1. Discovery and hit-to-lead evaluation of piperazine amides as selective, state-dependent NaV1.7 inhibitors
- Author
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Robert S. Foti, Brian A. Sparling, Thomas Kornecook, Erin F. DiMauro, Joseph Ligutti, Angel Guzman-Perez, Shuyan Yi, Howie Bregman, Michael Jarosh, Hua Gao, Hongbing Huang, Violeta Yu, Beth D. Youngblood, Bryan D. Moyer, Jessica Able, Benjamin Charles Milgram, and Matthew Weiss
- Subjects
0301 basic medicine ,Pharmacology ,Chemistry ,Stereochemistry ,Organic Chemistry ,Pharmaceutical Science ,Hit to lead ,Biochemistry ,03 medical and health sciences ,Piperazine ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,State dependent ,Drug Discovery ,Aqueous solubility ,Molecular Medicine ,Lead compound ,030217 neurology & neurosurgery - Abstract
NaV1.7 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 NaV1.7. After demonstrating significant pharmacodynamic activity with early lead compound 14 in a NaV1.7-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 NaV1.7 potency, selectivity over NaV1.5, aqueous solubility, and microsomal stability.
- Published
- 2017
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