Design and characterization of a selenium-containing inhibitor of activated thrombin-activatable fibrinolysis inhibitor (TAFIa), a zinc-containing metalloprotease.
Available therapies for thromboembolic disorders include thrombolytics, anticoagulants, and antiplatelets, but these are associated with complications such as bleeding. To develop an alternative drug which is clinically safe, we focused on activated thrombin-activatable fibrinolysis inhibitor (TAFIa) as the target molecule. TAFIa is a zinc-containing carboxypeptidase that significantly inhibits fibrinolysis. Here we designed and synthesized selenium-containing compounds 5-13 to discover novel TAFIa inhibitors having a superior zinc-coordinating group. Compounds 5-13 significantly inhibited TAFIa activity (IC(50) 2.2 × 10(-12) M - 2.6 × 10(-6) M). We found that selenol is a better functional group than thiol for coordinating to zinc at the active site of TAFIa. Furthermore, compound 12, which has an amino-chloro-pyridine ring, was found to be a potent and selective TAFIa inhibitor that lacks carboxypeptidase N inhibitory activity. Therefore, compound 12 is a promising candidate for the treatment of thromboembolic disorders. This is the first report of a selenium-containing inhibitor for TAFIa.
High Technology Research Center, Showa Pharmaceutical University, 3-3165 Higashi-Tamagawagakuen, Machida, Tokyo 194-8543, Japan. yamamoto@ac.shoyaku.ac.jp
Nobuko
N
Yoshimoto
Tomoyuki
T
Sasaki
Katsuyoshi
K
Sugimoto
Hidemi
H
Ishii
Keiko
K
Yamamoto
D025901:Carboxypeptidase B2 / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D012643:Selenium / Q000032:analysis*
D025901:Carboxypeptidase B2; D012643:Selenium