Recent efforts in the field of thrombin inhibitor research have focused on the identification of compounds with good oral bioavailability and pharmacokinetics. In this manuscript we describe a metabolism-based approach to the optimization of the 3-(2-phenethylamino)-6-methylpyrazinone acetamide template (e.g., 1) which resulted in the modification of each of the three principal components (i.e., P1, P2, P3) comprising this series. As a result of these studies, several potent thrombin inhibitors (e.g., 20, 24, 25) were identified which exhibit high levels of oral bioavailability and long plasma half-lives.
CITATION STYLE
Burgey, C. S., Robinson, K. A., Lyle, T. A., Sanderson, P. E. J., Lewis, S. D., Lucas, B. J., … Vacca, J. P. (2003). Metabolism-directed optimization of 3-aminopyrazinone acetamide thrombin inhibitors. Development of an orally bioavailable series containing P1 and P3 pyridines. Journal of Medicinal Chemistry, 46(4), 461–473. https://doi.org/10.1021/jm020311f
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