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Heterocyclic core analogs of a direct thrombin inhibitor
Timothy A Blizzard1, Sanjay Singh2, Basanagoud Patil2
1Merck Research Laboratories, Rahway, NJ, USA.
Abstract:
Thrombin is a serine protease that plays a key role in blood clotting. Pyrrolidine 1 is a potent thrombin inhibitor discovered at Merck several years ago. Seven analogs (2-8) of 1 in which the pyrrolidine core was replaced with various heterocycles were prepared and evaluated for activity against thrombin, clotting factors VIIa, IXa, Xa, and XIIa, and trypsin. The thiomorpholine analog 6 was the most active, essentially matching the thrombin inhibitory activity of 1 with slightly improved selectivity over trypsin.
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