Sulfonamides as Selective NaV1.7 Inhibitors: Optimizing Potency and Pharmacokinetics to Enable in Vivo Target Engagement

  • ACS Med Chem Lett. 2016 Sep 21;7(12):1062-1067. doi: 10.1021/acsmedchemlett.6b00243.
Isaac E Marx  1 ,  Thomas A Dineen  1 ,  Jessica Able  1 ,  Christiane Bode  1 ,  Howard Bregman  1 ,  Margaret Chu-Moyer  1 ,  Erin F DiMauro  1 ,  Bingfan Du  1 ,  Robert S Foti  1 ,  Robert T Fremeau Jr  1 ,  Hua Gao  1 ,  Hakan Gunaydin  1 ,  Brian E Hall  1 ,  Liyue Huang  1 ,  Thomas Kornecook  1 ,  Charles R Kreiman  1 ,  Daniel S La  1 ,  Joseph Ligutti  1 ,  Min-Hwa Jasmine Lin  1 ,  Dong Liu  1 ,  Jeff S McDermott  1 ,  Bryan D Moyer  1 ,  Emily A Peterson  1 ,  Jonathan T Roberts  1 ,  Paul Rose  1 ,  Jean Wang  1 ,  Beth D Youngblood  1 ,  Violeta Yu  1 ,  Matthew M Weiss  1
Affiliations
  • 1. Department of Medicinal Chemistry, Department of Molecular Engineering, Department of Pharmacokinetics and Drug Metabolism, Department of Neuroscience, and Department of Biologics, Amgen, Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, and One Amgen Center Drive, Thousand Oaks, California 91320, United States.
PMID: 27994738 DOI: 10.1021/acsmedchemlett.6b00243
Abstract

Human genetic evidence has identified the voltage-gated Sodium Channel NaV1.7 as an attractive target for the treatment of Pain. We initially identified naphthalene sulfonamide 3 as a potent and selective inhibitor of NaV1.7. Optimization to reduce biliary clearance by balancing hydrophilicity and hydrophobicity (Log D) while maintaining NaV1.7 potency led to the identification of quinazoline 16 (AM-2099). Compound 16 demonstrated a favorable pharmacokinetic profile in rat and dog and demonstrated dose-dependent reduction of histamine-induced scratching bouts in a mouse behavioral model following oral dosing.

Keywords
NaV1.5; NaV1.7; Sodium channel; histamine scratching model; pain.
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