Discovery of novel cyclopentane carboxylic acids as potent and selective inhibitors of NaV1.7

  • Bioorg Med Chem Lett. 2025 Feb 1:116:130033. doi: 10.1016/j.bmcl.2024.130033.
Shaoyi Sun  1 ,  Sultan Chowdhury  2 ,  Ivan Hemeon  2 ,  Abid Hasan  2 ,  Michael S Wilson  2 ,  Phillipe Bergeron  3 ,  Qi Jia  2 ,  Alla Y Zenova  2 ,  Mike E Grimwood  2 ,  Wei Gong  2 ,  Shannon M Decker  2 ,  Paul Bichler  2 ,  Jean-Christophe Andrez  2 ,  Thilo Focken  2 ,  Theresa Ngyuen  3 ,  Jiuxiang Zhu  4 ,  Andrew D White  4 ,  Girish Bankar  2 ,  Sarah Howard  3 ,  Elaine Chang  2 ,  Kuldip Khakh  2 ,  Sophia Lin  2 ,  Richard Dean  2 ,  J P Johnson Jr  2 ,  Jae H Chang  3 ,  David H Hackos  3 ,  Steve J McKerrall  3 ,  Ben Sellers  3 ,  Dan F Ortwine  3 ,  Charles J Cohen  2 ,  Brian S Safina  3 ,  Daniel P Sutherlin  3 ,  Christoph M Dehnhardt  2
Affiliations
  • 1. Xenon Pharmaceuticals Inc., 3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada. Electronic address: [email protected].
  • 2. Xenon Pharmaceuticals Inc., 3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada.
  • 3. Genentech Inc., 1 DNA Way, South San Francisco, CA 94080-4990, USA.
  • 4. Chempartner, Building No. 5, 998 Halei Rd., Zhangjiang Hi-Tech Park, Pudong New Area, Shanghai, PR China.
PMID: 39580005 DOI: 10.1016/j.bmcl.2024.130033
Abstract

Discovery efforts leading to the identification of cyclopentane carboxylic acid 31, a potent inhibitor of NaV1.7 that showed high selectivity over NaV1.5 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 NaV1.7 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.

Keywords
Cyclopentane carboxylic acid; Na(V)1.7; Pain; Proline; Voltage-gated sodium channel.
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