Key result
Acylsulfonamide analogues of the aldehyde-based inhibitor VRT-043198 showed potential as prodrugs, with their inhibition of caspase-mediated inflammation correlating with enzymatic potency.
Acylsulfonamide analogues of VRT-043198 may serve as a novel type of prodrug due to their sensitivity to hydrolysis at physiological pH.
No immediate clinical implications; leaves open further preclinical validation of acylsulfonamide caspase prodrugs.
C-based NMR. The propensity of acylsulfonamides with an aldehyde warhead to occur in a ring-closed conformation at physiological pH significantly increases the sensitivity to hydrolysis of the acylsulfonamide moiety, yielding the parent carboxylate containing inhibitors. These results indicate that the acylsulfonamide analogues of the aldehyde-based inhibitor VRT-043198 might have potential as a novel type of prodrug for the latter. Finally, inhibition of caspase 1 and 11 mediated inflammation in mouse macrophages was found to correlate with the potencies of the compounds in enzymatic assays.
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Adriaenssens et al. (2017) studied Caspase 1 and 11 mediated inflammation. Acylsulfonamide analogues of VRT-043198 was evaluated on Inhibition of caspase 1 and 11 mediated inflammation in mouse macrophages. Acylsulfonamide analogues of the aldehyde-based inhibitor VRT-043198 showed potential as prodrugs, with their inhibition of caspase-mediated inflammation correlating with enzymatic potency.
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