Abstract
The voltage-gated calcium channel Ca(v)2.2 (N-type calcium channel) is a critical regulator of synaptic transmission and has emerged as an attractive target for the treatment of chronic pain. We report here the discovery of sulfonamide-derived, state-dependent inhibitors of Ca(v)2.2. In particular, 19 is an inhibitor of Ca(v)2.2 that is selective over cardiac ion channels, with a good preclinical PK and biodistribution profile. This compound exhibits dose-dependent efficacy in preclinical models of inflammatory hyperalgesia and neuropathic allodynia and is devoid of ancillary cardiovascular or CNS pharmacology at the doses tested. Importantly, 19 exhibited no efficacy in Ca(v)2.2 gene-deleted mice. The discovery of metabolite 26 confounds further development of members of this aminopiperidine sulfonamide series. This discovery also suggests specific structural liabilities of this class of compounds that must be addressed.
MeSH terms
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Animals
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Calcium Channel Blockers / chemical synthesis
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Calcium Channel Blockers / pharmacokinetics
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Calcium Channel Blockers / pharmacology*
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Calcium Channels, N-Type / chemistry*
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Calcium Channels, N-Type / metabolism
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Calcium Channels, N-Type / physiology*
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Cells, Cultured
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Chronic Pain / drug therapy*
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Dogs
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Humans
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Hyperalgesia / drug therapy*
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Inflammation / drug therapy*
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Mice
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Mice, Knockout
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Microsomes, Liver / drug effects
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Neuralgia / drug therapy*
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Patch-Clamp Techniques
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Piperidines / chemical synthesis
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Piperidines / pharmacokinetics
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Piperidines / pharmacology*
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Rats
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Rats, Sprague-Dawley
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Sulfonamides / chemical synthesis
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Sulfonamides / pharmacokinetics
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Sulfonamides / pharmacology*
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Tissue Distribution
Substances
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Cacna1b protein, mouse
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Cacna1b protein, rat
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Calcium Channel Blockers
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Calcium Channels, N-Type
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N-cyclopropyl-N-(1-((5-fluoro-2-(methylsulfonyl)phenyl)carbonyl)piperidin-4-yl)-3-(trifluoromethyl)benzenesulfonamide
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Piperidines
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Sulfonamides