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Discovery efforts leading to the identification of cyclopentane carboxylic acid 31, a potent inhibitor of Na V 1.7 that showed high selectivity over Na V 1.5 and exhibited robust analgesic effects in an inherited erythromelalgia (IEM) transgenic mouse assay, are described herein. Key design elements that culminated in the discovery of 31 include exploration of proline substituents, replacement of the proline warhead with cyclopentane carboxylic acid, that led to significantly boosted Na V 1.7 potency, and replacement of the metabolically labile adamantane motif with the 2,6-dichlorobenzyl substituted piperidine system, that addressed metabolic instability and led to a significant improvement in PK., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Shaoyi Sun, Sultan Chowdhury, Ivan Hemeon, Abid Hasan, Michael S. Wilson, Qi Jia, Alla Y. Zenova, Mike E. Grimwood, Wei Gong, Shannon M. Decker, Paul Bichler, Jean-Christophe Andrez, Thilo Focken, Girish Bankar, Elaine Chang, Kuldip Khakh, Sophia Lin, Richard Dean, J. P. Johnson, Jr., Charles J. Cohen, and Christoph M. Dehnhardt are employees of Xenon Pharmaceuticals Inc. and may hold equity or stocks in the company. Phillipe Bergeron, Theresa Ngyuen, Sarah Howard, Jae H. Chang, David H. Hackos, Steve J. McKerrall, Ben Sellers, Dan F. Ortwine, Brian S. Safina, and Daniel P. Sutherlin are employees of Genentech Inc. and may hold equity or stocks in the company. Jiuxiang Zhu and Andrew D. White are employees of Chempartner and may hold equity or stocks in the company., (Copyright © 2024 Elsevier Ltd. All rights reserved.)