title: Synthesis and SAR study of new thiazole derivatives as vascular adhesion protein-1 (VAP-1) inhibitors for the treatment of diabetic macular edema: part 2.
abstract: Novel thiazole derivatives were synthesized and evaluated as vascular adhesion protein-1 (VAP-1) inhibitors. Although our previous compound 1 showed potent VAP-1 inhibitory activity, the activity differed between humans and rats. This issue was overcome by a hybrid design using human VAP-1 specific inhibitor 2, which was found by high-throughput screening (HTS), a docking study of a human VAP-1 homology model, and an analysis of sequence information for humans and rats. As a result, we identified compound 35c, which showed strong VAP-1 inhibitory activity (human IC(50) of 20 nM; rat IC(50) of 72 nM) and significant inhibitory effects in the ex vivo test.
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: Keisuke
authors.initials: K
authors.lastname: Imai
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Miyake
mesh_terms: D006631:Amine Oxidase (Copper-Containing) / Q000037:antagonists & inhibitors* / Q000097:blood; D000818:Animals; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors* / Q000097:blood; D003930:Diabetic Retinopathy / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008269:Macular Edema / Q000188:drug therapy*; D008958:Models, Molecular; D015394:Molecular Structure; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D015815:Cell Adhesion Molecules; D013844:Thiazoles; C076668:AOC3 protein, human; D006631:Amine Oxidase (Copper-Containing); C510433:vascular adhesion protein-1, rat