New potent cathepsin G phosphonate inhibitors

作者：Sienczyk Marcin; Lesner Adam^*; Wysocka Magdalena; Legowska Anna; Pietrusewicz Ewa; Rolka Krzysztof; Oleksyszyn Jozef

来源：Bioorganic & Medicinal Chemistry, 2008, 16(19): 8863-8867.

DOI：10.1016/j.bmc.2008.08.069

• cathepsin G
• phosphonate irreversible inhibitor
• peptidomimetic

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. Modi. cation of the lead structure Z-Phg(P)(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)Phg(P)(OC(6)H(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) PhgP(OC(6)H(4)-4-S-Me)(2) (19) with the highest k(obs)/I value ever reported in literature (256,000 M(1) s(1)).

• 出版日期2008-10-1