title: A novel inhibitor of activated thrombin-activatable fibrinolysis inhibitor (TAFIa) - part I: pharmacological characterization.
abstract: We have discovered a novel small-molecule (3-phosphinoylpropionic acid) inhibitor of activated thrombin activatable fibrinolysis inhibitor (TAFIa), BX 528, which had an IC (50) of 2 nM in an enzymatic assay and 50 nM in an in-vitro clot lysis assay, with 3,500- to 35,000-fold selectivity against other carboxypeptidases, such as CPN, CPZ and CPD, and 5- and 12-fold selectivity against CPE (CPH) and CPB, respectively. At 10 micro M, BX 528 had no significant activity (<50% inhibition or antagonism) in a panel of 137 enzymes and receptors. It had no effects on blood coagulation and platelet aggregation up to 300 and 10 micro M, respectively. The plasma half-life following intravenous administration was 0.85 hours in rats and 4.5 hours in dogs. No significant metabolism was detected in human, dog or rabbit hepatic microsomes, and no significant inhibition of cytochrome P450 3A4 and 2D6 up to 30 micro M. No cytotoxic or cell proliferative effects were found in three hepatic and renal cell lines up to 300 micro M and no mutagenic activity was seen in the Ames II screen. There were no significant hemodynamic effects in rats and dogs up to 100 and 30 mg/kg with peak plasma drug concentrations of approximately 1,000 and 300 micro M, respectively. In an in-vivo complement activation model in guinea pigs, BX 528 showed minimal inhibition of plasma CPN activity up to 60 mg/kg with peak plasma concentrations up to 250 micro M. Thus, these data demonstrate that BX 528 is a novel, potent, selective and safe TAFIa inhibitor.
authors.affiliation: Berlex Biosciences, 2600 Hilltop Drive, Richmond, CA, USA. yxwang2000@gmail.com
authors.forename: Yi-Xin
authors.initials: YX
authors.lastname: Wang
authors.forename: Lei
authors.initials: L
authors.lastname: Zhao
authors.forename: Mariko
authors.initials: M
authors.lastname: Nagashima
authors.forename: Jon
authors.initials: J
authors.lastname: Vincelette
authors.forename: Drew
authors.initials: D
authors.lastname: Sukovich
authors.forename: Weiwei
authors.initials: W
authors.lastname: Li
authors.forename: Babu
authors.initials: B
authors.lastname: Subramanyam
authors.forename: Shendong
authors.initials: S
authors.lastname: Yuan
authors.forename: Kumar
authors.initials: K
authors.lastname: Emayan
authors.forename: Imadul
authors.initials: I
authors.lastname: Islam
authors.forename: Paul
authors.initials: P
authors.lastname: Hrvatin
authors.forename: Judi
authors.initials: J
authors.lastname: Bryant
authors.forename: David R
authors.initials: DR
authors.lastname: Light
authors.forename: Ronald
authors.initials: R
authors.lastname: Vergona
authors.forename: John
authors.initials: J
authors.lastname: Morser
authors.forename: Brad O
authors.initials: BO
authors.lastname: Buckman
mesh_terms: D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects; D025901:Carboxypeptidase B2 / Q000037:antagonists & inhibitors*; D002268:Carboxypeptidases / Q000037:antagonists & inhibitors; D049109:Cell Proliferation / Q000187:drug effects; D004285:Dogs; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D006168:Guinea Pigs; D006207:Half-Life; D006801:Humans; D020128:Inhibitory Concentration 50; D008862:Microsomes, Liver / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D011422:Propionates / Q000493:pharmacokinetics / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D013379:Substrate Specificity
chemical_list: D004791:Enzyme Inhibitors; D011422:Propionates; D002268:Carboxypeptidases; D025901:Carboxypeptidase B2; C029658:propionic acid