Bioorganic and Medicinal Chemistry Letters p. 3676 - 3681 (2011)
Update date:2022-08-02
Topics:
Chowdhury, Sultan
Chafeev, Mikhail
Liu, Shifeng
Sun, Jianyu
Raina, Vandna
Chui, Ray
Young, Wendy
Kwan, Rainbow
Fu, Jianmin
Cadieux, Jay A.
Starting from the oxindole 2a identified through a high-throughput screening campaign, a series of NaV1.7 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 NaV1.7 blocker. This lead compound, which in turn showed a further 10-fold increase in potency, represents a promising structure for further optimization efforts.
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