Aminopiperidine Sulfonamide Cav2.2 Channel Inhibitors for the Treatment of Chronic Pain

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• 作者：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
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：November 26, 2012
• 年：2012
• 卷：55
• 期：22
• 页码：9847-9855
• 全文大小：397K
• 年卷期：v.55,no.22(November 26, 2012)
• ISSN：1520-4804

文摘

The voltage-gated calcium channel Cab>vb>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 Cab>vb>2.2. In particular, <b>19b> is an inhibitor of Cab>vb>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, <b>19b> exhibited no efficacy in Cab>vb>2.2 gene-deleted mice. The discovery of metabolite <b>26b> 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.