Substituted Pyridines as Sodium Channel Blockers: Patent Highlight

Benjamin Blass

doi:10.1021/ml300194f

editorial

. 2012 Jul 26;3(9):695–696. doi: 10.1021/ml300194f

Substituted Pyridines as Sodium Channel Blockers

Patent Highlight

Benjamin Blass ^1,^*

PMCID: PMC4025752 PMID: 24900533

Title:	Substituted Pyridines As Sodium Channel Blockers
Patent Application:	WO2012/085650	Publication Date:	June 28, 2012
Priority Application:	US61/426318	Priority Date:	December 22, 2012
Inventors:	Ni, C.; Park, M.; Shao, B.; Tafese, L.; Yao, J.; Youngman, M.; Zhou, X.
Assignee Company:	Purdue Pharma L.P.
Disease Area:	Pain	Biological Target:	Voltage-Gated Sodium Channel Na_v1.7
Summary:	Voltage-gated sodium channels are found in both the peripheral and the central nervous system and are the primary mechanism for generation of the rapid upstroke portion of the action potential of excitable cells. Proper function of these channels is critical to normal neuronal function, while aberrant channel function is associated with several medical conditions, including pain. It has been suggested that Nav1.7, a tetrodotoxin-sensitive channel that is preferentially expressed in peripheral sympathetic and sensory neurons, plays a key role in acute, inflammatory, and neuropathic pain. In addition, it has been demonstrated that a number of local anesthetics, such as lidocaine and bupivacaine, exert their biological effects by interfering with sodium ion influx, further suggesting a link between pain sensation and sodium channels. The present disclosure describes a series of substituted aminopyridines useful as NaV1.7 blockers for the treatment of pain.
Important Compound Classes:
Definitions:	Ar = Substituted aryl ring
	AA = Substituted amino acid side chain
	R¹ = Hydrogen, halogen, substituted alkyl
	R² = Hydrogen, substituted alkyl
Key Structures:
Biological Assay:	Nav1.7 FLIPR TETRA sodium dye assay with KCl salt and electrophysiological patch clamp (EP).
Biological Data:
Recent Review Articles:	Nantermet P. G.; Henze D. A.. Recent advances toward pain therapeutics. Annu. Rep. Med. Chem. 2011, 46, 19–32.
	Dib-Hajj S. D.; Cummins T. R.; Black J. A.; Waxman S. G.. Sodium channels in normal and pathological pain. Annu. Rev. Neurosci. 2010, 33, 325–347.
	Priest B. T.Future potential and status of selective sodium channel blockers for the treatment of pain. Curr. Opin. Drug Discovery Dev. 2009, 12 (5), 682–692.
Additional Information:	Additional possible indications suggested include neurodegeneration, cardiac arrhythmia, epilepsy, mental retardation, and movement disorder.