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Related Experiment Videos

Tetrahydro-isoquinoline-based factor Xa inhibitors

R Kucznierz1, F Grams, H Leinert

  • 1Chemical Research Department, Boehringer Mannheim GmbH, D-68298 Mannheim, Germany.

Journal of Medicinal Chemistry
|December 4, 1998
PubMed
Summary

New factor Xa (fXa) inhibitors based on TIPAC derivatives show potent activity. Molecular modeling reveals a preferred binding mode, with tetrahydro-isoquinoline in the S1 site and piperidine in the S4 site.

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Area of Science:

  • Medicinal Chemistry
  • Biochemistry
  • Pharmacology

Background:

  • Factor Xa (fXa) is a critical enzyme in the coagulation cascade.
  • Developing selective fXa inhibitors is a key therapeutic strategy for anticoagulation.
  • Previous inhibitors like DX-9065a provide a structural basis for designing new agents.

Purpose of the Study:

  • To synthesize and characterize novel derivatives of (2-amidino-1,2,3,4-tetrahydro-isoquinolin-7-yloxy)phenylacetic acid (TIPAC) as potential fXa inhibitors.
  • To investigate the structure-activity relationships and binding modes of these novel inhibitors.
  • To assess the selectivity of these compounds against related serine proteases like thrombin and trypsin.

Main Methods:

  • Multi-step organic synthesis to prepare TIPAC derivatives.

Related Experiment Videos

  • Enzyme inhibition assays to determine inhibition constants (Ki) against fXa, thrombin, and trypsin.
  • Molecular modeling studies utilizing X-ray crystal structures of fXa.

    • Main Results:

    • Synthesized TIPAC derivatives, with potent compounds (14, 17, 22-26) exhibiting Ki values of 21-55 nM for fXa.
    • Demonstrated high selectivity, with minimal inhibition of thrombin (Ki > 5 µM) and weak inhibition of trypsin (Ki = 0.08-5 µM).
    • Molecular modeling suggested a binding mode where the tetrahydro-isoquinoline moiety occupies the fXa S1 site and the piperidine moiety occupies the S4 site.

    Conclusions:

    • Novel dibasic fXa inhibitors based on TIPAC scaffolds exhibit potent and selective inhibition.
    • The binding mode involves dual occupancy of the S1 and S4 cation binding sites of fXa.
    • These findings provide a foundation for further development of TIPAC derivatives as anticoagulant agents.