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Discovery of NR2B-selective antagonists via scaffold hopping and pharmacokinetic profile optimization |
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| Authors: | Kosuke Anan Moriyasu Masui Aya Tazawa Minoru Tomida Yoshihiro Haga Masaharu Kume Shoichi Yamamoto Shunji Shinohara Hiroki Tsuji Shinji Shimada Shigenori Yagi Nobuyoshi Hasebe Hiroyuki Kai |
| Institution: | 1. Medicinal Chemistry Research Laboratory, Shionogi & Co., Ltd, 1-1 Futabacho, 3-chome, Toyonaka 561-0825, Japan;2. Drug Discovery & Disease Research Laboratory, Shionogi & Co., Ltd, 1-1 Futabacho, 3-chome, Toyonaka 561-0825, Japan;3. Research Laboratory for Development, Shionogi & Co., Ltd, 1-1 Futabacho, 3-chome, Toyonaka 561-0825, Japan;4. Shionogi Techno Advance Research Co., Ltd., 1-1 Futabacho, 3-chome, Toyonaka 561-0825, Japan |
| Abstract: | Selective N-methyl-d-aspartate receptor subunit 2B (NR2B) antagonists show potential as analgesic drugs, and do not cause side effects associated with non-selective N-methyl-d-aspartate (NMDA) antagonists. Using a scaffold-hopping approach, we previously identified isoxazole derivative 4 as a potent selective NR2B antagonist. In this study, further scaffold hopping of isoxazole derivative 4 and optimization of its pharmacokinetic profile led to the discovery of the orally bioavailable compound 6v. In a rat study of analgesia, 6v demonstrated analgesic effects against neuropathic pain. |
| Keywords: | NMDA receptor antagonist Scaffold hopping Analgesic activity |
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