fang Xiao ^{b,
,} ,
Wen-Chao Lu ^c, ,
Yu-Yun Sun ^a, ,
Jin Zhu ^a, ,
Jian Li ^{a,
,}

1.
a Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China;
2.
b Department of Pharmacy, The Second Hospital of Jilin University, Jilin 130041, China;
c China Resources Double-Crane Pharmaceutical Co.
c China Resources Double-Crane Pharmaceutical Co., Ltd., Beijing 100121, China

Corresponding author: Fang Xiao, Jian Li,

Received Date: 21 April 2014
Fund Project:

Abstract: 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.

Key words:

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

通讯作者: Fang Xiao,
Jian Li,

English

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

Corresponding author: Fang Xiao, Jian Li,

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