title: Synthesis and evaluation of 1-arylsulfonyl-3-piperazinone derivatives as factor Xa inhibitor.
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.
authors.affiliation: Chemistry Laboratory, Research Center, Mochida Pharmaceutical Co., Ltd., Gotemba, Shizuoka, Japan. hnishida@mochida.co.jp
authors.forename: H
authors.initials: H
authors.lastname: Nishida
authors.forename: Y
authors.initials: Y
authors.lastname: Miyazaki
authors.forename: Y
authors.initials: Y
authors.lastname: Kitamura
authors.forename: M
authors.initials: M
authors.lastname: Ohashi
authors.forename: T
authors.initials: T
authors.lastname: Matsusue
authors.forename: A
authors.initials: A
authors.lastname: Okamoto
authors.forename: Y
authors.initials: Y
authors.lastname: Hosaka
authors.forename: S
authors.initials: S
authors.lastname: Ohnishi
authors.forename: H
authors.initials: H
authors.lastname: Mochizuki
mesh_terms: D000925:Anticoagulants / Q000138:chemical synthesis* / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D065427:Factor Xa Inhibitors; D006801:Humans; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D010879:Piperazines / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors; D014361:Trypsin Inhibitors / Q000494:pharmacology
chemical_list: D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D007202:Indicators and Reagents; D010879:Piperazines; D014361:Trypsin Inhibitors; D013917:Thrombin