Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 16, Issue 10, Pages 2648-2653Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2006.01.046
Keywords
thrombin inhibitor; anticoagulant; factor IIa inhibitor; serine protease inhibitor; amidine
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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 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. (C) 2006 Elsevier Ltd. All rights reserved.
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