Journal of Medicinal Chemistry
Journal of Medicinal Chemistry
5 years ago

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

Sulfonamides as Selective NaV1.7 Inhibitors: Optimizing Potency, Pharmacokinetics, and Metabolic Properties to Obtain Atropisomeric Quinolinone (AM-0466) that Affords Robust in Vivo Activity
Emily A. Peterson, Violeta Yu, Daniel S. La, Kristin Taborn, Elma Feric Bojic, Hanh N. Nguyen, Joseph Ligutti, Russell F. Graceffa, John Stellwagen, Roman Shimanovich, Benjamin C. Milgram, Christopher Ilch, Steven Altmann, Hongbing Huang, Thomas Kornecook, Melanie Cooke, John Yeoman, Laurie Schenkel, Isaac E. Marx, Margaret Chu-Moyer, Robert T. Fremeau, Jean Wang, Angel Guzman-Perez, John Roberts, Liyue Huang, Christiane Boezio, Charles R. Kreiman, Dawn Zhu, Erin F. DiMauro, Loren M. Berry, Alessandro A. Boezio, Gwen Rescourio, Karina R. Vaida, Brian A. Sparling, Michael Jarosh, Hakan Gunaydin, Thomas A. Dineen, John R. Butler, Matthew M. Weiss, Robert S. Foti, Min-Hwa Jasmine Lin, Bryan D. Moyer, Jessica Able, Hua Gao
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.

Publisher URL: http://dx.doi.org/10.1021/acs.jmedchem.6b01850

DOI: 10.1021/acs.jmedchem.6b01850

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