Sulfonamides as Selective NaV1.7 Inhibitors: Optimizing Potency, Pharmacokinetics, and Metabolic Properties to Obtain Atropisomeric Quinolinone (AM-0466) that Affords Robust in Vivo Activity
| Autor: | Jessica Able, Benjamin C. Milgram, Loren Berry, Melanie Cooke, Liyue Huang, John Butler, Hongbing Huang, Violeta Yu, Kristin Taborn, John D. Roberts, Steven Altmann, Margaret Y. Chu-Moyer, John Yeoman, Jean Wang, Roman Shimanovich, Russell Graceffa, Matthew Weiss, Thomas Kornecook, Christopher P Ilch, Bryan D. Moyer, Christiane Boezio, Isaac E. Marx, Brian A. Sparling, Emily A. Peterson, Gwen Rescourio, Charles Kreiman, Elma Feric Bojic, Karina R. Vaida, Angel Guzman-Perez, Dawn Zhu, Hua Gao, Laurie B. Schenkel, Michael Jarosh, Hanh Nho Nguyen, Joseph Ligutti, Alessandro Boezio, Hakan Gunaydin, Daniel S. La, Thomas Dineen, Robert T. Fremeau, Robert S. Foti, Min-Hwa Jasmine Lin, Erin F. DiMauro, John Stellwagen |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
chemistry.chemical_classification Bicyclic molecule CYP3A4 Stereochemistry Chemistry Sodium channel Sulfonamide 03 medical and health sciences 030104 developmental biology 0302 clinical medicine In vivo Drug Discovery Molecular Medicine Structure–activity relationship Selectivity CYP2C9 030217 neurology & neurosurgery |
| Zdroj: | Journal of Medicinal Chemistry. 60:5990-6017 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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 (i... |
| Databáze: | OpenAIRE |
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