Title:	Cyclopropyl-spiro-piperidines Useful as Sodium Channel Blockers
Patent Application:	WO2012/047703A2	Publication Date:	April 12, 2012
Priority Application:	US61/389463	Priority Date:	October 4, 2010
Inventors:	Ho, G. D.; Tulshian, D.; Heap, C. R.
Assignee:	Schering Corporation
Disease Area:	Chronic and Neuropathic Pain	Biological Target:	Voltage-Gated Sodium Channel Nav1.7
Summary:	Voltage-gated ion channels are critical to the generation and propagation of electrical signals and action potentials in neuronal and muscle tissue. The voltage-gated sodium channels in particular mediate the rapid depolarization of cells, creating the rising phase of an action potential, which in turn activates voltage-gated calcium and potassium channels. To date, nine voltage-gated sodium channel subtypes have been identified, and blockers of these channels have been developed as antiarrhythmic agents, anticonvulsants, antiepileptics, and local anesthetics. Voltage-gated sodium channels have also been targeted for the treatment of neuropathic pain, as it has been established that these channels play a critical role in the nerve cells associated with this condition. Specifically, it has been hypothesized that neuropathic pain is a result of increased sodium channel activity in injured nerves and that selective blockade of sodium channels such as Nav1.7 would provide therapeutic relief. The present application describes a series of cyclopropyl-spiro-piperidines useful as sodium channel blockers for the treatment of chronic and neuropathic pain.
Important Compound Classes:
Definitions:	Z = a bond, C1–C6 alkyl, C(O), CO2, CONH, or SO2
	R1 = H, optionally substituted C6–C10 aryl, optionally substituted C5–C10 heteroaryl
	R2 = H, (CH2)nNR3R4, (CH2)nC5–C10 heterocyclyl, or NR3CO2R4
	Ra = H, halogen, C1–C10 alkyl, (CH2)nC3–C10 cycloalkyl, C6–C10 aryl, C5–C10 heteroaryl, C5–C10 heterocyclyl, OR5, N(R5)2, CONHR5, CO2R5, CN, CF3, or NO2
Key Structures:
Biological Assay:	Nav1.7 FLIPR and electrophysiological patch clamp using HEK293 or CHO-K1 cells.
Biological Data:
Synthesis:
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.