Synthesis and evaluation of 1-arylsulfonyl-3-piperazinone derivatives as a factor Xa inhibitor II. Substituent effect on biological activities.
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.
Nishida
Hidemitsu
H
Chemistry Laboratory, Research Center, Mochida Pharmaceutical Co., Ltd., Gotemba, Shizuoka, Japan. hnishida@mochida.co.jp
Miyazaki
Yutaka
Y
Mukaihira
Takafumi
T
Saitoh
Fumihiko
F
Fukui
Miyuki
M
Harada
Kousuke
K
Itoh
Manabu
M
Muraoka
Aki
A
Matsusue
Tomokazu
T
Okamoto
Atsushi
A
Hosaka
Yoshitaka
Y
Matsumoto
Miwa
M
Ohnishi
Shuhei
S
Mochizuki
Hidenori
H
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
D001190:Arylsulfonates; D065427:Factor Xa Inhibitors; D007202:Indicators and Reagents; D010879:Piperazines; D010880:Piperidines; D014361:Trypsin Inhibitors; D013917:Thrombin