We report the investigation of sulfonamide-derived Ca(v)two.two inhibitors selleck inhibitor to deal with drug-metabolism liabilities with this particular lead class of analgesics. Modification in the benzamide substituent presented improvements in each potency and Ferroptosis selectivity. Nevertheless, we discovered that formation of the persistent 3-(trifluoromethyl)-benzenesulfonamide metabolite was an endemic difficulty within the sulfonamide series and the replacement on the center aminopiperidine scaffold failed to avoid this metabolic pathway. This challenge was inevitably addressed by application of a bioisostere technique. The brand new gem-dimethyl sulfone series retained selleck products Ca(v)two.two potency without having the liability of your circulating sulfonamide metabolite.