Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10593083 | Bioorganic & Medicinal Chemistry Letters | 2012 | 6 Pages |
Abstract
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.
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Authors
Jay A. Cadieux, Zaihui Zhang, Maryanne Mattice, Alison Brownlie-Cutts, Jianmin Fu, Laszlo G. Ratkay, Rainbow Kwan, Jay Thompson, Joseph Sanghara, Jing Zhong, Y. Paul Goldberg,