2. Academic Validation
  3. The discovery of benzoxazine sulfonamide inhibitors of NaV1.7: Tools that bridge efficacy and target engagement

The discovery of benzoxazine sulfonamide inhibitors of NaV1.7: Tools that bridge efficacy and target engagement

  • Bioorg Med Chem Lett. 2017 Aug 1;27(15):3477-3485. doi: 10.1016/j.bmcl.2017.05.070.
Daniel S La 1,  Emily A Peterson 2,  Christiane Bode 2,  Alessandro A Boezio 2,  Howard Bregman 2,  Margaret Y Chu-Moyer 2,  James Coats 2,  Erin F DiMauro 2,  Thomas A Dineen 2,  Bingfan Du 2,  Hua Gao 3,  Russell Graceffa 2,  Hakan Gunaydin 3,  Angel Guzman-Perez 2,  Robert Fremeau Jr 4,  Xin Huang 3,  Christopher Ilch 4,  Thomas J Kornecook 5,  Charles Kreiman 2,  Joseph Ligutti 6,  Min-Hwa Jasmine Lin 7,  Jeff S McDermott 4,  Isaac Marx 2,  David J Matson 4,  Stefan I McDonough 4,  Bryan D Moyer 5,  Hanh Nho Nguyen 2,  Kristin Taborn 4,  Violeta Yu 4,  Matthew M Weiss 2
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Amgen Inc., 360 Binney Street, Cambridge, MA 02142, United States. Electronic address: daniel.la@sagerx.com.
  • 2 Department of Medicinal Chemistry, Amgen Inc., 360 Binney Street, Cambridge, MA 02142, United States.
  • 3 Department of Molecular Engineering, Amgen Inc., 360 Binney Street, Cambridge, MA 02142, United States.
  • 4 Department of Neuroscience, Amgen Inc., 360 Binney Street, Cambridge, MA 02142, United States.
  • 5 Department of Neuroscience, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States.
  • 6 Amgen, Thousand Oaks, CA, United States. Electronic address: jligutti@amgen.com.
  • 7 Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., 360 Binney Street, Cambridge, MA 02142, United States.
PMID: 28629594 DOI: 10.1016/j.bmcl.2017.05.070
Abstract

The voltage-gated Sodium Channel NaV1.7 has received much attention from the scientific community due to compelling human genetic data linking gain- and loss-of-function mutations to pain phenotypes. Despite this genetic validation of NaV1.7 as a target for pain, high quality pharmacological tools facilitate further understanding of target biology, establishment of target coverage requirements and subsequent progression into the clinic. Within the sulfonamide class of inhibitors, reduced potency on rat NaV1.7 versus human NaV1.7 was observed, rendering in vivo rat pharmacology studies challenging. Herein, we report the discovery and optimization of novel benzoxazine sulfonamide inhibitors of human, rat and mouse NaV1.7 which enabled pharmacological assessment in traditional behavioral rodent models of pain and in turn, established a connection between formalin-induced pain and histamine-induced pruritus in mice. The latter represents a simple and efficient means of measuring target engagement.

Keywords

Medicinal chemistry; Nav1.7; Pharmacology; Structure activity relationship.

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