title: 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.
abstract: 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.
authors.affiliation: Discovery Research Center, Mochida Pharmaceutical Co., Ltd., Gotemba, Shizuoka, Japan. hnishida@mochida.co.jp
authors.forename: Hidemitsu
authors.initials: H
authors.lastname: Nishida
authors.forename: Takafumi
authors.initials: T
authors.lastname: Mukaihira
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Saitoh
authors.forename: Kousuke
authors.initials: K
authors.lastname: Harada
authors.forename: Miyuki
authors.initials: M
authors.lastname: Fukui
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: Ikuya
authors.initials: I
authors.lastname: Shiromizu
authors.forename: Shuhei
authors.initials: S
authors.lastname: Ohnishi
authors.forename: Hidenori
authors.initials: H
authors.lastname: Mochizuki
mesh_terms: 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
chemical_list: D065427:Factor Xa Inhibitors; C493020:M55529; D011725:Pyridines; D013141:Spiro Compounds; D014361:Trypsin Inhibitors; D013917:Thrombin