Cyclopropyl-spiro-piperidines useful as sodium channel blockers

Article abstract of DOI:10.1021/ml300195b

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.

Full text of DOI:10.1021/ml300195b

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Cyclopropyl-spiro-piperidines Useful as Sodium Channel Blockers
Patent Highlight
Benjamin Blass*
Temple University School of Pharmacy, 3307 North Broad Street, Philadelphia, Pennsylvania 19140
Title:
Cyclopropyl-spiro-piperidines Useful as Sodium Channel Blockers
Patent Application:
Priority Application:
Inventors:
WO2012/047703A2
Publication Date:
Priority Date:
April 12, 2012
US61/389463
October 4, 2010
Ho, G. D.; Tulshian, D.; Heap, C. R.
Schering Corporation
Assignee:
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:
Biological Data:
Nav1.7 FLIPR and electrophysiological patch clamp using HEK293 or CHO-K1 cells.
Published: July 30, 2012
© 2012 American Chemical Society
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dx.doi.org/10.1021/ml300195b | ACS Med. Chem. Lett. 2012, 3, 697−698

ACS Medicinal Chemistry Letters
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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.
AUTHOR INFORMATION
Corresponding Author
*Tel: 215-707-1085. E-mail: benjamin.blass@temple.edu.
■
Notes
The authors declare no competing financial interest.
698
dx.doi.org/10.1021/ml300195b | ACS Med. Chem. Lett. 2012, 3, 697−698