Synthesis and inhibiting activities of 1-peptidyl-2-haloacetyl hydrazines toward cathepsin B and calpains (original) (raw)
1993, European Journal of Medicinal Chemistry
Twenty-four I-peptidyl-2-haloacetyl hydrazines which can be considered azapeptide halomethanes were synthesized and tested as models of'cathepsin B, calpain I and calpain II inhibitors. Reagents designed for cathepsin B inactivation include Z-Tyr, Z-Tyr(1) and Z-Leu-Leu attached to an a-azaglycine or a-azaalanine unit in P,. By use of kinetic analysis, they proved to irreversibly inactivate cathepsin B via a reversible enzyme-inhibitor intermediate. Second-order rate constants in the range 725-306 000 M-is-l were found for cathepsin B inactivation, with no more than 7 500 M-is-' for calpain II. K, for the reversible EI adducts ranged from 11 to 0.06 PM for cathepsin B. Structure of the possible reversible EI complex is proposed and used to discuss the effects of structural variation of the inhibitors on the kinetic parameters of inactivation.
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