Discovery of XEN907, a spirooxindole blocker of NaV1.7 for the treatment of pain

被引：129

作者：

Chowdhury, Sultan ^{[1
]}

Chafeev, Mikhail ^{[1
]}

Liu, Shifeng ^{[1
]}

Sun, Jianyu ^{[1
]}

Raina, Vandna ^{[1
]}

Chui, Ray ^{[2
]}

Young, Wendy ^{[2
]}

Kwan, Rainbow ^{[2
]}

Fu, Jianmin ^{[1
]}

Cadieux, Jay A. ^{[1
]}

机构：

[1] Xenon Pharmaceut Inc, Dept Med Chem, Burnaby, BC V5G 4W8, Canada

[2] Xenon Pharmaceut Inc, Dept Biol Sci, Burnaby, BC V5G 4W8, Canada

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2011年 / 21卷 / 12期

关键词：

Sodium channel; SCN9A; Pain; Spirooxindole; Oxindole; GATED SODIUM-CHANNELS; MUTATIONS; SCN9A; PHARMACOLOGY; TARGETS; POTENT; FURAN;

D O I：

10.1016/j.bmcl.2011.04.088

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Starting from the oxindole 2a identified through a high-throughput screening campaign, a series of Na(V)1.7 blockers were developed. Following the elimination of undesirable structural features, preliminary optimization of the oxindole C-3 and N-1 substituents afforded the simplified analogue 9b, which demonstrated a 10-fold increase in target potency versus the original HTS hit. A scaffold rigidification strategy then led to the discovery of XEN907, a novel spirooxindole Na(V)1.7 blocker. This lead compound, which in turn showed a further 10-fold increase in potency, represents a promising structure for further optimization efforts. (C) 2011 Elsevier Ltd. All rights reserved.

引用

页码：3676 / 3681

页数：6

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