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–CH2–d-cyclohexylalanyl-3,4-dehydroprolyl–NH–CH2–aryl-C(NH)NH2 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.

Graphical abstractHighly potent thrombin inhibitors and their SAR with focus on the P1-position are described. The aryl P1-moiety mimicking the Arg 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.Figure optionsDownload full-size imageDownload as PowerPoint slide