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.
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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)
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Copyright | Copyright © 2014 Elsevier Ltd. All rights reserved. |
Chemical References |
- Analgesics
- NAV1.7 Voltage-Gated Sodium Channel
- Quinoxalines
- Sodium Channel Blockers
- Spiro Compounds
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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
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