Bioavailable pyrrolo-benzo-1,4-diazines as Na(v)1.7 sodium channel blockers for the treatment of pain.

Abstract

A series of pyrrolo-benzo-1,4-diazine analogs have been synthesized to improve the profile of the previous lead compound 1. The syntheses, structure-activity relationships, and selected pharmacokinetic data of these analogs are described. The optimization efforts allowed the identification of 33, a quinoline amide exhibiting potent Na(v)1.7 inhibitory activity and moderate selectivity over Na(v)1.5. Compound 33 displayed anti-nociceptive oral efficacy in a rat CFA inflammatory pain model at 100 mpk and in a rat spinal nerve ligation neuropathic pain model with an EC50 75 μM.

• Authors: Shu-Wei Yang, Ginny D Ho, Deen Tulshian, Ana Bercovici, Zheng Tan, Jennifer Hanisak, Stephanie Brumfield, Julius Matasi, Xianfeng Sun, Samuel A Sakwa, R Jason Herr, Xiaoping Zhou, Terry Bridal, Mark Urban, Jeffrey Vivian, Diane Rindgen, Steve Sorota
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 24 Issue 21 Pg. 4958-62 (Nov 01 2014) ISSN: 1464-3405 [Electronic] England
• PMID: 25288187 (Publication Type: Journal Article)
• Copyright: Copyright © 2014 Elsevier Ltd. All rights reserved.

Chemical References

• Analgesics
• NAV1.7 Voltage-Gated Sodium Channel
• Quinoxalines
• Sodium Channel Blockers
• Spiro Compounds

Topics

• Analgesics (chemistry, pharmacology)
• Animals
• Ganglia, Spinal (drug effects)
• Molecular Structure
• NAV1.7 Voltage-Gated Sodium Channel (chemistry)
• Neuralgia (drug therapy)
• Patch-Clamp Techniques
• Quinoxalines (chemistry)
• Rats
• Sodium Channel Blockers (chemistry, pharmacology)
• Spinal Nerves (drug effects)
• Spiro Compounds (chemistry, pharmacology)
• Structure-Activity Relationship