1,2,4-Triazolsulfone: A novel isosteric replacement of acylsulfonamides in the context of Na V 1.7 inhibition

• Published in: Bioorganic & medicinal chemistry letters 2018-06, Vol.28 (11), p.2103-2108
• Main Authors: Boezio, Alessandro A, Andrews, Kristin, Boezio, Christiane, Chu-Moyer, Margaret, Copeland, Katrina W, DiMauro, Erin F, Foti, Robert S, Fremeau, Jr, Robert T, Gao, Hua, Geuns-Meyer, Stephanie, Graceffa, Russell F, Gunaydin, Hakan, Huang, Hongbing, La, Daniel S, Ligutti, Joseph, Moyer, Bryan D, Peterson, Emily A, Yu, Violeta, Weiss, Matthew M
• Format: Article
• Language: English
• Subjects: Animals; Dose-Response Relationship, Drug; Humans; Microsomes, Liver - drug effects; Microsomes, Liver - metabolism; Molecular Structure; NAV1.7 Voltage-Gated Sodium Channel - metabolism; Rats; Structure-Activity Relationship; Sulfonamides - chemistry; Sulfonamides - pharmacology
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2018.04.035

Recently, the identification of several classes of aryl sulfonamides and acyl sulfonamides that potently inhibit Na 1.7 and demonstrate high levels of selectivity over other Na 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, selective Na 1.7 inhibitor, lacking these acidic functional groups. Herein, we report the discovery of a novel series of inhibitors wherein a triazolesulfone has been designed to serve as a bioisostere for the acyl sulfonamide. This work culminated in the delivery of a potent series of inhibitors which demonstrated good levels of selectivity over Na 1.5 and favorable pharmacokinetics in rodents.