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Sulfonamides as Selective Na V 1.7 Inhibitors: Optimizing Potency, Pharmacokinetics, and Metabolic Properties to Obtain Atropisomeric Quinolinone (AM-0466) that Affords Robust in Vivo Activity

2017; American Chemical Society; Volume: 60; Issue: 14 Linguagem: Inglês

10.1021/acs.jmedchem.6b01850

1520-4804

Russell F. Graceffa, Alessandro A. Boezio, Jessica Able, Steven Altmann, Loren Berry, Christiane Boezio, John R. Butler, Margaret Y. Chu‐Moyer, Melanie Cooke, Erin F. DiMauro, Thomas A. Dineen, Elma Ferić Bojić, R. Foti, Robert T. Fremeau, Angel Guzmán-Pérez, Hua Gao, Hakan Günaydin, Hongbing Huang, Liyue Huang, Christopher P. Ilch, Michael Jarosh, Thomas Kornecook, Charles R. Kreiman, Daniel S. La, Joseph Ligutti, Benjamin C. Milgram, Min-Hwa Jasmine Lin, Isaac E. Marx, Hanh Nho Nguyen, Emily A. Peterson, Gwen Rescourio, John G. Roberts, Laurie B. Schenkel, Roman Shimanovich, Brian A. Sparling, John Stellwagen, Kristin Taborn, Karina R. Vaida, Jean Wang, John T. S. Yeoman, Violeta Yu, Dawn Zhu, Bryan D. Moyer, Matthew M. Weiss,

Coordination Chemistry and Organometallics

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.