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 Ca_v2.2 (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_v2.2. In particular, 19 is an inhibitor of Ca_v2.2 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_v2.2 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.