A super active cyclic hexapeptide analog of somatostatin

Daniel F. Veber, Richard Saperstein, Ruth F. Nutt, Roger M. Freidinger, Stephen F. Brady, Paul Curley, Debra S. Perlow, William J. Paleveda, C. Dylion Colton, Anthony G. Zacchei, Dominick J. Tocco, Dale R. Hoff, Richard L. Vandlen, John E. Gerich, Larry Hall, Lawrence Mandarino, Eugene H. Cordes, Paul S. Anderson, Ralph Hirschmann

    Research output: Contribution to journalArticlepeer-review

    144 Scopus citations

    Abstract

    The cyclic hexapeptide, cyclo (Pro-Phe-D-Trp-Lys-Thr-Phe), I, has been shown to have the biological properties of somatostatin. We now report structure-activity studies which optimize the potency of this cyclic hexapeptide series with the synthesis of cyclo (N-Me-Ala-Tyr-D-Trp-Lys-Val-Phe), II, which is 50-100 times more potent than somatostatin for the inhibition of insulin, glucagon and growth hormone release. The hydroxyl group of tyrosine is seen to lend a 10-fold enhancement to the potency. Potency also is found to be correlated with hydrophobicity. II is found to improve the control of postprandial hyperglycemia in diabetic animals when given in combination with insulin. The analog is found to be quite stable in the blood and in the gastrointestinal tract, but the bioavailability after oral administration is only 1-3%. The biological properties and long duration of II should allow clinical evaluation of the inhibition of glucagon release as an adjunct to insulin in the treatment of patients with diabetes.

    Original languageEnglish (US)
    Pages (from-to)1371-1378
    Number of pages8
    JournalLife Sciences
    Volume34
    Issue number14
    DOIs
    StatePublished - 1984

    ASJC Scopus subject areas

    • Biochemistry, Genetics and Molecular Biology(all)
    • Pharmacology, Toxicology and Pharmaceutics(all)

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