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Synthesis of (2R, 3R, 4R, 5S)-5-tert-Butyloxycarbonylamino-3,4-Dihydroxy-2-1sopropyl-3,4-O,O-Isopropylidene-6-CyctohexyI-Hexanoic Acid

  • Allen Scott
  • Brian G. Conway
  • Mark A. Krook
Part of the Methods in Molecular Medicine™ book series (MIMM, volume 23)

Abstract

The dipeptidic dihydroxyethylene isostere (27, 3R, 4R, 5S)-5-tert-butyloxy-carbonylamino-3,4-dihydroxy-2-isopropyl-3,4-O,O-isoprop-ylidene-6-cyclohexyl-hexanoic acid, 15, is a representative building block of an important class of unnatural dipeptide mimics. This pseudo-dipeptide of Cha-Val is considered to be a transition-state analog mimic that produces potent inhibitors of the enzyme renin when incorporated into angiotensinogen substrate peptide sequence (1). The same strategy has also been proven successful in the development of potent inhibitors of other aspartyl proteases, including HIV protease (2). This synthetic method has been proven successful in the preparation of 100-g-scale quantity of this important building block, which was used in the preparation of a potent HIV protease inhibitory peptidomimetic, PNU-75875, which was proven effective in the treatment of SIV-infected monkeys (3).

Keywords

Magnesium Sulfate Argon Pressure Anhydrous Magnesium Sulfate Phosphomolybdic Acid Complete Reaction Mixture 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. 1.
    Thaisrivongs, S., Pals, D. T., Kroll, L. T., Turner, S. R., and Han, F.-S. (1987) Renin inhibitors. Design of angiotensinogen transition-state analogues containing novel (2R,3R,4R,5S)-5-amino-3,4-dihydroxy-2-isopropyl-7-methyloctanoic acid. J. Med. Chem. 30, 976–982.CrossRefGoogle Scholar
  2. 2.
    Thaisrivongs, S., Tomasselli, A.G., Moon, J. B., Hui, J. O., McQuade, T. J., Turner, S. R., et al. (1991) Inhibitors of the protease from human immunodeficiency virus: design and modelling of a compound containing a dihydroxyethylene isostere insert with high binding affinity and effective anti-viral activity. J. Med Chem. 34, 2344–2356.CrossRefGoogle Scholar
  3. 3.
    Martin, L. N., Soike, K. F., Murphey-Corb, M., Bohm, R. P., Roberts, E. D., Kakuk, T. J., et al. (1994) Effects of a peptidomimetic inhibitor of retroviral proteases (U-75875) on simian immunodeficiency virus infection in rhesus monkeys. Antimicrob. Agents Chemother. 38, 1277–1283.Google Scholar

Copyright information

© Humana Press Inc., Totowa, NJ 1999

Authors and Affiliations

  • Allen Scott
    • 1
  • Brian G. Conway
    • 1
  • Mark A. Krook
    • 1
  1. 1.Chemical and Fermentation OperationsPharmacia & Upjohn, Inc.Kalamazoo

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