title: Synthesis and evaluation of 1-arylsulfonyl-3-piperazinone derivatives as a factor Xa inhibitor II. Substituent effect on biological activities.
abstract: Intravascular clot formation is an important event in a number of cardiovascular diseases. The prevention of blood coagulation has become a major target for new therapeutic agents. Factor Xa (FXa) is a trypsin-like serine protease that plays a key role in the blood coagulation cascade and represents an attractive target for anticoagulant drug development. We have investigated substituents in the central part of a lead compound (3: M55113), and discovered that compound M55551 (34: (R)-4-[(6-Chloro-2-naphthalenyl)sulfonyl]-6-oxo-1-[[1-(4-pyridinyl)-4-piperidinyl]methyl]-2-piperazinecarboxylic acid) is a potent inhibitor of FXa (IC(50)=0.006 microM), with high selectivity for FXa over trypsin and thrombin. The activity of this compound is ten times more powerful than the lead compound.
authors.affiliation: Chemistry Laboratory, Research Center, Mochida Pharmaceutical Co., Ltd., Gotemba, Shizuoka, Japan. hnishida@mochida.co.jp
authors.forename: Hidemitsu
authors.initials: H
authors.lastname: Nishida
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Miyazaki
authors.forename: Takafumi
authors.initials: T
authors.lastname: Mukaihira
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Saitoh
authors.forename: Miyuki
authors.initials: M
authors.lastname: Fukui
authors.forename: Kousuke
authors.initials: K
authors.lastname: Harada
authors.forename: Manabu
authors.initials: M
authors.lastname: Itoh
authors.forename: Aki
authors.initials: A
authors.lastname: Muraoka
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Matsusue
authors.forename: Atsushi
authors.initials: A
authors.lastname: Okamoto
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Hosaka
authors.forename: Miwa
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Shuhei
authors.initials: S
authors.lastname: Ohnishi
authors.forename: Hidenori
authors.initials: H
authors.lastname: Mochizuki
mesh_terms: D001190:Arylsulfonates / Q000138:chemical synthesis / Q000494:pharmacology; D003460:Crystallization; D065427:Factor Xa Inhibitors; D006860:Hydrogen Bonding; D007202:Indicators and Reagents; D010084:Oxidation-Reduction; D010879:Piperazines / Q000138:chemical synthesis / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors; D014361:Trypsin Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: D001190:Arylsulfonates; D065427:Factor Xa Inhibitors; D007202:Indicators and Reagents; D010879:Piperazines; D010880:Piperidines; D014361:Trypsin Inhibitors; D013917:Thrombin