1. Aminopiperidine sulfonamide Cav2.2 channel inhibitors for the treatment of chronic pain.
- Author
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Shao PP, Ye F, Chakravarty PK, Varughese DJ, Herrington JB, Dai G, Bugianesi RM, Haedo RJ, Swensen AM, Warren VA, Smith MM, Garcia ML, McManus OB, Lyons KA, Li X, Green M, Jochnowitz N, McGowan E, Mistry S, Sun SY, Abbadie C, Kaczorowski GJ, and Duffy JL
- Subjects
- Animals, Calcium Channel Blockers chemical synthesis, Calcium Channel Blockers pharmacokinetics, Calcium Channels, N-Type metabolism, Cells, Cultured, Dogs, Humans, Mice, Mice, Knockout, Microsomes, Liver drug effects, Patch-Clamp Techniques, Piperidines chemical synthesis, Piperidines pharmacokinetics, Rats, Rats, Sprague-Dawley, Sulfonamides chemical synthesis, Sulfonamides pharmacokinetics, Tissue Distribution, Calcium Channel Blockers pharmacology, Calcium Channels, N-Type chemistry, Calcium Channels, N-Type physiology, Chronic Pain drug therapy, Hyperalgesia drug therapy, Inflammation drug therapy, Neuralgia drug therapy, Piperidines pharmacology, Sulfonamides pharmacology
- 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.
- Published
- 2012
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