title: Synthesis and biological evaluation of substituted pyrazoles as blockers of divalent metal transporter 1 (DMT1).
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.
authors.affiliation: Department of Medicinal Chemistry, Xenon Pharmaceuticals Inc., 3650 Gilmore Way, Burnaby, British Columbia, Canada V5G 4W8. jcadieux@xenon-pharma.com
authors.forename: Jay A
authors.initials: JA
authors.lastname: Cadieux
authors.forename: Zaihui
authors.initials: Z
authors.lastname: Zhang
authors.forename: Maryanne
authors.initials: M
authors.lastname: Mattice
authors.forename: Alison
authors.initials: A
authors.lastname: Brownlie-Cutts
authors.forename: Jianmin
authors.initials: J
authors.lastname: Fu
authors.forename: Laszlo G
authors.initials: LG
authors.lastname: Ratkay
authors.forename: Rainbow
authors.initials: R
authors.lastname: Kwan
authors.forename: Jay
authors.initials: J
authors.lastname: Thompson
authors.forename: Joseph
authors.initials: J
authors.lastname: Sanghara
authors.forename: Jing
authors.initials: J
authors.lastname: Zhong
authors.forename: Y Paul
authors.initials: YP
authors.lastname: Goldberg
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D027682:Cation Transport Proteins / Q000737:chemistry*; D002614:Chelating Agents / Q000737:chemistry; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004583:Electrons; D006432:Hemochromatosis / Q000188:drug therapy*; D056945:Hep G2 Cells; D006801:Humans; D006860:Hydrogen Bonding; D020128:Inhibitory Concentration 50; D019190:Iron Overload / Q000188:drug therapy; D008956:Models, Chemical; D010539:Permeability; D011720:Pyrazoles / Q000737:chemistry*; D051381:Rats; D013789:Thalassemia / Q000378:metabolism*; D000099236:Solute Carrier Family 11, Member 2
chemical_list: D027682:Cation Transport Proteins; D002614:Chelating Agents; D011720:Pyrazoles; D000099236:Solute Carrier Family 11, Member 2