title: Synthesis and evaluation of imidazole acetic acid inhibitors of activated thrombin-activatable fibrinolysis inhibitor as novel antithrombotics.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, West Point, Pennsylvania 19486, USA. james_barrow@merck.com
authors.forename: James C
authors.initials: JC
authors.lastname: Barrow
authors.forename: Philippe G
authors.initials: PG
authors.lastname: Nantermet
authors.forename: Shaun R
authors.initials: SR
authors.lastname: Stauffer
authors.forename: Phung L
authors.initials: PL
authors.lastname: Ngo
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Steinbeiser
authors.forename: Shi-Shan
authors.initials: SS
authors.lastname: Mao
authors.forename: Steven S
authors.initials: SS
authors.lastname: Carroll
authors.forename: Carolyn
authors.initials: C
authors.lastname: Bailey
authors.forename: Dennis
authors.initials: D
authors.lastname: Colussi
authors.forename: Michelle
authors.initials: M
authors.lastname: Bosserman
authors.forename: Christine
authors.initials: C
authors.lastname: Burlein
authors.forename: Jacquelynn J
authors.initials: JJ
authors.lastname: Cook
authors.forename: Gary
authors.initials: G
authors.lastname: Sitko
authors.forename: Philip R
authors.initials: PR
authors.lastname: Tiller
authors.forename: Cynthia M
authors.initials: CM
authors.lastname: Miller-Stein
authors.forename: Mark
authors.initials: M
authors.lastname: Rose
authors.forename: Daniel R
authors.initials: DR
authors.lastname: McMasters
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Vacca
authors.forename: Harold G
authors.initials: HG
authors.lastname: Selnick
mesh_terms: 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
chemical_list: 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