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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.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Zhang Z,Kodumuru V,Sviridov S,Liu S,Chafeev M,Chowdhury S,Chakka N,Sun J,Gauthier SJ,Mattice M,Ratkay LG,Kwan R,Thompson J,Cutts AB,Fu J,Kamboj R,Goldberg YP,Cadieux JA

doi

10.1016/j.bmcl.2012.05.129

subject

Has Abstract

pub_date

2012-08-01 00:00:00

pages

5108-13

issue

15

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(12)00770-6

journal_volume

22

pub_type

杂志文章

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