title: Development of an oxazolopyridine series of dual thrombin/factor Xa inhibitors via structure-guided lead optimization.
abstract: Thrombin-inhibitor X-ray crystal structures, in combination with the installation of binding elements optimized within the pyrazinone series of thrombin inhibitors, were utilized to transform a weak triazolopyrimidine lead into a series of potent oxazolopyridines. A modification intended to attenuate plasma protein binding (i.e., conversion of the P3 pyridine to a piperidine) conferred significant factor Xa activity to this series. Ultimately, these dual thrombin/factor Xa inhibitors demonstrated excellent in vitro and in vivo anticoagulant efficacy.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA.
authors.forename: James Z
authors.initials: JZ
authors.lastname: Deng
authors.forename: Daniel R
authors.initials: DR
authors.lastname: McMasters
authors.forename: Philippe M A
authors.initials: PM
authors.lastname: Rabbat
authors.forename: Peter D
authors.initials: PD
authors.lastname: Williams
authors.forename: Craig A
authors.initials: CA
authors.lastname: Coburn
authors.forename: Youwei
authors.initials: Y
authors.lastname: Yan
authors.forename: Lawrence C
authors.initials: LC
authors.lastname: Kuo
authors.forename: S Dale
authors.initials: SD
authors.lastname: Lewis
authors.forename: Bobby J
authors.initials: BJ
authors.lastname: Lucas
authors.forename: Julie A
authors.initials: JA
authors.lastname: Krueger
authors.forename: Berta
authors.initials: B
authors.lastname: Strulovici
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Vacca
authors.forename: Terry A
authors.initials: TA
authors.lastname: Lyle
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Burgey
mesh_terms: D000991:Antithrombins / Q000737:chemistry* / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D065427:Factor Xa Inhibitors; D008958:Models, Molecular; D015394:Molecular Structure; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000991:Antithrombins; D065427:Factor Xa Inhibitors; D011725:Pyridines