Discovery and evaluation of potent P1 aryl heterocycle-based thrombin inhibitors

Mary Beth Young, James C. Barrow, Kristen L. Glass, George F. Lundell, Christina L. Newton, Janetta M. Pellicore, Kenneth E. Rittle, Harold G. Selnick, Kenneth J. Stauffer, Joseph P. Vacca, Peter D. Williams, Dennis Bohn, Franklin C. Clayton, Jacquelynn J. Cook, Julie A. Krueger, Lawrence C. Kuo, S. Dale Lewis, Bobby J. Lucas, Daniel R. McMasters, Cynthia Miller-SteinBeth L. Pietrak, Audrey A. Wallace, Rebecca B. White, Bradley Wong, Youwei Yan, Philippe G. Nantermet

Research output: Contribution to journalArticlepeer-review

85 Scopus citations


In an effort to discover potent, clinically useful thrombin inhibitors, a rapid analogue synthetic approach was used to explore the P1 region. Various benzylamines were coupled to a pyridine/pyrazinone P2-P 3 template. One compound with an o-thiadiazole benzylic substitution was found to have a thrombin Ki of 0.84 nM. A study of ortho-substituted five-membered-ring heterocycles was undertaken and subsequently demonstrated that the o-triazole and tetrazole rings were optimal. Combination of these potent P1 aryl heterocycles with a variety of P2-P3 groups produced a compound with an extraordinary thrombin inhibitory activity of 1.4 pM. It is hoped that this potency enhancement in P1 will allow for more diversification in the P 2-P3 region to ultimately address additional pharmacological concerns.

Original languageEnglish (US)
Pages (from-to)2995-3008
Number of pages14
JournalJournal of medicinal chemistry
Issue number12
StatePublished - Jun 3 2004
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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