Format

Send to

Choose Destination
J Med Chem. 2012 Feb 9;55(3):1171-80. doi: 10.1021/jm2011996. Epub 2012 Jan 25.

A new strategy for the development of highly potent and selective plasmin inhibitors.

Author information

1
Department of Pharmacy, Institute of Pharmaceutical Chemistry, Philipps University Marburg, Marbacher Weg 6, D-35032 Marburg, Germany.

Abstract

A new structure-based strategy for the design of potent and selective plasmin inhibitors was developed. These compounds could be prepared by cyclizations between the P3 and P2 amino acid residues of substrate-analogue inhibitors using metathesis or a copper-catalyzed azide alkyne cycloaddition in combination with standard peptide couplings. The most potent bis-triazole derivative 10 inhibits plasmin and plasma kallikrein with K(i) of 0.77 and 2.4 nM, respectively, whereas it has poor activity against the related trypsin-like serine proteases thrombin, factor Xa, or activated protein C. Modeling experiments revealed that inhibitor 10 adopts a compact and rigid structure that fits well into the relatively open active site of plasmin and plasma kallikrein, while it is rejected from sterically demanding residues present in loops of the other enzymes. These results from modeling confirm the selectivity profile found for inhibitor 10 in enzyme kinetic studies. Such compounds might be useful lead structures for the development of new antifibrinolytic drugs for use in cardiac surgery with cardiopulmonary bypass or organ transplantations to reduce bleeding complications.

PMID:
22276953
DOI:
10.1021/jm2011996
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for American Chemical Society
Loading ...
Support Center