Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 4, Issue 11, Pages 1064-1068Publisher
AMER CHEMICAL SOC
DOI: 10.1021/ml4002612
Keywords
Ca(v)2.2; N-type calcium channel; pain; sulfonamide; bioisostere; sulfone
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We report the investigation of sulfonamide-derived Ca(v)2.2 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 Ca(v)2.2 potency without the liability of the circulating sulfonamide metabolite.
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