2. Academic Validation
  3. Identification of Selective Acyl Sulfonamide-Cycloalkylether Inhibitors of the Voltage-Gated Sodium Channel (NaV) 1.7 with Potent Analgesic Activity

Identification of Selective Acyl Sulfonamide-Cycloalkylether Inhibitors of the Voltage-Gated Sodium Channel (NaV) 1.7 with Potent Analgesic Activity

  • J Med Chem. 2019 Jan 24;62(2):908-927. doi: 10.1021/acs.jmedchem.8b01621.
Shaoyi Sun 1,  Qi Jia 1,  Alla Y Zenova 1,  Michael S Wilson 1,  Sultan Chowdhury 1,  Thilo Focken 1,  Jun Li 2,  Shannon Decker 1,  Michael E Grimwood 1,  Jean-Christophe Andrez 1,  Ivan Hemeon 1,  Tao Sheng 1,  Chien-An Chen 3,  Andy White 3,  David H Hackos 2,  Lunbin Deng 2,  Girish Bankar 1,  Kuldip Khakh 1,  Elaine Chang 1,  Rainbow Kwan 1,  Sophia Lin 1,  Karen Nelkenbrecher 1,  Benjamin D Sellers 2,  Antonio G DiPasquale 2,  Jae Chang 2,  Jodie Pang 2,  Luis Sojo 1,  Andrea Lindgren 1,  Matthew Waldbrook 1,  Zhiwei Xie 1,  Clint Young 1,  James P Johnson 1,  C Lee Robinette 1,  Charles J Cohen 1,  Brian S Safina 2,  Daniel P Sutherlin 2,  Daniel F Ortwine 2,  Christoph M Dehnhardt 1
Affiliations

Affiliations

  • 1 Xenon Pharmaceuticals Inc. , 200-3650 Gilmore Way , Burnaby , British Columbia V5G 4W8 , Canada.
  • 2 Genentech Inc. , 1 DNA Way , South San Francisco , California 94080-4990 , United States.
  • 3 ChemPartner , Building No. 5, 998 Halei Road, Zhangjiang Hi-Tech Park, Pudong New Area , Shanghai 201203 , P. R. China.
PMID: 30499663 DOI: 10.1021/acs.jmedchem.8b01621
Abstract

Herein, we report the discovery and optimization of a series of orally bioavailable acyl sulfonamide NaV1.7 inhibitors that are selective for NaV1.7 over NaV1.5 and highly efficacious in in vivo models of pain and hNaV1.7 target engagement. An analysis of the physicochemical properties of literature NaV1.7 inhibitors suggested that acyl sulfonamides with high fsp3 could overcome some of the pharmacokinetic (PK) and efficacy challenges seen with existing series. Parallel library syntheses lead to the identification of analogue 7, which exhibited moderate potency against NaV1.7 and an acceptable PK profile in rodents, but relatively poor stability in human liver microsomes. Further, design strategy then focused on the optimization of potency against hNaV1.7 and improvement of human metabolic stability, utilizing induced fit docking in our previously disclosed X-ray cocrystal of the NaV1.7 voltage sensing domain. These investigations culminated in the discovery of tool compound 33, one of the most potent and efficacious NaV1.7 inhibitors reported to date.

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