Design of Conformationally Constrained Acyl Sulfonamide Isosteres: Identification of N-([1,2,4]Triazolo[4,3-a]pyridin-3-yl)methane-sulfonamides as Potent and Selective hNaV1.7 Inhibitors for the Treatment of Pain
| Autor: | Girish Bankar, Charles J. Cohen, Bowen Li, Kuldip Khakh, Sultan Chowdhury, Elaine Chang, Paul Robert Bichler, Christoph Martin Dehnhardt, Daniel P. Sutherlin, Jodie Pang, Michael D. Wilson, Yi Zhang, Zhiwei Xie, Matthew Waldbrook, C. Lee Robinette, Jae H. Chang, Karen Nelkenbrecher, Ivan William Hemeon, Alla Yurevna Zenova, Tao Sheng, Samuel J. Goodchild, Clint Young, Navjot Chahal, Rainbow Kwan, Daniel F. Ortwine, Brian Safina, Sophia Lin, Andrew D. White, Parisa Karimi Tari, Qi Jia, J. P. Johnson, Thilo Focken, Chien-An Chen, David H. Hackos, Shannon Decker, Noah G. Shuart, Luis Sojo, Christine Chabot, Shaoyi Sun, Michael Edward Grimwood |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
chemistry.chemical_classification Genetically modified mouse Stereochemistry Aryl Sodium channel In vitro Sulfonamide 03 medical and health sciences chemistry.chemical_compound 030104 developmental biology 0302 clinical medicine chemistry In vivo Drug Discovery Lipophilicity Molecular Medicine Potency 030217 neurology & neurosurgery |
| Zdroj: | Journal of Medicinal Chemistry. 61:4810-4831 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | The sodium channel NaV1.7 has emerged as a promising target for the treatment of pain based on strong genetic validation of its role in nociception. In recent years, a number of aryl and acyl sulfonamides have been reported as potent inhibitors of NaV1.7, with high selectivity over the cardiac isoform NaV1.5. Herein, we report on the discovery of a novel series of N-([1,2,4]triazolo[4,3-a]pyridin-3-yl)methanesulfonamides as selective NaV1.7 inhibitors. Starting with the crystal structure of an acyl sulfonamide, we rationalized that cyclization to form a fused heterocycle would improve physicochemical properties, in particular lipophilicity. Our design strategy focused on optimization of potency for block of NaV1.7 and human metabolic stability. Lead compounds 10, 13 (GNE-131), and 25 showed excellent potency, good in vitro metabolic stability, and low in vivo clearance in mouse, rat, and dog. Compound 13 also displayed excellent efficacy in a transgenic mouse model of induced pain. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
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