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 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  but with improved selectivity over trypsin.

SAR of heterocyclic core analogs of a direct thrombin inhibitor

244th National Meeting (2012)

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