Active site-directed thrombin inhibitors: alpha-hydroxyacyl-prolyl-arginals. New orally active stable analogs of D-Phe-Pro-Arg-H.
D-alpha-Hydroxyacyl-prolyl-arginals have been designed and synthesized as orally active stable analogs of D-Phe-Pro-Arg-H, the active site-directed peptidyl thrombin inhibitor prototype. Many of the new analogs possess high in vitro anticoagulant activity while having little effect on fibrinolysis. Compounds GYKI-66104 (2), -66131 (3) and -66132 (5) effectively delay the clotting time in rabbits ex vivo and prevent thrombus formation in various thrombosis models in rabbits and rats when applied in a single oral dose of 5 mg kg-1.
Bajusz
S
S
Institute for Drug Research, Budapest, Hungary.
Barabás
E
E
Fauszt
I
I
Fehér
A
A
Horváth
G
G
Juhász
A
A
Szabó
A G
AG
Széll
E
E
D000284:Administration, Oral; D000595:Amino Acid Sequence; D000818:Animals; D000925:Anticoagulants / Q000138:chemical synthesis* / Q000494:pharmacology; D000991:Antithrombins / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology; D001665:Binding Sites; D001777:Blood Coagulation / Q000187:drug effects; D015195:Drug Design; D005342:Fibrinolysis / Q000187:drug effects; D007202:Indicators and Reagents; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors*; D013927:Thrombosis / Q000517:prevention & control*
D000925:Anticoagulants; D000991:Antithrombins; D007202:Indicators and Reagents; D009842:Oligopeptides; C077952:phenylalanyl-prolyl-arginine; D013917:Thrombin