Discovery of benzylisothioureas as potent divalent metal transporter 1 (DMT1) inhibitors.
Bioorg Med Chem Lett
; 22(15): 5108-13, 2012 Aug 01.
Article
in En
| MEDLINE
| ID: mdl-22749870
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Thiourea
/
Cation Transport Proteins
Limits:
Animals
/
Humans
Language:
En
Journal:
Bioorg Med Chem Lett
Journal subject:
BIOQUIMICA
/
QUIMICA
Year:
2012
Type:
Article
Affiliation country:
Canada