Synthesis and evaluation of imidazole acetic acid inhibitors of activated thrombin-activatable fibrinolysis inhibitor as novel antithrombotics.
Thrombin-activatable fibrinolysis inhibitor (TAFI) is an important regulator of fibrinolysis, and inhibitors of this enzyme have potential use in antithrombotic and thrombolytic therapy. Appropriately substituted imidazole acetic acids such as 10j were found to be potent inhibitors of activated TAFI and selective versus the related carboxypeptidases CPA, CPN, and CPM but not CPB. Further, 10j accelerated clot lysis in vitro and was shown to be efficacious in a primate model of thrombosis.
Barrow
James C
JC
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, West Point, Pennsylvania 19486, USA. james_barrow@merck.com
Nantermet
Philippe G
PG
Stauffer
Shaun R
SR
Ngo
Phung L
PL
Steinbeiser
Melissa A
MA
Mao
Shi-Shan
SS
Carroll
Steven S
SS
Bailey
Carolyn
C
Colussi
Dennis
D
Bosserman
Michelle
M
Burlein
Christine
C
Cook
Jacquelynn J
JJ
Sitko
Gary
G
Tiller
Philip R
PR
Miller-Stein
Cynthia M
CM
Rose
Mark
M
McMasters
Daniel R
DR
Vacca
Joseph P
JP
Selnick
Harold G
HG
D000085:Acetates / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000631:Aminopyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D025901:Carboxypeptidase B2 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D004285:Dogs; D005343:Fibrinolytic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D066298:In Vitro Techniques; D008861:Microsomes / Q000378:metabolism; D008958:Models, Molecular; D011422:Propionates / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
C480545:3-(2-aminopyridin-5-yl)-2-(1-isopentylimidazol-4-yl)propanoic acid; D000085:Acetates; D000631:Aminopyridines; D005343:Fibrinolytic Agents; D007093:Imidazoles; D011422:Propionates; D011480:Protease Inhibitors; D025901:Carboxypeptidase B2