title: Design, synthesis, and SAR of anthranilamide-based factor Xa inhibitors incorporating substituted biphenyl P4 motifs.
abstract: Anthranilamides 4 and 5 were designed and synthesized as selective and orally bioavailable factor Xa inhibitors. Structural modifications aimed at lowering their lipophilicity were performed at the central phenyl ring and at the S4 binding biphenyl region by incorporating water solublizing substituents. The resulting compounds (e.g., 7, 8, 14, 30a, and 32b) are highly potent in vitro, and show improved activity in human plasma-based thrombin generation assay.
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: Erick A
authors.initials: EA
authors.lastname: Goldman
authors.forename: Zhaozhong J
authors.initials: ZJ
authors.lastname: Jia
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: Gary
authors.initials: G
authors.lastname: Park
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; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D065427:Factor Xa Inhibitors; D006801:Humans; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013927:Thrombosis / Q000188:drug therapy / Q000517:prevention & control; D062367:ortho-Aminobenzoates / Q000138:chemical synthesis* / Q000494:pharmacology*
chemical_list: D000577:Amides; D065427:Factor Xa Inhibitors; D062367:ortho-Aminobenzoates