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 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.
Lange
Udo E W
UE
Abbott GmbH & Co. KG, D-67061 Ludwigshafen, Germany. udo.lange@abbott.com
Baucke
Dorit
D
Hornberger
Wilfried
W
Mack
Helmut
H
Seitz
Werner
W
Höffken
H Wolfgang
HW
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
D000991:Antithrombins