Low molecular weight activated protein C inhibitors as a potential treatment for hemophilic disorders.
The synthesis and evaluation of inhibitors of activated protein C (aPC) are reported. This serine protease is partly responsible for the degradation of factor VIIIa, involved in the regulation of bleeding in hemophilia A. Benzamidine-containing derivatives were found to be potent aPC inhibitors, some of them showing selectivity against the procoagulant protease thrombin. Moreover, compound 1 significantly restored the generation of thrombin in hemophiliac plasma.
De Nanteuil
Guillaume
G
Division D of Medicinal Chemistry and Division of Angiology, Institut de Recherches Servier, 11 Rue des Moulineaux, 92150 Suresnes, France. guillaume.denanteuil@fr.netgrs.com
Gloanec
Philippe
P
Béguin
Suzette
S
Giesen
Peter L A
PL
Hemker
H Coenraad
HC
Mennecier
Philippe
P
Rupin
Alain
A
Verbeuren
Tony J
TJ
D001550:Benzamidines / Q000737:chemistry / Q000494:pharmacology*; D015944:Factor VIIIa / Q000378:metabolism; D006467:Hemophilia A / Q000188:drug therapy*; D006470:Hemorrhage / Q000517:prevention & control*; D006801:Humans; D015394:Molecular Structure; D008970:Molecular Weight; D011486:Protein C / Q000037:antagonists & inhibitors*; D015842:Serine Proteinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000096:biosynthesis
D001550:Benzamidines; D011486:Protein C; D015842:Serine Proteinase Inhibitors; D015944:Factor VIIIa; D013917:Thrombin