Synthesis and biological evaluation of substituted pyrazoles as blockers of divalent metal transporter 1 (DMT1)

被引：38

作者：

Cadieux, Jay A. ^{[1
]}

Zhang, Zaihui ^{[1
]}

Mattice, Maryanne ^{[2
]}

Brownlie-Cutts, Alison ^{[2
]}

Fu, Jianmin ^{[1
]}

Ratkay, Laszlo G. ^{[2
]}

Kwan, Rainbow ^{[2
]}

Thompson, Jay ^{[2
]}

Sanghara, Joseph ^{[2
]}

Zhong, Jing ^{[2
]}

Goldberg, Y. Paul ^{[3
]}

机构：

[1] Xenon Pharmaceut Inc, Dept Med Chem, Burnaby, BC V5G 4W8, Canada

[2] Xenon Pharmaceut Inc, Dept Biol Sci, Burnaby, BC V5G 4W8, Canada

[3] Xenon Pharmaceut Inc, Dept Biol Clin, Burnaby, BC V5G 4W8, Canada

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2012年 / 22卷 / 01期

基金：

加拿大自然科学与工程研究理事会;

关键词：

Pyrazole; Hemochromatosis; DMT1; Iron overload; Thalassemia; HEREDITARY HEMOCHROMATOSIS; IRON-METABOLISM; INHIBITORS; INTESTINE; DIAGNOSIS; THERAPY; ASSAY;

D O I：

10.1016/j.bmcl.2011.11.069

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Three distinct series of substituted pyrazole blockers of divalent metal transporter 1 (DMT1) were elaborated from the high-throughput screening pyrazolone hit 1. Preliminary hit-to-lead efforts revealed a preference for electron-withdrawing substituents in the 4-amido-5-hydroxypyrazole series 6a-l. In turn, this preference was more pronounced in a series of 4-aryl-5-hydroxypyrazoles 8a-j. The representative analogs 6f and 12f were found to be efficacious in a rodent model of acute iron hyperabsorption. These three series represent promising starting points for lead optimization efforts aimed at the discovery of DMT1 blockers as iron overload therapeutics. (C) 2011 Elsevier Ltd. All rights reserved.

引用

页码：90 / 95

页数：6

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