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

• Published in: Bioorganic & medicinal chemistry 2013-07, Vol.21 (13), p.3873-3881
• Main Authors: Inoue, Takayuki, Morita, Masataka, Tojo, Takashi, Nagashima, Akira, Moritomo, Ayako, Miyake, Hiroshi
• Format: Article
• Language: English
• Subjects: 1H-Imidazol-2-amine derivative; adhesion; Amine Oxidase (Copper-Containing) - antagonists & inhibitors; Amine Oxidase (Copper-Containing) - metabolism; Amines - chemistry; Amines - pharmacokinetics; Amines - pharmacology; Animals; Cell Adhesion Molecules - antagonists & inhibitors; Cell Adhesion Molecules - metabolism; Diabetes Mellitus, Experimental - complications; Diabetic Retinopathy - drug therapy; Diabetic Retinopathy - metabolism; edema; Guanidine bioisostere; Humans; Inhibitor; Macular edema; Macular Edema - drug therapy; Macular Edema - metabolism; Male; Models, Molecular; Molecular Docking Simulation; oral administration; permeability; Rats; Rats, Sprague-Dawley; structure-activity relationships; Thiazoles - chemistry; Thiazoles - pharmacokinetics; Thiazoles - pharmacology; Vascular adhesion protein-1
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2013.04.011

The 1H-imidazol-2-amine derivative 37b is a potent, selective and orally active VAP-1 inhibitor. 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=0.019μM, rat IC50=0.0051μM). 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.