Synthesis and evaluation of 1-arylsulfonyl-3-piperazinone derivatives as factor Xa inhibitors IV. A series of new derivatives containing a spiro[5H-oxazolo[3,2-a]pyrazine-2(3H),4'-piperidin]-5-one skeleton.
In the course of development of factor Xa (FXa) inhibitor in an investigation involving the synthesis of 1-arylsulfonyl-3-piperazinone derivatives, we found new compounds containing a unique spiro skeleton. Among such compounds, (-)-7-[(6-chloro-2-naphthalenyl)sulfonyl]tetrahydro-8a-(methoxymethyl)-1'-(4-pyridinyl)-spiro[5H-oxazolo[3,2-a]pyrazine-2(3H),4'-piperidin]-5-one (28, M55529) had activity more favorable than those of previously reported compounds. The inhibitory activity of M55529 for FXa is IC(50)=2 nM, with high selectivity for FXa over thrombin and trypsin.
Nishida
Hidemitsu
H
Discovery Research Center, Mochida Pharmaceutical Co., Ltd., Gotemba, Shizuoka, Japan. hnishida@mochida.co.jp
Mukaihira
Takafumi
T
Saitoh
Fumihiko
F
Harada
Kousuke
K
Fukui
Miyuki
M
Matsusue
Tomokazu
T
Okamoto
Atsushi
A
Hosaka
Yoshitaka
Y
Matsumoto
Miwa
M
Shiromizu
Ikuya
I
Ohnishi
Shuhei
S
Mochizuki
Hidenori
H
D018360:Crystallography, X-Ray; D003500:Cyclization; D065427:Factor Xa Inhibitors; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology*; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors; D014361:Trypsin Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology
D065427:Factor Xa Inhibitors; C493020:M55529; D011725:Pyridines; D013141:Spiro Compounds; D014361:Trypsin Inhibitors; D013917:Thrombin