jm7b01826_si_002.cif (22.57 kB)

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

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posted on 08.05.2018, 00:00 by Thilo Focken, Sultan Chowdhury, Alla Zenova, Michael E. Grimwood, Christine Chabot, Tao Sheng, Ivan Hemeon, Shannon M. Decker, Michael Wilson, Paul Bichler, Qi Jia, Shaoyi Sun, Clint Young, Sophia Lin, Samuel J. Goodchild, Noah G. Shuart, Elaine Chang, Zhiwei Xie, Bowen Li, Kuldip Khakh, Girish Bankar, Matthew Waldbrook, Rainbow Kwan, Karen Nelkenbrecher, Parisa Karimi Tari, Navjot Chahal, Luis Sojo, C. Lee Robinette, Andrew D. White, Chien-An Chen, Yi Zhang, Jodie Pang, Jae H. Chang, David H. Hackos, J. P. Johnson, Charles J. Cohen, Daniel F. Ortwine, Daniel P. Sutherlin, Christoph M. Dehnhardt, Brian S. Safina
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.