Orally active thrombin inhibitors. Part 2: Optimization of the P2-moiety

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 24 h the antithrombin activity of the most active inhibitors with IC50s in the nanomolar range was determined in dogs demonstrating high thrombin inhibitory activity in plasma and an appropriate duration of action after oral administration.

Graphical abstractThe convergent synthesis of highly potent thrombin inhibitors and their SAR with focus on the P2-position is described. The special ‘dehydroproline’ effect on the in vitro potency and in vivo activity is discussed for selected examples.Figure optionsDownload full-size imageDownload as PowerPoint slide