Identification of Selective Acyl Sulfonamide–Cycloalkylether Inhibitors of the Voltage-Gated Sodium Channel (NaV) 1.7 with Potent Analgesic Activity
| Autor: | Qi Jia, Jean-Christophe Andrez, Charles J. Cohen, Jae H. Chang, Kuldip Khakh, J. P. Johnson, Chien-An Chen, Jun Li, Karen Nelkenbrecher, Thilo Focken, Zhiwei Xie, Daniel F. Ortwine, Brian Safina, Michael Edward Grimwood, Andrew D. White, Christoph Martin Dehnhardt, Shannon Decker, Ivan William Hemeon, David H. Hackos, Sophia Lin, Jodie Pang, Luis Sojo, Girish Bankar, Andrea Lindgren, Matthew Waldbrook, Elaine Chang, C. Lee Robinette, Shaoyi Sun, Antonio G. DiPasquale, Tao Sheng, Clint Young, Rainbow Kwan, Benjamin D. Sellers, Sultan Chowdhury, Michael Scott Wilson, Lunbin Deng, Daniel P. Sutherlin, Alla Yurevna Zenova |
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| Rok vydání: | 2018 |
| Předmět: |
0303 health sciences
Chemistry Sodium channel Pharmacology 01 natural sciences Molecular Docking Simulation 0104 chemical sciences 010404 medicinal & biomolecular chemistry 03 medical and health sciences Pharmacokinetics In vivo Docking (molecular) Drug Discovery Microsome Molecular Medicine Structure–activity relationship Potency 030304 developmental biology |
| Zdroj: | Journal of Medicinal Chemistry. 62:908-927 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.8b01621 |
| Popis: | Herein, we report the discovery and optimization of a series of orally bioavailable acyl sulfonamide NaV1.7 inhibitors that are selective for NaV1.7 over NaV1.5 and highly efficacious in in vivo models of pain and hNaV1.7 target engagement. An analysis of the physicochemical properties of literature NaV1.7 inhibitors suggested that acyl sulfonamides with high fsp3 could overcome some of the pharmacokinetic (PK) and efficacy challenges seen with existing series. Parallel library syntheses lead to the identification of analogue 7, which exhibited moderate potency against NaV1.7 and an acceptable PK profile in rodents, but relatively poor stability in human liver microsomes. Further, design strategy then focused on the optimization of potency against hNaV1.7 and improvement of human metabolic stability, utilizing induced fit docking in our previously disclosed X-ray cocrystal of the NaV1.7 voltage sensing domain. These investigations culminated in the discovery of tool compound 33, one of the most potent and... |
| Databáze: | OpenAIRE |
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