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 hNa V 1.7 Inhibitors for the Treatment of Pain

• Published in: Journal of medicinal chemistry 2018-06, Vol.61 (11), p.4810
• Main Authors: Focken, Thilo, Chowdhury, Sultan, Zenova, Alla, Grimwood, Michael E, Chabot, Christine, Sheng, Tao, Hemeon, Ivan, Decker, Shannon M, Wilson, Michael, Bichler, Paul, Jia, Qi, Sun, Shaoyi, Young, Clint, Lin, Sophia, Goodchild, Samuel J, Shuart, Noah G, Chang, Elaine, Xie, Zhiwei, Li, Bowen, Khakh, Kuldip, Bankar, Girish, Waldbrook, Matthew, Kwan, Rainbow, Nelkenbrecher, Karen, Karimi Tari, Parisa, Chahal, Navjot, Sojo, Luis, Robinette, C Lee, White, Andrew D, Chen, Chien-An, Zhang, Yi, Pang, Jodie, Chang, Jae H, Hackos, David H, Johnson, Jr, J P, Cohen, Charles J, Ortwine, Daniel F, Sutherlin, Daniel P, Dehnhardt, Christoph M, Safina, Brian S
• Format: Article
• Language: English
• ISSN: 1520-4804
• DOI: 10.1021/acs.jmedchem.7b01826

The sodium channel Na 1.7 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 Na 1.7, with high selectivity over the cardiac isoform Na 1.5. 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 Na 1.7 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 Na 1.7 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.