title: 3-Mercaptopropionic acids as efficacious inhibitors of activated thrombin activatable fibrinolysis inhibitor (TAFIa).
abstract: A novel series of cyclic potent, selective, small molecule, thiol-based inhibitors of activated thrombin activatable fibrinolysis inhibitor (TAFIa) and the crystal structures of TAFIa inhibitors bound to porcine pancreatic carboxypeptidase B are described. Three series of cyclic arginine and lysine mimetic inhibitors vary significantly in their selectivity against other human basic carboxypeptidases, carboxypeptidase N and carboxypeptidase B. (-)2a displays TAFIa IC50 = 3 nM and 600-fold selectivity against CPN. Inhibition of TAFIa with (rac)2a resulted in dose dependent acceleration of human plasma clot lysis in vitro and was efficacious as an adjunct to tPA in an in vivo rabbit jugular vein thrombolysis model.
authors.affiliation: Department of Medicinal Chemistry, 2600 Hilltop Drive, Richmond, CA 94804, USA.
authors.forename: Imadul
authors.initials: I
authors.lastname: Islam
authors.forename: Judi
authors.initials: J
authors.lastname: Bryant
authors.forename: Karen
authors.initials: K
authors.lastname: May
authors.forename: Raju
authors.initials: R
authors.lastname: Mohan
authors.forename: Shendong
authors.initials: S
authors.lastname: Yuan
authors.forename: Lorraine
authors.initials: L
authors.lastname: Kent
authors.forename: John
authors.initials: J
authors.lastname: Morser
authors.forename: Lei
authors.initials: L
authors.lastname: Zhao
authors.forename: Ron
authors.initials: R
authors.lastname: Vergona
authors.forename: Kathy
authors.initials: K
authors.lastname: White
authors.forename: Marc
authors.initials: M
authors.lastname: Adler
authors.forename: Marc
authors.initials: M
authors.lastname: Whitlow
authors.forename: Brad O
authors.initials: BO
authors.lastname: Buckman
mesh_terms: D015097:3-Mercaptopropionic Acid / Q000494:pharmacology*; D000818:Animals; D001120:Arginine; D043424:Carboxypeptidase B / Q000037:antagonists & inhibitors; D025901:Carboxypeptidase B2 / Q000037:antagonists & inhibitors*; D018360:Crystallography, X-Ray; D005343:Fibrinolytic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D008239:Lysine; D001121:Lysine Carboxypeptidase / Q000037:antagonists & inhibitors; D018716:Molecular Mimicry; D010456:Peptides, Cyclic; D011817:Rabbits; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013552:Swine
chemical_list: D005343:Fibrinolytic Agents; D010456:Peptides, Cyclic; D001120:Arginine; D015097:3-Mercaptopropionic Acid; D043424:Carboxypeptidase B; D025901:Carboxypeptidase B2; D001121:Lysine Carboxypeptidase; D008239:Lysine