1,2,4-Triazolsulfone: A novel isosteric replacement of acylsulfonamides in the context of NaV1.7 inhibition | UAMS Department of Biomedical Informatics

Bioorg Med Chem Lett. 2018 Jun 15;28(11):2103-2108. doi: 10.1016/j.bmcl.2018.04.035. Epub 2018 Apr 17

Boezio AA, Andrews K, Boezio C, Chu-Moyer M, Copeland KW, DiMauro EF, Foti RS, Fremeau RT Jr, Gao H, Geuns-Meyer S, Graceffa RF, Gunaydin H, Huang H, La DS, Ligutti J, Moyer BD, Peterson EA, Yu V, Weiss MM

Abstract

Recently, the identification of several classes of aryl sulfonamides and acyl sulfonamides that potently inhibit Na_V1.7 and demonstrate high levels of selectivity over other Na_V isoforms have been reported. The fully ionizable nature of these inhibitors has been shown to be an important part of the pharmacophore for the observed potency and isoform selectivity. The requirement of this functionality, however, has presented challenges associated with optimization toward inhibitors with drug-like properties and minimal off-target activity. In an effort to obviate these challenges, we set out to develop an orally bioavailable…