Aminopiperidine sulfonamide Cav2.2 channel inhibitors for the treatment of chronic pain.

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.
Authors	Pengcheng P Shao, Feng Ye, Prasun K Chakravarty, Deepu J Varughese, James B Herrington, Ge Dai, Randal M Bugianesi, Rodolfo J Haedo, Andrew M Swensen, Vivien A Warren, McHardy M Smith, Maria L Garcia, Owen B McManus, Kathryn A Lyons, Xiaohua Li, Mitchell Green, Nina Jochnowitz, Erin McGowan, Shruti Mistry, Shu-Yu Sun, Catherine Abbadie, Gregory J Kaczorowski, Joseph L Duffy
Journal	Journal of medicinal chemistry (J Med Chem) Vol. 55 Issue 22 Pg. 9847-55 (Nov 26 2012) ISSN: 1520-4804 [Electronic] United States
PMID	23098566 (Publication Type: Journal Article)
Chemical References	Cacna1b protein, mouse Cacna1b protein, rat Calcium Channel Blockers Calcium Channels, N-Type N-cyclopropyl-N-(1-((5-fluoro-2-(methylsulfonyl)phenyl)carbonyl)piperidin-4-yl)-3-(trifluoromethyl)benzenesulfonamide Piperidines Sulfonamides
Topics	Animals Calcium Channel Blockers (chemical synthesis, pharmacokinetics, pharmacology) Calcium Channels, N-Type (chemistry, metabolism, physiology) Cells, Cultured Chronic Pain (drug therapy) Dogs Humans Hyperalgesia (drug therapy) Inflammation (drug therapy) Mice Mice, Knockout Microsomes, Liver (drug effects) Neuralgia (drug therapy) Patch-Clamp Techniques Piperidines (chemical synthesis, pharmacokinetics, pharmacology) Rats Rats, Sprague-Dawley Sulfonamides (chemical synthesis, pharmacokinetics, pharmacology) Tissue Distribution

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