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

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

  • J Med Chem. 2012 Nov 26;55(22):9847-55. doi: 10.1021/jm301056k.
Pengcheng P Shao 1,  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
Affiliations

Affiliation

  • 1 Departments of Medicinal Chemistry, Merck Research Laboratories, Rahway, New Jersey 07065, USA. pengcheng.shao@merck.com
PMID: 23098566 DOI: 10.1021/jm301056k
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.

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