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

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Abstract

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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Acknowledgments

The authors are grateful to Audrey Wang, Xing Cheng, Jing Zhong and Ivana Rajlic (for technical assistance) as well as Henry Verschoof (for helpful discussions during the preparation of this Letter).

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