Design and synthesis of highly constrained factor Xa inhibitors: Amidine-Substituted bis(benzoyl)-[1,3]-diazepan-2-ones and bis(benzylidene)-bis(gem-dimethyl)cycloketones

Jian Cui, David Crich, Donald Wink, Matthew Lam, Arnold L. Rheingold, David A. Case, Wen Tao Fu, Yasheen Zhou, Mohan Rao, Arthur J. Olson, Michael E. Johnson

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14 Scopus citations


Two conformationally constrained templates have been designed to provide selective inhibitors of the coagulation cascade serine protease, Factor Xa (FXa). The most active inhibitor, 2,7-bis[(Z)-p-amidinobenzylidene)]-3,3,6,6-tetramethylcycloheptanone, exhibits a Ki of 42 nM against FXa, with strong selectivity against thrombin (1000-fold), trypsin (300-fold) and plasmin (900-fold). With only two freely rotatable bonds, molecular modeling suggests that one amidine group is positioned into the S1 pocket, forming hydrogen bonds with the side chain of Asp189, similar to other amidine-based inhibitors, with the second benzamidine positioned into the S4 pocket in a position to form strong cation-pi bonding with the S4 aryl cage. We suggest that this interaction plays an important role in the specificity of these inhibitors against other serine proteases.

Original languageEnglish (US)
Pages (from-to)3379-3392
Number of pages14
JournalBioorganic and Medicinal Chemistry
Issue number16
StatePublished - Aug 5 2003
Externally publishedYes


All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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