Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – Tripeptides – e.g. – tripeptide thyroliberin – etc.
Patent
1993-06-17
1996-01-23
Warden, Jill
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
Tripeptides, e.g., tripeptide thyroliberin , etc.
530330, A61K 3800, C07K 500, C07K 700, C07K 1700
Patent
active
054865972
DESCRIPTION:
BRIEF SUMMARY
This invention relates to tetrapeptide derivatives and analogues, and more particularly to tetrapeptide derivatives and analogues which are antagonists of the effects of gastrin and/or cholecystokinin (CCK) or which display gastrin and/or CCK like partial agonist activity. The invention also relates to methods for preparing such gastrin and/or CCK receptor ligands and to compounds which are useful as intermediates in such methods.
Gastrin and the CCK's are structurally-related neuropeptides which exist in gastrointestinal tissue and in the CNS (see Mutt V., Gastrointestinal Hormones, Glass G. B. J., ed., Raven Press, N.Y., p 169 and Nisson G., ibid, p. 127).
Several forms of gastrin are found including 34-, 17-, and 14-amino acid species with the minimum active fragment being the C-terminal tetrapeptide (TrpMetAspPhe-NH.sub.2) which is reported in the literature to have full pharmacological activity (see Tracey H. J. and Gregory R. A., Nature (London), 1964, 204, 935). Much effort has been devoted to the synthesis of analogues of this tetrapeptide (and the N-protected derivative Boc-TrpMetAspPhe-NH.sub.2) in an attempt to elucidate the relationship between structure and activity. Some 500 compounds were examined for agonist activity by Morley (Proc. Roy. Soc. B, 1968, 170, 97; J. Chem. Soc. (C), 1969, 809).
Gastrin is one of the three primary stimulants of gastric acid secretion. A number of gastrin antagonists have been proposed for various therapeutic applications, including the prevention of gastrin-related disorders, gastrointestinal ulcers, Zollinger-Ellison syndrome, antral G Cell hyperplasia and other conditions in which lowered gastrin activity is desirable. The hormone has also been shown to have a trophic action on cells in the stomach and so an antagonist may be expected to be useful in the treatment of cancers, particularly in the stomach.
Natural cholecystokinin is a 33 amino acid peptide (CCK-33), the C-terminal 5 amino acids of which are identical to those of gastrin. Also found naturally is the C-terminal octapeptide (CCK-8) of CCK-33.
The cholecystokinins are reported to be important in the regulation of appetite. They stimulate intestinal motility, gall bladder contraction, pancreatic enzyme secretion, and are known to have a trophic action on the pancreas. They also inhibit gastric emptying and have various effects in the CNS. Possible therapeutic uses for cholecystokinin antagonists include the control of appetite disorders such as anorexia nervosa, and the treatment of pancreatic inflammation, biliary tract disease and various psychiatric disorders. Other possible uses are in the potentiation of opiate (e.g. morphine) analgesia, and in the treatment of cancers, especially of the pancreas. Moreover, ligands for cholecystokinin receptors in the brain (so-called CCK.sub.B receptors) have been claimed to possess anxiolytic activity.
Natural hormones and hormone-like drugs (agonists) can bind to their specific receptors and then fully activate receptor-mediated effects (efficacy). Antagonists are compounds which have no efficacy but retain affinity. Therefore, when receptors are occupied by antagonists they can completely suppress the effects of the corresponding hormone. Partial agonists have only a relative loss of efficacy. Given alone they cannot produce as high a maximum effect as the hormone. Thus a partial agonist which is occupying all the receptors and producing, say, only 20% of the hormone's maximum effect will, therefore, antagonise the hormone's effect at all levels above 20%. Partial agonists are, therefore, potentially useful drugs for two reasons: (1) they antagonise high levels of hormonal activity but set a lower bound to the degree of antagonism--they cannot totally suppress natural hormone activity at any dose level and (2) they can produce tissue-selective antagonism where the receptor density is not uniformly expressed in different tissues. (See Kenakin T. P. and Beek D., J. Pharmac. Exp. Ther, 1980, 213, 406 and Black J. W. and Leff P., Proc. R. Soc. Lond. B, 1983, 22
REFERENCES:
Yabe et al., "Synthesis and Biological Activity of Tetragastrin Analogues modifying the Tryptophan Residue", Chem. Pharm. Bull. 25(10):2731-2734 (1977).
Comprehensive Medicinal Chemistry, vol. 3, pp. 932-936, Sammes et al. eds., Pergamon Press, Oxford (1990).
Shiosaki et al., "Development of CCK-Tetrapeptide Analogues as Potent and Selective CCK-A Receptor Agonists", J. Med. Chem. 33:2950-2952 (1990).
Broughton Howard B.
Buck Ildiko M.
Davies Jonathan M. R.
Hull Robert A. D.
Kalindjian Sarkis B.
Huff Sheela J.
James Black Foundation Limited
Warden Jill
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