Potent and selective bicyclic lactam inhibitors of thrombin. Part 4: transition state inhibitors.
Bicyclic piperazinone based thrombin inhibitors of general structure 2 were prepared and evaluated in vitro and in vivo. These inhibitors, having in common an electrophilic basic trans-cyclohexylamine P1 residue, displayed high thrombin affinity, high selectivity against trypsin and good in vivo efficacy in the rat arterial thrombosis model.
Bachand
B
B
BioChem Pharma Inc., Laval, Québec, Canada. bachandb@biochempharma.com
Tarazi
M
M
St-Denis
Y
Y
Edmunds
J J
JJ
Winocour
P D
PD
Leblond
L
L
Siddiqui
M A
MA
D000818:Animals; D001780:Blood Coagulation Tests; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis / Q000494:pharmacology; D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D004195:Disease Models, Animal; D005343:Fibrinolytic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D007769:Lactams / Q000138:chemical synthesis / Q000494:pharmacology*; D008958:Models, Molecular; D051381:Rats; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors*; D013927:Thrombosis / Q000188:drug therapy; D014361:Trypsin Inhibitors / Q000494:pharmacology
D019086:Bridged Bicyclo Compounds, Heterocyclic; D005343:Fibrinolytic Agents; D007769:Lactams; D014361:Trypsin Inhibitors; D013917:Thrombin