title: Orally active thrombin inhibitors. Part 1: optimization of the P1-moiety.
abstract: The synthesis and SAR of novel nanomolar thrombin inhibitors with the common backbone HOOC-CH(2)-d-cyclohexylalanyl-3,4-dehydroprolyl-NH-CH(2)-aryl-C(=NH)NH(2) are described together with their ecarin clotting time (ECT) prolongation as measure for thrombin inhibition ex vivo. The aryl P1-moiety mimicking the arginine part of the d-Phe-Pro-Arg derived thrombin inhibitors turned out to be a key component for in vitro potency and in vivo activity. Optimization of this part led to compounds with improved antithrombin activity in rats and dogs after oral administration compared to the recently launched anticoagulant melagatran.
authors.affiliation: Abbott GmbH & Co. KG, D-67061 Ludwigshafen, Germany. helmut.mack@abbott.com
authors.forename: Helmut
authors.initials: H
authors.lastname: Mack
authors.forename: Dorit
authors.initials: D
authors.lastname: Baucke
authors.forename: Wilfried
authors.initials: W
authors.lastname: Hornberger
authors.forename: Udo E W
authors.initials: UE
authors.lastname: Lange
authors.forename: Werner
authors.initials: W
authors.lastname: Seitz
authors.forename: H Wolfgang
authors.initials: HW
authors.lastname: Höffken
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000991:Antithrombins / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D004285:Dogs; D008958:Models, Molecular; D051381:Rats; D013329:Structure-Activity Relationship; D014961:X-Ray Diffraction
chemical_list: D000991:Antithrombins