title: Discovery of benzylisothioureas as potent divalent metal transporter 1 (DMT1) inhibitors.
abstract: Inhibition of intestinal brush border DMT1 offers a novel therapeutic approach to the prevention and treatment of disorders of iron overload. Several series of diaryl and tricyclic benzylisothiourea compounds as novel and potent DMT1 inhibitors were discovered from the original hit compound 1. These compounds demonstrated in vitro potency against DMT1, desirable cell permeability properties and a dose-dependent inhibition of iron uptake in an acute rat model of iron hyperabsorption. Tricyclic compounds increased the in vitro potency by up to 16-fold versus the original hit. Diaryl compounds 6b and 14a demonstrated significant iron absorption inhibition in vivo with both 25 and 50 mg/kg doses. The diaryl and tricyclic compounds described in this report represent promising structural templates for further optimization.
authors: Department of Medicinal Chemistry, Xenon Pharmaceuticals Inc., Burnaby, British Columbia, Canada.
authors: Zaihui
authors: Z
authors: Zhang
authors: Vishnumurthy
authors: V
authors: Kodumuru
authors: Serguei
authors: S
authors: Sviridov
authors: Shifeng
authors: S
authors: Liu
authors: Mikhail
authors: M
authors: Chafeev
authors: Sultan
authors: S
authors: Chowdhury
authors: Nagasree
authors: N
authors: Chakka
authors: Jianyu
authors: J
authors: Sun
authors: Simon J
authors: SJ
authors: Gauthier
authors: Maryanne
authors: M
authors: Mattice
authors: Laszlo G
authors: LG
authors: Ratkay
authors: Rainbow
authors: R
authors: Kwan
authors: Jay
authors: J
authors: Thompson
authors: Alison Brownlie
authors: AB
authors: Cutts
authors: Jianmin
authors: J
authors: Fu
authors: Rajender
authors: R
authors: Kamboj
authors: Y Paul
authors: YP
authors: Goldberg
authors: Jay A
authors: JA
authors: Cadieux
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D027682:Cation Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000187:drug effects; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007501:Iron / Q000378:metabolism; D019190:Iron Overload / Q000378:metabolism / Q000473:pathology; D051381:Rats; D013329:Structure-Activity Relationship; D013890:Thiourea / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000099236:Solute Carrier Family 11, Member 2
chemical_list: D027682:Cation Transport Proteins; D007501:Iron; D013890:Thiourea; D000099236:Solute Carrier Family 11, Member 2