2. Academic Validation
  3. Synthesis and biological evaluation of substituted pyrazoles as blockers of divalent metal transporter 1 (DMT1)

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

  • Bioorg Med Chem Lett. 2012 Jan 1;22(1):90-5. doi: 10.1016/j.bmcl.2011.11.069.
Jay A Cadieux 1,  Zaihui Zhang,  Maryanne Mattice,  Alison Brownlie-Cutts,  Jianmin Fu,  Laszlo G Ratkay,  Rainbow Kwan,  Jay Thompson,  Joseph Sanghara,  Jing Zhong,  Y Paul Goldberg
Affiliations

Affiliation

  • 1 Department of Medicinal Chemistry, Xenon Pharmaceuticals Inc., 3650 Gilmore Way, Burnaby, British Columbia, Canada V5G 4W8. jcadieux@xenon-pharma.com
PMID: 22154351 DOI: 10.1016/j.bmcl.2011.11.069
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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