title: Orally active thrombin inhibitors. Part 2: optimization of the P2-moiety.
abstract: Synthesis and SAR of orally active thrombin inhibitors of the d-Phe-Pro-Arg type with focus on the P2-moiety are described. The unexpected increase in in vitro potency, oral bioavailability, and in vivo activity of inhibitors with dehydroproline as P2-isostere is discussed. Over a period of 24h the antithrombin activity of the most active inhibitors with IC(50)s in the nanomolar range was determined in dogs demonstrating high thrombin inhibitory activity in plasma and an appropriate duration of action after oral administration.
authors.affiliation: Abbott GmbH & Co. KG, D-67061 Ludwigshafen, Germany. udo.lange@abbott.com
authors.forename: Udo E W
authors.initials: UE
authors.lastname: Lange
authors.forename: Dorit
authors.initials: D
authors.lastname: Baucke
authors.forename: Wilfried
authors.initials: W
authors.lastname: Hornberger
authors.forename: Helmut
authors.initials: H
authors.lastname: Mack
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 / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D004285:Dogs; D013329:Structure-Activity Relationship
chemical_list: D000991:Antithrombins