Identification of Selective Acyl Sulfonamide–Cycloalkylether Inhibitors of the Voltage-Gated Sodium Channel (Na_V) 1.7 with Potent Analgesic Activity

Abstract

Herein, we report the discovery and optimization of a series of orally bioavailable acyl sulfonamide NaV1.7 inhibitors that are selective for NaV1.7 over NaV1.5 and highly efficacious in in vivo models of pain and hNaV1.7 target engagement. An analysis of the physicochemical properties of literature NaV1.7 inhibitors suggested that acyl sulfonamides with high fsp3 could overcome some of the pharmacokinetic (PK) and efficacy challenges seen with existing series. Parallel library syntheses lead to the identification of analogue 7, which exhibited moderate potency against NaV1.7 and an acceptable PK profile in rodents, but relatively poor stability in human liver microsomes. Further, design strategy then focused on the optimization of potency against hNaV1.7 and improvement of human metabolic stability, utilizing induced fit docking in our previously disclosed X-ray cocrystal of the NaV1.7 voltage sensing domain. These investigations culminated in the discovery of tool compound 33, one of the most potent and efficacious NaV1.7 inhibitors reported to date.

A New Lead Identification Strategy: Screening an sp3‐rich and Lead‐like Compound Library Composed of 7‐Azanorbornane Derivatives

“…Compounds with higher Fsp 3 values tend to possess more drug‐like properties such as high solubility and low promiscuity, and these compounds are more likely to achieve clinical success. Indeed, by enhancing the Fsp 3 values in the course of lead optimization, many research groups succeeded in improving physical properties of candidate compounds …”

Voltage-gated Sodium Channels and Blockers: An Overview and Where Will They Go?

“…In fact, to date, it has been established that sodium channels are essential for the transition of pain sensation. In particular, at least three subtypes presented in human dorsal root ganglion (DRG) neurons, Nav1.7, Nav1.8 and Nav1.9 have been identified as the key players in transportation of pain signals [35][36][37][38][39] . Nav1.7 channels activate and inactivate rapidly.…”

Discovery of aryl sulfonamide-selective Nav1.7 inhibitors with a highly hydrophobic ethanoanthracene core

“…Similar hydrophobic fragments also exist in the inhibitor GNE-131 and compound 1d (Fig. 1 ) [ 19 , 20 ]. In addition, compound 10o also has an alkaline tetrahydropyrrole side chain, which is similar to the ethylazetidine group in GX-936.…”

“…Based on that design, compound 1d has a simplified adamantane moiety instead of an adamantyl group and maintains good activity while displaying increased liver microsomal stability and improved efficacy (Fig. 1 ) [ 20 ]. Looking at the structure of known Nav1.7 inhibitors, it is not difficult to find that aryl sulfonamide or acyl sulfonamide group is important for activity and selectivity.…”