Sulfonamides as Selective NaV1.7 Inhibitors: Optimizing Potency, Pharmacokinetics, and Metabolic Properties to Obtain Atropisomeric Quinolinone (AM-0466) that Affords Robust in Vivo Activity

  • J Med Chem. 2017 Jul 27;60(14):5990-6017. doi: 10.1021/acs.jmedchem.6b01850.
Russell F Graceffa ,  Alessandro A Boezio ,  Jessica Able  1 ,  Steven Altmann ,  Loren M Berry ,  Christiane Boezio ,  John R Butler ,  Margaret Chu-Moyer ,  Melanie Cooke ,  Erin F DiMauro ,  Thomas A Dineen ,  Elma Feric Bojic ,  Robert S Foti ,  Robert T Fremeau Jr ,  Angel Guzman-Perez ,  Hua Gao ,  Hakan Gunaydin ,  Hongbing Huang ,  Liyue Huang ,  Christopher Ilch ,  Michael Jarosh ,  Thomas Kornecook  1 ,  Charles R Kreiman ,  Daniel S La ,  Joseph Ligutti  1 ,  Benjamin C Milgram ,  Min-Hwa Jasmine Lin ,  Isaac E Marx ,  Hanh N Nguyen ,  Emily A Peterson ,  Gwen Rescourio ,  John Roberts ,  Laurie Schenkel ,  Roman Shimanovich ,  Brian A Sparling ,  John Stellwagen ,  Kristin Taborn ,  Karina R Vaida ,  Jean Wang ,  John Yeoman ,  Violeta Yu ,  Dawn Zhu ,  Bryan D Moyer  1 ,  Matthew M Weiss
Affiliations
  • 1. Department of Neuroscience, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
PMID: 28324649 DOI: 10.1021/acs.jmedchem.6b01850
Abstract

Because of its strong genetic validation, NaV1.7 has attracted significant interest as a target for the treatment of Pain. We have previously reported on a number of structurally distinct bicyclic heteroarylsulfonamides as NaV1.7 inhibitors that demonstrate high levels of selectivity over other NaV isoforms. Herein, we report the discovery and optimization of a series of atropisomeric quinolinone sulfonamide inhibitors [ Bicyclic sulfonamide compounds as Sodium Channel inhibitors and their preparation . WO 2014201206, 2014 ] of NaV1.7, which demonstrate nanomolar inhibition of NaV1.7 and exhibit high levels of selectivity over other Sodium Channel isoforms. After optimization of metabolic and pharmacokinetic properties, including PXR activation, CYP2C9 inhibition, and CYP3A4 TDI, several compounds were advanced into in vivo target engagement and efficacy models. When tested in mice, compound 39 (AM-0466) demonstrated robust pharmacodynamic activity in a NaV1.7-dependent model of histamine-induced pruritus (itch) and additionally in a capsaicin-induced nociception model of Pain without any confounding effect in open-field activity.