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Bioorg Med Chem Lett. 2019 May 1;29(9):1143-1147. doi: 10.1016/j.bmcl.2019.02.017. Epub 2019 Feb 15.

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

Author information

1
Medicinal Chemistry Research Laboratory, Shionogi & Co., Ltd, 1-1 Futabacho, 3-chome, Toyonaka 561-0825, Japan. Electronic address: kousuke.anan@shionogi.co.jp.
2
Medicinal Chemistry Research Laboratory, Shionogi & Co., Ltd, 1-1 Futabacho, 3-chome, Toyonaka 561-0825, Japan.
3
Drug Discovery & Disease Research Laboratory, 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.
5
Research Laboratory for Development, Shionogi & 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:

Analgesic activity; NMDA receptor antagonist; Scaffold hopping

PMID:
30833109
DOI:
10.1016/j.bmcl.2019.02.017

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