Discovery and hit-to-lead evaluation of piperazine amides as selective, state-dependent NaV1.7 inhibitorsThe authors declare no competing financial interests.Electronic supplementary information (ESI) available: Assay protocols, experimental procedures, spectra of key compounds. See DOI: 10.1039/c6md00578k

Na V 1.7 is a particularly compelling target for the treatment of pain. Herein, we report the discovery and evaluation of a series of piperazine amides that exhibit state-dependent inhibition of Na V 1.7. After demonstrating significant pharmacodynamic activity with early lead compound 14 in a Na V 1.7-dependent behavioural mouse model, we systematically established SAR trends throughout each sector of the scaffold. The information gleaned from this modular analysis was then applied additively to quickly access analogues that encompass an optimal balance of properties, including Na V 1.7 potency, selectivity over Na V 1.5, aqueous solubility, and microsomal stability. Optimization of a screening hit led to the identification of Na V 1.7 inhibitors with a desirable balance of properties.