Abstract
A new series of aryls, including benzo[d]imidazole/isoxazole/pyrazole, conjugated to 3N-substituted-azabicyclo[3.1.0]hexane derivatives were designed and synthesized as inhibitors of T-type calcium channels. Among the synthesized compounds, 3N-R-substituted azabicyclo[3.1.0]hexane carboxamide derivatives containing 5-isobutyl-1-phenyl-pyrazole ring exhibited potent and selective T-channel inhibition and good metabolic stability without CYP450 inhibition. Compounds 10d and 10e contained hydrophobic substituents at the 3N-position and exhibited potent in vitro efficacy, as well as neuropathic pain alleviation in rats.
Keywords:
6-Pyrazoylamido-3-N-substituted-azabicyclo[3.1.0]hexane; Neuropathic pain; T-type calcium channel inhibitor.
Copyright © 2016 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Administration, Oral
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Animals
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Azabicyclo Compounds / administration & dosage
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Azabicyclo Compounds / chemical synthesis
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Azabicyclo Compounds / chemistry
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Azabicyclo Compounds / pharmacology*
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Calcium Channel Blockers / administration & dosage
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Calcium Channel Blockers / chemical synthesis
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Calcium Channel Blockers / chemistry
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Calcium Channel Blockers / pharmacology*
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Calcium Channels, T-Type / metabolism*
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Disease Models, Animal
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HEK293 Cells
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Humans
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Male
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Neuralgia / drug therapy*
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Neuralgia / metabolism
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Pyrazoles / administration & dosage
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Pyrazoles / chemical synthesis
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Pyrazoles / chemistry
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Pyrazoles / pharmacology*
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Rats
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Structure-Activity Relationship
Substances
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Azabicyclo Compounds
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Calcium Channel Blockers
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Calcium Channels, T-Type
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Pyrazoles