Novel 1H-imidazol-2-amine derivatives as potent and orally active vascular adhesion protein-1 (VAP-1) inhibitors for diabetic macular edema treatment.

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 1 H -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 IC 50  = 0.019 μM, rat IC 50  = 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.