Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.
J Med Chem. 2010 Mar 25;53(6):2651-5. doi: 10.1021/jm901790w.
Potent and noncovalent inhibitors of caspase-1 were produced by incorporating a secondary amine (reduced amide) isostere in place of the conventional electrophile (e.g., aldehyde) that normally confers high potency to cysteine protease inhibitors. Benzyl- or cyclohexylamines produced potent, reversible, and competitive inhibitors that were selective for caspase-1 (e.g., K(i) = 47 nM) over caspases 3 and 8 with minimal cytotoxicity. Unlike most cysteine protease inhibitors, these compounds do not react covalently and indiscriminately with thiols.
通过在常规亲电试剂（如醛）的位置引入仲胺（还原酰胺）等排体，产生了强效且非共价的半胱氨酸蛋白酶抑制剂。苄基或环己基胺产生了强效、可逆和竞争性抑制剂，对 caspase-1（例如，K(i) = 47 nM）具有选择性，对 caspase 3 和 8 的选择性较小，细胞毒性最小。与大多数半胱氨酸蛋白酶抑制剂不同，这些化合物不会与巯基发生非选择性的共价反应。
