Metabolism-directed optimization of 3-aminopyrazinone acetamide thrombin inhibitors. Development of an orally bioavailable series containing P1 and P3 pyridines

Christopher S. Burgey, Kyle A. Robinson, Terry A. Lyle, Philip E.J. Sanderson, S. Dale Lewis, Bobby J. Lucas, Julie A. Krueger, Rominder Singh, Cynthia Miller-Stein, Rebecca B. White, Bradley Wong, Elizabeth A. Lyle, Peter D. Williams, Craig A. Coburn, Bruce D. Dorsey, James C. Barrow, Maria T. Stranieri, Marie A. Holahan, Gary R. Sitko, Jacquelynn J. CookDaniel R. McMasters, Colleen M. McDonough, William M. Sanders, Audrey A. Wallace, Franklin C. Clayton, Dennis Bohn, Yvonne M. Leonard, Theodore J. Detwiler, Joseph J. Lynch, Youwei Yan, Zhongguo Chen, Lawrence Kuo, Stephen J. Gardell, Jules A. Shafer, Joseph P. Vacca

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)461-473
Number of pages13
JournalJournal of medicinal chemistry
Volume46
Issue number4
DOIs
StatePublished - Feb 13 2003
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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  • Cite this

    Burgey, C. S., Robinson, K. A., Lyle, T. A., Sanderson, P. E. J., Lewis, S. D., Lucas, B. J., Krueger, J. A., Singh, R., Miller-Stein, C., White, R. B., Wong, B., Lyle, E. A., Williams, P. D., Coburn, C. A., Dorsey, B. D., Barrow, J. C., Stranieri, M. T., Holahan, M. A., Sitko, G. R., ... 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