Sultan Chowdhury, Mikhail Chafeev, Shifeng Liu, Jianyu Sun, Vandna Raina, Ray Chui, Wendy Young, Rainbow Kwan, Jianmin Fu, Jay A. Cadieux, Sultan Chowdhury, Mikhail Chafeev, Shifeng Liu, Jianyu Sun, Vandna Raina, Ray Chui, Wendy Young, Rainbow Kwan, Jianmin Fu, Jay A. Cadieux
文献索引：Bioorg. Med. Chem. Lett. 21 , 3676-3681, (2011)
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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.Copyright © 2011 Elsevier Ltd. All rights reserved.
