Discovery of NR2B-selective antagonists via scaffold hopping and pharmacokinetic profile optimization

被引：5

作者：

Anan, Kosuke ^{[1
]}

Masui, Moriyasu ^{[1
]}

Tazawa, Aya ^{[1
]}

Tomida, Minoru ^{[1
]}

Haga, Yoshihiro ^{[1
]}

Kume, Masaharu ^{[1
]}

Yamamoto, Shoichi ^{[2
]}

Shinohara, Shunji ^{[4
]}

Tsuj, Hiroki ^{[4
]}

Shimada, Shinji ^{[4
]}

Yagi, Shigenori ^{[3
]}

Hasebe, Nobuyoshi ^{[3
]}

Kai, Hiroyuki ^{[1
]}

机构：

[1] Shionogi & Co Ltd, Med Chem Res Lab, 1-1 Futabacho,3 Chome, Toyonaka, Osaka 5610825, Japan

[2] Shionogi & Co Ltd, Drug Discovery & Dis Res Lab, 1-1 Futabacho,3 Chome, Toyonaka, Osaka 5610825, Japan

[3] Shionogi & Co Ltd, Res Lab Dev, 1-1 Futabacho,3 Chome, Toyonaka, Osaka 5610825, Japan

[4] Shionogi Techno Advance Res Co Ltd, 1-1 Futabacho,3 Chome, Toyonaka, Osaka 5610825, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2019年 / 29卷 / 09期

关键词：

NMDA receptor antagonist; Scaffold hopping; Analgesic activity; FUNGICIDAL ACTIVITIES; RECEPTOR ANTAGONISTS; DISORDERS; GLUTAMATE; PAIN;

D O I：

10.1016/j.bmcl.2019.02.017

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：1143 / 1147

页数：5

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