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 |
| |
Authors: | Takayuki Inoue Masataka Morita Takashi Tojo Akira Nagashima Ayako Moritomo Keisuke Imai Hiroshi Miyake |
| |
Affiliation: | 1. Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan;2. Astellas Business Service Co., Ltd, 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan;3. Astellas Research Technology Co., Ltd, 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan |
| |
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 IC50 of 20 nM; rat IC50 of 72 nM) and significant inhibitory effects in the ex vivo test. |
| |
Keywords: | VAP-1 Inhibitor Guanidine Species difference Hybrid Homology model Sequence information |
本文献已被 ScienceDirect 等数据库收录! |
|