کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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1378858 | 982012 | 2006 | 7 صفحه PDF | دانلود رایگان |
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.
Highly 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 as PowerPoint slide
Journal: Bioorganic & Medicinal Chemistry Letters - Volume 16, Issue 10, 15 May 2006, Pages 2641–2647