Cyclopropyl-spiro-piperidines Useful as Sodium Channel Blockers: Patent Highlight

Benjamin Blass

doi:10.1021/ml300195b

editorial

. 2012 Jul 30;3(9):697–698. doi: 10.1021/ml300195b

Cyclopropyl-spiro-piperidines Useful as Sodium Channel Blockers

Patent Highlight

Benjamin Blass ^1,^*

PMCID: PMC4025821 PMID: 24900534

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 Na_v1.7
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
	R^a = 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:	Na_v1.7 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.