期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 21, 期 12, 页码 3676-3681出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2011.04.088
关键词
Sodium channel; SCN9A; Pain; Spirooxindole; Oxindole
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.
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