Synthesis and evaluation of 1-arylsulfonyl-3-piperazinone derivatives as factor Xa inhibitor

Chemical & Pharmaceutical Bulletin
H NishidaH Mochizuki

Abstract

Intravascular clot formation is an important factor in a number of cardiovascular diseases. Therefore, the prevention of blood coagulation has become a major target for new therapeutic agents. One attractive approach is the inhibition of factor Xa (FXa), which is a key enzyme in coagulation cascade responsible for the generation of thrombin by limited proteolysis of its zymogen, prothrombin. We have investigated 1-arylsulfonyl-3-piperazinone derivatives, containing a 4-(piperidino)pyridine group in place of guanidino and/or amidino groups, and discovered compound M55113 (30a: 4-[(6-Chloro-2-naphthalenyl)sulfonyl]-1-[[1-(4-pyridinyl)-4-piperidinyl]methyl]piperazinone), as a potent inhibitor of FXa (IC50=0.06 microM) with high selectivity for FXa over trypsin and thrombin.

References

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Oct 1, 1993·Trends in Pharmacological Sciences·C TapparelliN S Cook
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Citations

Dec 8, 2009·Medicinal Research Reviews·Yu-Kai Lee, Mark R Player
Dec 1, 2005·European Journal of Pharmacology·Yoshitaka HosakaHidemi Ishii
Sep 15, 2007·Bioorganic & Medicinal Chemistry Letters·Yan ShiRobert Zahler
Aug 13, 2002·Current Opinion in Pulmonary Medicine·Kenneth A BauerAlexander G G Turpie
May 10, 2005·Journal of Combinatorial Chemistry·Alexei P IlyinAlexandre V Ivachtchenko

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