Issue 4, 2017

Discovery and hit-to-lead evaluation of piperazine amides as selective, state-dependent NaV1.7 inhibitors

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.

Graphical abstract: Discovery and hit-to-lead evaluation of piperazine amides as selective, state-dependent NaV1.7 inhibitors

Supplementary files

Article information

Article type
Research Article
Submitted
14 Oct 2016
Accepted
30 Nov 2016
First published
02 Dec 2016

Med. Chem. Commun., 2017,8, 744-754

Discovery and hit-to-lead evaluation of piperazine amides as selective, state-dependent NaV1.7 inhibitors

B. A. Sparling, S. Yi, J. Able, H. Bregman, E. F. DiMauro, R. S. Foti, H. Gao, A. Guzman-Perez, H. Huang, M. Jarosh, T. Kornecook, J. Ligutti, B. C. Milgram, B. D. Moyer, B. Youngblood, V. L. Yu and M. M. Weiss, Med. Chem. Commun., 2017, 8, 744 DOI: 10.1039/C6MD00578K

To request permission to reproduce material from this article, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Spotlight

Advertisements