2. Academic Validation
  3. Discovery of Acyl-sulfonamide Nav1.7 Inhibitors GDC-0276 and GDC-0310

Discovery of Acyl-sulfonamide Nav1.7 Inhibitors GDC-0276 and GDC-0310

  • J Med Chem. 2021 Mar 25;64(6):2953-2966. doi: 10.1021/acs.jmedchem.1c00049.
Brian S Safina 1,  Steven J McKerrall 1,  Shaoyi Sun 2,  Chien-An Chen 3,  Sultan Chowdhury 2,  Qi Jia 2,  Jun Li 1,  Alla Y Zenova 2,  Jean-Christophe Andrez 2,  Girish Bankar 2,  Philippe Bergeron 1,  Jae H Chang 1,  Elaine Chang 2,  Jun Chen 1,  Richard Dean 2,  Shannon M Decker 2,  Antonio DiPasquale 1,  Thilo Focken 2,  Ivan Hemeon 2,  Kuldip Khakh 2,  Amy Kim 1,  Rainbow Kwan 2,  Andrea Lindgren 2,  Sophia Lin 2,  Jonathan Maher 1,  Janette Mezeyova 2,  Dinah Misner 1,  Karen Nelkenbrecher 2,  Jodie Pang 1,  Rebecca Reese 1,  Shannon D Shields 1,  Luis Sojo 2,  Tao Sheng 2,  Henry Verschoof 2,  Matthew Waldbrook 2,  Michael S Wilson 2,  Zhiwei Xie 2,  Clint Young 2,  Tanja S Zabka 1,  David H Hackos 1,  Daniel F Ortwine 1,  Andrew D White 3,  J P Johnson Jr 2,  C Lee Robinette 2,  Christoph M Dehnhardt 2,  Charles J Cohen 2,  Daniel P Sutherlin 1
Affiliations

Affiliations

  • 1 Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
  • 2 Xenon Pharmaceuticals, Inc., 200-3650 Gilmore Way, Burnaby, British Columbia V5G 4W8, Canada.
  • 3 Chempartner, Building No. 5, 998 Halei Road, Zhangjiang Hi-Tech Park, Pudong New Area, Shanghai 201203, P.R. China.
PMID: 33682420 DOI: 10.1021/acs.jmedchem.1c00049
Abstract

Nav1.7 is an extensively investigated target for pain with a strong genetic link in humans, yet in spite of this effort, it remains challenging to identify efficacious, selective, and safe inhibitors. Here, we disclose the discovery and preclinical profile of GDC-0276 (1) and GDC-0310 (2), selective Nav1.7 inhibitors that have completed Phase 1 trials. Our initial search focused on close-in analogues to early compound 3. This resulted in the discovery of GDC-0276 (1), which possessed improved metabolic stability and an acceptable overall pharmacokinetics profile. To further derisk the predicted human pharmacokinetics and enable QD dosing, additional optimization of the scaffold was conducted, resulting in the discovery of a novel series of N-benzyl piperidine Nav1.7 inhibitors. Improvement of the metabolic stability by blocking the labile benzylic position led to the discovery of GDC-0310 (2), which possesses improved Nav selectivity and pharmacokinetic profile over 1.

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