Design, synthesis, and SAR of anthranilamide-based factor Xa inhibitors with improved functional activity.
Compound 2 containing an aminomethylbenzoyl moiety as the S4 binding motif was synthesized in order to modulate hydrophlicity of anthranilamide-based factor Xa inhibitors with substituted biphenyl P4 groups. Structure-activity relationship studies around 2 have led to a series of potent factor Xa inhibitors which are highly active in the human plasma-based thrombin generation assay with 2XTG values less than 1 microM. Compound 55 shows strong antithrombotic activity in our rabbit deep vein thrombosis model, and also exhibits good oral bioavailability and a long half life in rats.
Zhang
Penglie
P
Millennium Pharmaceuticals, Inc., 256 E. Grand Avenue, South San Francisco, CA 94080, USA. penglie.zhang@mpi.com
Bao
Liang
L
Zuckett
Jingmei F
JF
Jia
Zhaozhong J
ZJ
Woolfrey
John
J
Arfsten
Ann
A
Edwards
Susan
S
Sinha
Uma
U
Hutchaleelaha
Athiwat
A
Lambing
Joseph L
JL
Hollenbach
Stanley J
SJ
Scarborough
Robert M
RM
Zhu
Bing-Yan
BY
D000284:Administration, Oral; D000577:Amides / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D001682:Biological Availability; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D065427:Factor Xa Inhibitors; D006801:Humans; D015394:Molecular Structure; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013927:Thrombosis / Q000188:drug therapy; D062367:ortho-Aminobenzoates / Q000138:chemical synthesis* / Q000494:pharmacology*
D000577:Amides; D065427:Factor Xa Inhibitors; D062367:ortho-Aminobenzoates