Design, synthesis and structure-activity relationships of benzoxazinone-based factor Xa inhibitors.
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.
Huang
Wenrong
W
Millennium Pharmaceuticals, Inc., 256 E. Grand Avenue, South San Francisco, CA 94080, USA.
Zhang
Penglie
P
Zuckett
Jingmei F
JF
Wang
Lingyan
L
Woolfrey
John
J
Song
Yonghong
Y
Jia
Zhaozhong J
ZJ
Clizbe
Lane A
LA
Su
Ting
T
Tran
Katherine
K
Huang
Brian
B
Wong
Paul
P
Sinha
Uma
U
Park
Gary
G
Reed
Andrea
A
Malinowski
John
J
Hollenbach
Stanley J
SJ
Scarborough
Robert M
RM
Zhu
Bing-Yan
BY
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
D000814:Aniline Compounds; D065427:Factor Xa Inhibitors; D007202:Indicators and Reagents; D010078:Oxazines; D014361:Trypsin Inhibitors; D013917:Thrombin