3-Mercaptopropionic acids as efficacious inhibitors of activated thrombin activatable fibrinolysis inhibitor (TAFIa).
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.
Islam
Imadul
I
Department of Medicinal Chemistry, 2600 Hilltop Drive, Richmond, CA 94804, USA.
Bryant
Judi
J
May
Karen
K
Mohan
Raju
R
Yuan
Shendong
S
Kent
Lorraine
L
Morser
John
J
Zhao
Lei
L
Vergona
Ron
R
White
Kathy
K
Adler
Marc
M
Whitlow
Marc
M
Buckman
Brad O
BO
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
D005343:Fibrinolytic Agents; D010456:Peptides, Cyclic; D001120:Arginine; D015097:3-Mercaptopropionic Acid; D043424:Carboxypeptidase B; D025901:Carboxypeptidase B2; D001121:Lysine Carboxypeptidase; D008239:Lysine