title: Design, synthesis, and SAR of anthranilamide-based factor Xa inhibitors with improved functional activity.
abstract: 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.
authors.affiliation: Millennium Pharmaceuticals, Inc., 256 E. Grand Avenue, South San Francisco, CA 94080, USA. penglie.zhang@mpi.com
authors.forename: Penglie
authors.initials: P
authors.lastname: Zhang
authors.forename: Liang
authors.initials: L
authors.lastname: Bao
authors.forename: Jingmei F
authors.initials: JF
authors.lastname: Zuckett
authors.forename: Zhaozhong J
authors.initials: ZJ
authors.lastname: Jia
authors.forename: John
authors.initials: J
authors.lastname: Woolfrey
authors.forename: Ann
authors.initials: A
authors.lastname: Arfsten
authors.forename: Susan
authors.initials: S
authors.lastname: Edwards
authors.forename: Uma
authors.initials: U
authors.lastname: Sinha
authors.forename: Athiwat
authors.initials: A
authors.lastname: Hutchaleelaha
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Lambing
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: 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*
chemical_list: D000577:Amides; D065427:Factor Xa Inhibitors; D062367:ortho-Aminobenzoates