期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 22, 期 1, 页码 90-95出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2011.11.069
关键词
Pyrazole; Hemochromatosis; DMT1; Iron overload; Thalassemia
资金
- Genome British Columbia
- Natural Sciences and Engineering Research Council of Canada
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.
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