title: 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.
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. takayuki.inoue@astellas.com
authors.forename: Takayuki
authors.initials: T
authors.lastname: Inoue
authors.forename: Masataka
authors.initials: M
authors.lastname: Morita
authors.forename: Takashi
authors.initials: T
authors.lastname: Tojo
authors.forename: Akira
authors.initials: A
authors.lastname: Nagashima
authors.forename: Ayako
authors.initials: A
authors.lastname: Moritomo
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Miyake
mesh_terms: D006631:Amine Oxidase (Copper-Containing) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000588:Amines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications; D003930:Diabetic Retinopathy / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D008269:Macular Edema / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013844:Thiazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D000588:Amines; D015815:Cell Adhesion Molecules; D013844:Thiazoles; C076668:AOC3 protein, human; D006631:Amine Oxidase (Copper-Containing); C510433:vascular adhesion protein-1, rat