Design and synthesis of novel α-aminoamides derivatives as Nav1.7 inhibitors for antinociception

Three novel series of alpha-aminoamides derivatives were designed and synthesized based on ralfinamide, and their Nav1.7 inhibitory activities were evaluated using manual patch clamp electrophysiology. Active compounds inhibited Nav1.7 with half maximal inhibitory concentration (IC50) values ranging from 2.9 mu mol/L to 21.4 mu mol/L. Among them, the most potent compound 19h exhibited about 12-fold potency better than ralfinamide. The investigation of their structure-activity relationship gives a strategy to improve the Nav1.7 inhibition of ralfinamide analogues. Compound 19h was efficacious in antinociception in the mouse spared nerve injury (SNI) model of neuropathic pain without causing sedation in the open field test. (C) 2021 Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.

Automated summary

Three novel series of alpha-aminoamides derivatives were synthesized based on ralfinamide, and their inhibitory activities against Nav1.7 were evaluated. The most potent compound 19h exhibited significantly higher activity than ralfinamide, and the structure-activity relationship investigation provided a strategy for improving the Nav1.7 inhibition of ralfinamide analogues.