title: Synthesis and SAR study of new thiazole derivatives as vascular adhesion protein-1 (VAP-1) inhibitors for the treatment of diabetic macular edema.
abstract: Vascular adhesion protein-1 (VAP-1), an amine oxidase that is also known as a semicarbazide-sensitive amine oxidase (SSAO), is present in particularly high levels in human plasma, and is considered a potential therapeutic target for various inflammatory diseases, including diabetes complications such as macular edema. In our VAP-1 inhibitor program, structural modifications following high-throughput screening (HTS) of our compound library resulted in the discovery that thiazole derivative 10, which includes a guanidine group, shows potent human VAP-1 inhibitory activity (IC(50) of 230 nM; rat IC(50) of 14 nM). Moreover, compound 10 exhibited significant inhibitory effects on ocular permeability in STZ-induced diabetic rats.
authors: Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan. takayuki.inoue@astellas.com
authors: Takayuki
authors: T
authors: Inoue
authors: Masataka
authors: M
authors: Morita
authors: Takashi
authors: T
authors: Tojo
authors: Kousei
authors: K
authors: Yoshihara
authors: Akira
authors: A
authors: Nagashima
authors: Ayako
authors: A
authors: Moritomo
authors: Mitsuru
authors: M
authors: Ohkubo
authors: Hiroshi
authors: H
authors: Miyake
mesh_terms: D006631:Amine Oxidase (Copper-Containing) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors* / Q000378:metabolism; D048909:Diabetes Complications; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000473:pathology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use; D006146:Guanidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use; D006207:Half-Life; D006801:Humans; D008269:Macular Edema / Q000188:drug therapy / Q000209:etiology; D008297:Male; D062105:Molecular Docking Simulation; D010539:Permeability / Q000187:drug effects; D017434:Protein Structure, Tertiary; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D015815:Cell Adhesion Molecules; D004791:Enzyme Inhibitors; D006146:Guanidines; C582996:N-(4-(2-(4-((amino(imino)methyl)amino)phenyl)ethyl)-1,3-thiazol-2-yl)acetamide; D013844:Thiazoles; C076668:AOC3 protein, human; D006631:Amine Oxidase (Copper-Containing)