2. Academic Validation
  3. Structure- and Ligand-Based Discovery of Chromane Arylsulfonamide Nav1.7 Inhibitors for the Treatment of Chronic Pain

Structure- and Ligand-Based Discovery of Chromane Arylsulfonamide Nav1.7 Inhibitors for the Treatment of Chronic Pain

  • J Med Chem. 2019 Apr 25;62(8):4091-4109. doi: 10.1021/acs.jmedchem.9b00141.
Steven J McKerrall 1,  Teresa Nguyen 1,  Kwong Wah Lai 2,  Philippe Bergeron 1,  Lunbin Deng 1,  Antonio DiPasquale 1,  Jae H Chang 1,  Jun Chen 1,  Tania Chernov-Rogan 1,  David H Hackos 1,  Jonathan Maher 1,  Daniel F Ortwine 1,  Jodie Pang 1,  Jian Payandeh 1,  William R Proctor 1,  Shannon D Shields 1,  Jennifer Vogt 1,  Pengfei Ji 2,  Wenfeng Liu 2,  Elisa Ballini 3,  Lilia Schumann 3,  Glauco Tarozzo 3,  Girish Bankar 4,  Sultan Chowdhury 4,  Abid Hasan 4,  J P Johnson Jr 4,  Kuldip Khakh 4,  Sophia Lin 4,  Charles J Cohen 4,  Christoph M Dehnhardt 4,  Brian S Safina 1,  Daniel P Sutherlin 1
Affiliations

Affiliations

  • 1 Genentech, Inc. , 1 DNA Way , South San Francisco , California 94080 , United States.
  • 2 WuXi AppTec Co., Ltd. , 288 Fute Zhong Road , Waigaoqiao Free Trade Zone, Shanghai 200131 , People's Republic of China.
  • 3 Evotec AG , Essener Bogen 7 , 22419 Hamburg , Germany.
  • 4 Xenon Pharmaceuticals, Inc. , 200-3650 Gilmore Way , Burnaby , British Columbia V5G 4W8 , Canada.
PMID: 30943032 DOI: 10.1021/acs.jmedchem.9b00141
Abstract

Using structure- and ligand-based design principles, a novel series of piperidyl chromane arylsulfonamide Nav1.7 inhibitors was discovered. Early optimization focused on improvement of potency through refinement of the low energy ligand conformation and mitigation of high in vivo clearance. An in vitro hepatotoxicity hazard was identified and resolved through optimization of lipophilicity and lipophilic ligand efficiency to arrive at GNE-616 (24), a highly potent, metabolically stable, subtype selective inhibitor of Nav1.7. Compound 24 showed a robust PK/PD response in a Nav1.7-dependent mouse model, and site-directed mutagenesis was used to identify residues critical for the isoform selectivity profile of 24.

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