1. New potent cathepsin G phosphonate inhibitors
- Author
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Sieńczyk, Marcin, Lesner, Adam, Wysocka, Magdalena, Łęgowska, Anna, Pietrusewicz, Ewa, Rolka, Krzysztof, and Oleksyszyn, Józef
- Subjects
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ENZYMES , *CATALYSTS , *PHOSPHONATES , *CHYMOTRYPSIN - Abstract
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-PhgP(OPh)2 (1) (k obs/I =91M−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 15,600M−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 k obs/I value ever reported in literature (256,000M−1 s−1). [Copyright &y& Elsevier]
- Published
- 2008
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