From selective substrate analogue factor Xa inhibitors to dual inhibitors of thrombin and factor Xa. Part 3.
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.
Dönnecke
Daniel
D
Curacyte Discovery GmbH, Winzerlaer Str. 2, D-07745 Jena, Germany.
Schweinitz
Andrea
A
Stürzebecher
Anne
A
Steinmetzer
Peter
P
Schuster
Maj
M
Stürzebecher
Uta
U
Nicklisch
Silke
S
Stürzebecher
Jörg
J
Steinmetzer
Torsten
T
D000596:Amino Acids / Q000378:metabolism; D000925:Anticoagulants / Q000138:chemical synthesis / Q000494:pharmacology*; D000991:Antithrombins / Q000138:chemical synthesis / Q000494:pharmacology*; D001777:Blood Coagulation / Q000187:drug effects* / Q000502:physiology; D019774:Blood Coagulation Factor Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D065427:Factor Xa Inhibitors; D006801:Humans; D008956:Models, Chemical; D010446:Peptide Fragments / Q000378:metabolism; D013379:Substrate Specificity; D013917:Thrombin / Q000037:antagonists & inhibitors*
D000596:Amino Acids; D000925:Anticoagulants; D000991:Antithrombins; D019774:Blood Coagulation Factor Inhibitors; D065427:Factor Xa Inhibitors; D010446:Peptide Fragments; D013917:Thrombin