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

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...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2014-11, Vol.24 (21), p.4958-4962
Main Authors: Yang, Shu-Wei, Ho, Ginny D, Tulshian, Deen, Bercovici, Ana, Tan, Zheng, Hanisak, Jennifer, Brumfield, Stephanie, Matasi, Julius, Sun, Xianfeng, Sakwa, Samuel A, Herr, R Jason, Zhou, Xiaoping, Bridal, Terry, Urban, Mark, Vivian, Jeffrey, Rindgen, Diane, Sorota, Steve
Format: Article
Language:English
Subjects:
Analgesics - chemistry
Analgesics - 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
Sodium Channel Blockers - pharmacology
Spinal Nerves - drug effects
Spiro Compounds - chemistry
Spiro Compounds - pharmacology
Structure-Activity Relationship
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Summary: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.
ISSN:1464-3405
DOI:10.1016/j.bmcl.2014.09.038