title: Design, synthesis, and SAR of monobenzamidines and aminoisoquinolines as factor Xa inhibitors.
abstract: Monoamidine FXa inhibitors 3 were designed and synthesized. SAR studies and molecular modeling led to the design of conformationally constrained diaryl ethers 4 and 5, as well as benzopyrrolidinone 7 as potent FXa inhibitors. The monoamidines show high efficacy in a DVT model, but lack desirable oral bioavailability. The benzopyrrolidinone-based aminoisoquinolines 8 do not show significant improvement in oral bioavailability.
authors.affiliation: Department of Medicinal Chemistry, 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: Jingmei F
authors.initials: JF
authors.lastname: Zuckett
authors.forename: John
authors.initials: J
authors.lastname: Woolfrey
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: Stan
authors.initials: S
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; D000818:Animals; D001550:Benzamidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D015195:Drug Design; D065427:Factor Xa Inhibitors; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D001550:Benzamidines; D065427:Factor Xa Inhibitors; D007546:Isoquinolines; D015842:Serine Proteinase Inhibitors