title: Design and synthesis of potent and selective macrocyclic thrombin inhibitors.
abstract: A series of potent and selective proline- and pyrazinone-based macrocyclic thrombin inhibitors is described. Detailed SAR studies led to the incorporation of specific functional groups in the tether that enhanced functional activity against thrombin and provided exquisite selectivity against trypsin and tPA. X-ray crystallography and molecular modeling studies revealed the inhibitor-enzyme interactions responsible for this selectivity.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. philippe_nanternet@merck.com
authors.forename: Philippe G
authors.initials: PG
authors.lastname: Nantermet
authors.forename: James C
authors.initials: JC
authors.lastname: Barrow
authors.forename: Christina L
authors.initials: CL
authors.lastname: Newton
authors.forename: Janetta M
authors.initials: JM
authors.lastname: Pellicore
authors.forename: MaryBeth
authors.initials: M
authors.lastname: Young
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: Daniel R
authors.initials: DR
authors.lastname: McMasters
authors.forename: Youwei
authors.initials: Y
authors.lastname: Yan
authors.forename: Lawrence C
authors.initials: LC
authors.lastname: Kuo
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Vacca
authors.forename: Harold G
authors.initials: HG
authors.lastname: Selnick
mesh_terms: D000991:Antithrombins / Q000138:chemical synthesis* / Q000494:pharmacology; D001665:Binding Sites; D018360:Crystallography, X-Ray; D015195:Drug Design; D008958:Models, Molecular; D011392:Proline / Q000737:chemistry; D011719:Pyrazines / Q000737:chemistry; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000737:chemistry; D014357:Trypsin / Q000737:chemistry
chemical_list: D000991:Antithrombins; D011719:Pyrazines; D011392:Proline; D014357:Trypsin; D013917:Thrombin