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

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

Affiliation

  • 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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