From selective substrate analogue factor Xa inhibitors to dual inhibitors of thrombin and factor Xa. Part 3

Daniel Dönnecke; Andrea Schweinitz; Anne Stürzebecher; Peter Steinmetzer; Maj Schuster; Uta Stürzebecher; Silke Nicklisch; Jörg Stürzebecher; Torsten Steinmetzer

doi:10.1016/j.bmcl.2007.03.105

From selective substrate analogue factor Xa inhibitors to dual inhibitors of thrombin and factor Xa. Part 3

Bioorg Med Chem Lett. 2007 Jun 15;17(12):3322-9. doi: 10.1016/j.bmcl.2007.03.105. Epub 2007 Apr 6.

Authors

Daniel Dönnecke¹, Andrea Schweinitz, Anne Stürzebecher, Peter Steinmetzer, Maj Schuster, Uta Stürzebecher, Silke Nicklisch, Jörg Stürzebecher, Torsten Steinmetzer

Affiliation

¹ Curacyte Discovery GmbH, Winzerlaer Str. 2, D-07745 Jena, Germany.

PMID: 17462889
DOI: 10.1016/j.bmcl.2007.03.105

Abstract

Highly potent and selective substrate analogue factor Xa inhibitors were obtained by incorporation of non-basic or modestly basic P1 residues known from the development of thrombin inhibitors. The modification of the P2 and P3 amino acids strongly influenced the selectivity and provided potent dual factor Xa and thrombin inhibitors without affecting the fibrinolytic enzymes. Several inhibitors demonstrated excellent anticoagulant efficacy in standard clotting assays in human plasma.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acids / metabolism
Anticoagulants / chemical synthesis
Anticoagulants / pharmacology*
Antithrombins / chemical synthesis
Antithrombins / pharmacology*
Blood Coagulation / drug effects*
Blood Coagulation / physiology
Blood Coagulation Factor Inhibitors / chemical synthesis
Blood Coagulation Factor Inhibitors / pharmacology*
Factor Xa Inhibitors*
Humans
Models, Chemical
Peptide Fragments / metabolism
Substrate Specificity
Thrombin / antagonists & inhibitors*

Substances

Amino Acids
Anticoagulants
Antithrombins
Blood Coagulation Factor Inhibitors
Factor Xa Inhibitors
Peptide Fragments
Thrombin