Recent advances in serine protease inhibitors as anticoagulant agents.
The drawbacks and limitations of existing anticoagulant therapy which may result in serious adverse effects and a high mortality rate, have given rise to many anticoagulant development programmes in the last decade, focusing mainly at development of thrombin and FXa low-molecular weight inhibitors. A detailed understanding of blood coagulation pathways, functioning of the serine proteases thrombin, FXa, FVIIa and FIXa and elucidation of their crystal structures resulted in many potent compounds, among which some have entered the clinical phase or have been approved for use in clinical practice. Recently, the focus of anticoagulant research turned to inhibition of the TF:FVIIa complex, with some promising clinical candidates on the horizon. This article provides an overview of the current development status of serine protease inhibitors as anticoagulants, including new trends such as dual coagulation factor inhibitors.
Prezelj
Andrej
A
Lek Pharmaceuticals d.d., Drug Discovery, Ljubljana, Slovenia.
Anderluh
Petra Stefanic
PS
Peternel
Luka
L
Urleb
Uros
U
D000818:Animals; D000925:Anticoagulants / Q000737:chemistry* / Q000494:pharmacology*; D001665:Binding Sites; D001777:Blood Coagulation / Q000187:drug effects; D015195:Drug Design; D015949:Factor IXa / Q000037:antagonists & inhibitors / Q000737:chemistry; D015942:Factor VIIa / Q000037:antagonists & inhibitors / Q000737:chemistry; D015951:Factor Xa / Q000737:chemistry; D065427:Factor Xa Inhibitors; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D011487:Protein Conformation; D012697:Serine Endopeptidases / Q000737:chemistry* / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000737:chemistry
D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D015842:Serine Proteinase Inhibitors; D012697:Serine Endopeptidases; D015942:Factor VIIa; D015949:Factor IXa; D013917:Thrombin; D015951:Factor Xa