title: Design, synthesis and structure-activity relationships of benzoxazinone-based factor Xa inhibitors.
abstract: A series of benzoxazinone derivatives was designed and synthesized as factor Xa inhibitors. We demonstrated that the naphthyl moiety in the aniline-based compounds 1 and 2 can be replaced with benzene-fused heterobicycles and biaryls to give factor Xa inhibitors with improved trypsin selectivity. The P4 modifications lead to monoamidines which are moderately active. The benzoxazinones 41-45 are potent against factor Xa, retain the improved trypsin selectivity of the corresponding aniline-based compounds, and show strong antithrombotic effect dose responsively.
authors.affiliation: Millennium Pharmaceuticals, Inc., 256 E. Grand Avenue, South San Francisco, CA 94080, USA.
authors.forename: Wenrong
authors.initials: W
authors.lastname: Huang
authors.forename: Penglie
authors.initials: P
authors.lastname: Zhang
authors.forename: Jingmei F
authors.initials: JF
authors.lastname: Zuckett
authors.forename: Lingyan
authors.initials: L
authors.lastname: Wang
authors.forename: John
authors.initials: J
authors.lastname: Woolfrey
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Song
authors.forename: Zhaozhong J
authors.initials: ZJ
authors.lastname: Jia
authors.forename: Lane A
authors.initials: LA
authors.lastname: Clizbe
authors.forename: Ting
authors.initials: T
authors.lastname: Su
authors.forename: Katherine
authors.initials: K
authors.lastname: Tran
authors.forename: Brian
authors.initials: B
authors.lastname: Huang
authors.forename: Paul
authors.initials: P
authors.lastname: Wong
authors.forename: Uma
authors.initials: U
authors.lastname: Sinha
authors.forename: Gary
authors.initials: G
authors.lastname: Park
authors.forename: Andrea
authors.initials: A
authors.lastname: Reed
authors.forename: John
authors.initials: J
authors.lastname: Malinowski
authors.forename: Stanley J
authors.initials: SJ
authors.lastname: Hollenbach
authors.forename: Robert M
authors.initials: RM
authors.lastname: Scarborough
authors.forename: Bing-Yan
authors.initials: BY
authors.lastname: Zhu
mesh_terms: D000814:Aniline Compounds / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D065427:Factor Xa Inhibitors; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D008958:Models, Molecular; D008968:Molecular Conformation; D010078:Oxazines / Q000138:chemical synthesis* / Q000494:pharmacology*; D011817:Rabbits; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000378:metabolism; D014361:Trypsin Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: D000814:Aniline Compounds; D065427:Factor Xa Inhibitors; D007202:Indicators and Reagents; D010078:Oxazines; D014361:Trypsin Inhibitors; D013917:Thrombin