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1,2,5-Trisubstituted 1,4-diazepine-3-one: A novel dipeptidomimetic molecular scaffold

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Summary

The continuing effort to transform bioactive peptides into non-peptide peptidomimetics of therapeutic potential requires a diversity of tools such as molecular scaffolds, pseudopeptide modifications, and conformation mimetics. To this end, a novel polyfunctional monoheterocyclic system, 1,2,5-trisubstituted hexahydro-3-oxo-1H-1,4-diazepine ring (DAP), was designed. The linear precursor for the DAP was generated through a reductive alkylation step including a modified side chain and an α-amino function of two amino acid derivatives. Structural analysis of model diastereomeric DAPs, employing1H and13C NMR and computer simulation, revealed the conformational preferences of this system. The structural similarities to the 1,4-benzodiazepine, a common molecular scaffold for many non-peptidic peptidomimetic agents, and the pronounced dipeptidomimetic character of the DAP system offer a new powerful tool to medicinal chemists engaged in rational peptide-based drug design.

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References

  1. Kemp, D.S. and McNamara, P., Tetrahedron Lett., 23 (1982) 3761.

    Article  CAS  Google Scholar 

  2. Freidinger, R.M., Schwenk-Perlow, D. and Veber, D.F., J. Org. Chem., 47 (1982) 104.

    Article  CAS  Google Scholar 

  3. DiMaio, J. and Belleau, B., J. Chem. Soc., Perkin Trans, I (1989) 1687.

    Article  Google Scholar 

  4. Yamashita, T., Kojima, Y., Hirotsu, K. and Ohsuka, A., Int. J. Pept. Protein Res., 33 (1989) 110.

    Article  CAS  Google Scholar 

  5. Hölzemann, G., Kontakte (Darmstadt) 1 (1991) 3.

    Google Scholar 

  6. Hölzemann, G., Kontakte (Darmstadt) 2 (1991) 55.

    Google Scholar 

  7. Sato, M., Lee, J.Y.H., Nakanishi, H., Johnson, M.E., Chrusciel, R.A. and Kahn, M., Biochem. Biophys. Res. Commun., 187 (1992) 999.

    Article  PubMed  CAS  Google Scholar 

  8. Callahan, J.F., Newlander, K.A., Burgess, J.L., Eggleston, D.S., Nichols, A., Wong, A. and Huffman, W.F., Tetrahedron, 49 (1993) 3479.

    Article  CAS  Google Scholar 

  9. Farmer, P.S., In Ariens, E.J. (Ed.) Drug Design, Vol. X, Academic Press, New York, NY, 1980, pp. 19–43.

    Google Scholar 

  10. Hirschmann, R., Nicolaou, K.C., Pietranico, S., Salvino, J., Leahy, E.M., Sprengeler, P.A., Furst, G., Smith III, A.B., Strader, C.D., Cascieri, M.A., Candelore, M.R., Donaldson, C., Vale, W. and Maechler, L., J. Am. Chem. Soc., 114 (1992) 9217.

    Article  CAS  Google Scholar 

  11. Chorev, M., Roubini, E., Gilon, C. and Selinger, Z., Biopolymers, 31 (1991) 725.

    Article  PubMed  CAS  Google Scholar 

  12. DeWitt, S.H., Kiely, J.S., Stankovic, C.J., Schroeder, M.C., Cody, D.M.R. and Pavia, M.R., Proc. Natl. Acad. Sci. USA, 90 (1993) 6909.

    Article  PubMed  CAS  Google Scholar 

  13. Sawyer, T.K., In Taylor, M.D. and Amidon, G.L. (Eds.) Peptides-Based Drug Design Controlling Transport and Metabolism, American Chemical Society, Washington, DC, 1995, pp. 385–422, and references therein.

    Google Scholar 

  14. Weitz, I.S., Pellegrini, M., Mierke, D.F. and Chorev, M., J. Org. Chem., 62 (1997) 2527.

    Article  PubMed  CAS  Google Scholar 

  15. Pellegrini, M., Weitz, I.S., Chorev, M. and Mierke, D.F., J. Am. Chem. Soc., 43 (1997) 2430.

    Article  Google Scholar 

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Authors and Affiliations

  1. Pharmaceutical Chemistry Department, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, 91120, Jerusalem, Israel

    Iris S. Weitz & Michael Chorev

  2. Carlson School of Chemistry, Clark University, 950 Main Street, 01610, Worcester, MA, U.S.A.

    Maria Pellegrini & Dale F. Mierke

  3. Division of Bone and Mineral Metabolism, Thorndike and Charles A. Dana Laboratories Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue (HIM 944), 02215, Boston, MA, U.S.A.

    Miriam Royo & Michael Chorev

  4. Department of Pharmacology and Molecular Toxicology, University of Massachusetts, Medical Center, 55 Lake Avenue North, 01655, Worcester, MA, U.S.A.

    Dale F. Mierke

Authors
  1. Iris S. Weitz
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  2. Maria Pellegrini
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  3. Miriam Royo
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  4. Dale F. Mierke
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  5. Michael Chorev
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Weitz, I.S., Pellegrini, M., Royo, M. et al. 1,2,5-Trisubstituted 1,4-diazepine-3-one: A novel dipeptidomimetic molecular scaffold. Lett Pept Sci 5, 83–86 (1998). https://doi.org/10.1007/BF02443444

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  • DOI: https://doi.org/10.1007/BF02443444

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