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 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.

Novel Capsaicin Analogues as Potential Anticancer Agents: Synthesis, Biological Evaluation, and In Silico Approach

“…In this regard, both synthetic procedures were suitable for amide and ester formation and provided satisfactory yields (values between 60% and 74%). The synthetic steps are depicted in Scheme 1 [23,24].…”

Probing the Catalytic Mechanism of Copper Amine Oxidase from Arthrobacter globiformis with Halide Ions

“…It has been reported that human serum CAOs cause angiopathy in diabetes (9). Therefore, various CAO inhibitors have been developed as therapeutic drugs (10,11).…”

PXS-4681A, a Potent and Selective Mechanism-Based Inhibitor of SSAO/VAP-1 with Anti-Inflammatory Effects In Vivo

“…A complete uninterrupted enzyme inhibition is likely to be a challenge for the noncovalent/reversible inhibitors going forward, and higher or more frequent dosing to achieve this may reduce the therapeutic window. For example, an in vivo study using compound 7 (dosing daily at 10 mg/kg PO over 2 weeks) indicated that this inhibitor was not able to completely inhibit plasma SSAO/VAP-1 levels 24 h after the final dose (Inoue et al, 2013c), further supporting this critical pharmacokinetic/ pharmacodynamic relationship.…”