New potent cathepsin G phosphonate inhibitors

Abstract

Cathepsin G is an enzyme with dual chymotrypsin and trypsin-like specificity. As a leukocyte proteinase it is involved in the early stages of the immune response. In this work the synthesis and inhibitory activity of diaryl phosphonic-type irreversible cathepsin G inhibitors are described. Modification of the lead structure Z-Phg P(OPh) 2 ( 1) ( k obs/ I = 91 M −1 s −1) in phenyl ester moieties followed by incorporation of the basic functional group into the aromatic side chain yielded highly potent cathepsin G inhibitor Z-(4-guanidine)Phg P(OC 6H 4-4- S-Me) 2 ( 12) with the apparent second-order inhibition value at 15,600 M −1 s −1. Further elongation of the obtained compound by tripeptide resulted in the inhibitor Ac-Phe-Val-Thr-(4-guanidine)Phg P(OC 6H 4-4- S-Me) 2 ( 19) with the highest k obs/ I value ever reported in literature (256,000 M −1 s −1).