PubMed 24900606

Referenced in Channelpedia wiki pages of: none

Automatically associated channels: Cav2.2

Title: Improved Cav2.2 Channel Inhibitors through a gem-Dimethylsulfone Bioisostere Replacement of a Labile Sulfonamide.

Authors: Pengcheng P Shao, Feng Ye, Prasun K Chakravarty, 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, date & volume: ACS Med Chem Lett, 2013 Nov 14 , 4, 1064-8

PubMed link:

We report the investigation of sulfonamide-derived Cav2.2 inhibitors to address drug-metabolism liabilities with this lead class of analgesics. Modification of the benzamide substituent provided improvements in both potency and selectivity. However, we discovered that formation of the persistent 3-(trifluoromethyl)benzenesulfonamide metabolite was an endemic problem in the sulfonamide series and that the replacement of the center aminopiperidine scaffold failed to prevent this metabolic pathway. This issue was eventually addressed by application of a bioisostere strategy. The new gem-dimethyl sulfone series retained Cav2.2 potency without the liability of the circulating sulfonamide metabolite.