Orally active thrombin inhibitors. Part 1: optimization of the P1-moiety.
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.
Mack
Helmut
H
Abbott GmbH & Co. KG, D-67061 Ludwigshafen, Germany. helmut.mack@abbott.com
Baucke
Dorit
D
Hornberger
Wilfried
W
Lange
Udo E W
UE
Seitz
Werner
W
Höffken
H Wolfgang
HW
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
D000991:Antithrombins