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From a peptide lead to an orally active peptidomimetic fibrinogen receptor antagonist

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Summary

Antagonists of the platelet fibrinogen receptor (GP IIb/IIIa receptor) are expected to be a new promising class of antithrombotic agents. The binding of fibrinogen to the fibrinogen receptor depends on an Arg-Gly-Asp-Ser (RGDS) tetrapeptide recognition motif. Structural modifications of the RGDS lead have led to the discovery of a non-peptide RGD mimetic GP IIb/IIIa antagonist20 (S 1197). Compound20 inhibits dose-dependently and reversibly human platelet aggregation. Modeling studies based on structure-activity data revealed the following structural features of the drug as important for receptor binding: the amidino group, the carboxylate group, hydrophobic substitutions at the carboxyl-terminus and at the side chain carrying the positive charge, the carboxyl-terminal NH group of the β-amino acid as a hydrogen bond donor and one oxygen atom of the hydantoin as a hydrogen bond acceptor. The ethyl ester prodrug of20 (S 5740) is an orally active antithrombotic agent which has the potential to be used to treat and prevent thrombotic diseases in humans.

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References

  1. Fitzgerald, D.J., Roy, L., Catella, F. and Fitzgerald, G.A., New Engl. J. Med., 315 (1986) 983.

    Article  PubMed  CAS  Google Scholar 

  2. Fuster, V., Steele, P.M. and Chesebro, J.H., J. Am. Coll. Cardiol., 5 (1985) 175B.

    Article  PubMed  CAS  Google Scholar 

  3. Harrison, M.J.G., Circulation, 81 (Suppl. I) (1990) I-20.

    Google Scholar 

  4. Davies, M.J. and Thomas, A.C., Br. Heart J. 53 (1985) 363.

    PubMed  CAS  Google Scholar 

  5. Phillips, D.R., Charo, I.F., Parise, L.V. and Fitzgerald, L.A., Blood, 71 (1988) 831.

    PubMed  CAS  Google Scholar 

  6. Hawiger, J., Hum. Pathol., 18 (1987), 111.

    PubMed  CAS  Google Scholar 

  7. Cook, N.S., Kottirsch, G. and Zerwes, H.-G., Drugs Future, 19 (1994) 135.

    Google Scholar 

  8. Weller, T., Alig, L., Hürzeler Müller, M., Kouns, W.C., and Steiner, B., Drugs Future, 19 (1994) 461.

    Google Scholar 

  9. Austel, V., Himmelsbach, F. and Müller, T., Drugs Future, 19 (1994) 757.

    Google Scholar 

  10. Lefkovits, J., Plow, E.F. and Topol, E.J., New Engl. J. Med., 332 (1995) 1553.

    Article  PubMed  CAS  Google Scholar 

  11. The EPIC investigators, New Engl. J. Med., 330 (1994) 956.

    Article  Google Scholar 

  12. Ruoslahti, E., J. Clin. Invest., 87 (1991), 1.

    Article  PubMed  CAS  Google Scholar 

  13. Just, M., Hropot, M., Jablonka, B., König, W., and Stilz, H.U., Thromb. Haemost., 73 (1995) 1444.

    Google Scholar 

  14. Jablonka, B., Just, M., König, W. and Stilz, H.U., Naunyn-Schmied. Arch. Pharmacol., 353s (1995) R29 (116).

    Google Scholar 

  15. Stilz, H.U., Jablonka, B., Just, M., Knolle, J., Paulus, E.F. and Zoller, G., J. Med. Chem., 39 (1996) 2118.

    Article  PubMed  CAS  Google Scholar 

  16. Stilz, H.U., Beck, G., Just, M. and Jablonka, B., Bull. Soc. Chim. Belg., 105 (1996) 711.

    CAS  Google Scholar 

  17. Brooks, B., Bruccoleri, R., Olafson, B., States, D., Swaminathan, S., and Karplus, M., J. Comput. Chem., 4 (1983) 187.

    Article  CAS  Google Scholar 

  18. Catalyst, HipHop, v.3.1, Molecular Simulations, San Diego, CA, U.S.A., 1996.

  19. SYBYL, Molecular Modeling Software, v. 6.2, Tripos Inc., St. Louis, MO, U.S.A., 1995.

  20. Cramer III, R.D., Patterson, D.E. and Bunce, J.D., J. Am. Chem. Soc., 110 (1988) 5959.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Chemical Research Agent, Hoechst Marion Roussel, The Health Care Division of Hoechst AG, D-65926, Frankfurt am Main, Germany

    Hans Ulrich Stilz, Otmar Klingler, Wolfgang König, Volkmar Wehner & Gerhard Zoller

  2. Core ResearchFunctins Agent, Hoechst Marion Roussel, The Health Care Division of Hoechst AG, D-65926, Frankfurt am Main, Germany

    Wolfgang Guba

  3. DG Cardiovascular Agent, Hoechst Marion Roussel, The Health Care Division of Hoechst AG, D-65926, Frankfurt am Main, Germany

    Bernd Jablonka & Melitta Just

Authors
  1. Hans Ulrich Stilz
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  2. Wolfgang Guba
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  3. Bernd Jablonka
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  4. Melitta Just
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  5. Otmar Klingler
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  6. Wolfgang König
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  7. Volkmar Wehner
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  8. Gerhard Zoller
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Stilz, H.U., Guba, W., Jablonka, B. et al. From a peptide lead to an orally active peptidomimetic fibrinogen receptor antagonist. Lett Pept Sci 5, 215–221 (1998). https://doi.org/10.1007/BF02443472

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  • DOI: https://doi.org/10.1007/BF02443472

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