Novel 1H-imidazol-2-amine derivatives as potent and orally active vascular adhesion protein-1 (VAP-1) inhibitors for diabetic macular edema treatment.
Bioorg Med Chem
; 21(13): 3873-81, 2013 Jul 01.
Article
in En
| MEDLINE
| ID: mdl-23664164
ABSTRACT
Novel thiazole derivatives were synthesized and evaluated as vascular adhesion protein-1 (VAP-1) inhibitors. Although we previously identified a compound (2) with potent VAP-1 inhibitory activity in rats, the human activity was relatively weak. Here, to improve the human VAP-1 inhibitory activity of compound 2, we first evaluated the structure-activity relationships of guanidine bioisosteres as simple small molecules and identified a 1H-benzimidazol-2-amine (5) with potent activity compared to phenylguanidine (1). Based on the structure of compound 5, we synthesized a highly potent VAP-1 inhibitor (37b; human IC50=0.019 µM, rat IC50=0.0051 µM). Orally administered compound 37b also markedly inhibited ocular permeability in streptozotocin-induced diabetic rats after oral administration, suggesting it is a promising compound for the treatment of diabetic macular edema.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Thiazoles
/
Cell Adhesion Molecules
/
Macular Edema
/
Amine Oxidase (Copper-Containing)
/
Diabetic Retinopathy
Limits:
Animals
/
Humans
/
Male
Language:
En
Journal:
Bioorg Med Chem
Journal subject:
BIOQUIMICA
/
QUIMICA
Year:
2013
Document type:
Article
Affiliation country:
Japón