Takayuki Inoue, Masataka Morita, Takashi Tojo, Akira Nagashima, Ayako Moritomo, Hiroshi Miyake
Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. takayuki.inoue@astellas.com
Bioorganic & medicinal chemistry 2013 Jul 1Novel 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. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.
Takayuki Inoue, Masataka Morita, Takashi Tojo, Akira Nagashima, Ayako Moritomo, Hiroshi Miyake. Novel 1H-imidazol-2-amine derivatives as potent and orally active vascular adhesion protein-1 (VAP-1) inhibitors for diabetic macular edema treatment. Bioorganic & medicinal chemistry. 2013 Jul 1;21(13):3873-81
PMID: 23664164
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