New potent cathepsin G phosphonate inhibitors

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-PhgP(OPh)2 (1) (kobs/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)PhgP(OC6H4-4-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)PhgP(OC6H4-4-S-Me)2 (19) with the highest kobs/I value ever reported in literature (256,000 M−1 s−1).

Structure–activity relationship (SAR) studies of phophonate cathepsin G inhibitors.Figure optionsDownload as PowerPoint slide