Synthesis of 13C‐Labeled Pyrazinone Thrombin Inhibitors and Elucidation of Metabolic Activation Pathways

In support of a research program aimed at discovering orally bioavailable thrombin inhibitors, ¹³C‐ labeled 3‐aminopyrazinone acetamide thrombin inhibitors have been prepared to aid in the structural elucidation of key metabolites during preclinical and clinical studies. A method for the ¹³C‐labeling of pyrazinones utilizing ¹³C‐glycine as a building block has been developed in a good overall yield. Two targets with labels at different positions have been prepared. NMR Studies not only led to the structure of a major metabolite, but also revealed a likely metabolic pathway, which will provide structural guidance for the design and synthesis of future thrombin inhibitors as well as other pyrazinone‐containing compounds.