| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | April 29, 1997 |
| PATENT TITLE |
Selective amylin antagonist peptides and uses therefor |
| PATENT ABSTRACT | Peptides that inhibit amylin activity and that exhibit selectivity for amylin receptors relative to calcitonin and CGRP receptors are provided. These peptides may be used in the treatment of conditions where it is of benefit to reduce amylin activity, including the treatment of Type 2 diabetes mellitus, impaired glucose tolerance, obesity, insulin resistance and hypertension |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | July 21, 1993 |
| PATENT REFERENCES CITED |
Patel, Biochem Soc. Trans., 17(5) 1989, p. 931. McMartin, Biochem. Soc. Trans. 17(5) 1989, pp. 931-934. Bundgaard et al., Biochem Soc. Trans., 17(5) 1989, pp. 947-949. Morrison and Boyda, Organic Chemistry, 4th Ed., Allyn and Bacon, Inc., 1983, pp. 1117-1120. U.S. Application Serial No. 07/794,288, filed Nov. 19, 1992, for "Novel Amylin Antagonist Peptides and Uses Therefor". Amara, S.G. et al., Science 229:1094-1097 (1985). Cooper, G.J.S. et al., Proc. Natl. Acad. Sci. USA 85:7763-7766 (1988). Cooper, G.J.S. et al., Proc. Natl. Acad. Sci. USA 85:7763-7766 (1988). Cooper, G.J.S. et al., Biochem. Biophys. Acta. 1014:247-258 (1989). Cooper, G.J.S. et al., Progress in Growth Factor Research 1:99-105 (1989). |
| PATENT CLAIMS |
I claim: 1. An amylin antagonist peptide having the formula: X-R.sub.1 ThrGlnR.sub.2 LeuAlaAsnR.sub.3 LeuValArgLeuGlnThrTyr-ProArgThrAsnValGlyR.sub.4 AsnThrTyr--NH.sub.2 wherein R.sub.1 is the amino acid residue Ala or a bond; R.sub.2 is an amino acid residue selected from the group consisting of Arg, Gln, Lys, Asn and Leu; R.sub.3 is an amino acid residue selected from the group consisting of Gln, Glu, Asn, Asp and Phe; R.sub.4 is an amino acid residue selected from the group consisting of Ala and Ser; and X is hydrogen or an acetyl group. 2. The amylin antagonist peptide according to claim 1 wherein R.sub.1 is Ala, R.sub.2 is Arg, R.sub.3 is Glu, R.sub.4 is Ser, and X is an acetyl group. 3. The amylin antagonist peptide according to claim 1 wherein R.sub.1 is Ala, R.sub.2 is Arg, R.sub.3 is Gln, R.sub.4 is Ser, and X is an acetyl group. 4. The amylin antagonist peptide according to claim 1 wherein R.sub.1 is Ala, R.sub.2 is Leu, R.sub.3 is Glu, R.sub.4 is Ser, and X is an acetyl group. 5. The amylin antagonist peptide according to claim 1 wherein R.sub.1 is Ala, R.sub.2 is Gln, R.sub.3 is Glu, R.sub.4 is Ser, and X is an acetyl group. 6. The amylin antagonist peptide according to claim 1 wherein R.sub.1 is Ala, R.sub.2 is Leu, R.sub.3 is Gln, R.sub.4 is Ser, and X is hydrogen. 7. The amylin antagonist peptide according to claim 1 wherein R.sub.1 is Ala, R.sub.2 is Gln, R.sub.3 is Gln, R.sub.4 is Ser, and X is hydrogen. -------------------------------------------------------------------------------- |
| PATENT DESCRIPTION |
FIELD OF THE INVENTION The present invention relates to peptides which inhibit amylin activity. These peptides may be used in the treatment of Type 2 diabetes mellitus and other disorders, including obesity, insulin resistance, impaired glucose tolerance, hypertension, disorders associated with renin secretion, and other disorders where amylin activity is beneficially reduced. BACKGROUND OF THE INVENTION Amylin is a recently discovered peptide which has marked effects on carbohydrate metabolism in vitro and in vivo, including the ability to inhibit the uptake of glucose and to suppress the synthesis of glycogen in isolated skeletal muscle. Cooper, G. J. S. et al., Proc. Natl. Acad. Sci. USA 85:7763-7766 (1988). A defect in amylin homeostasis is believed to contribute to insulin resistance and the development of Type 2 diabetes mellitus, Cooper, G. J. S. et al., Biochim. Biophys. Acta. 1014:247-258 (1989), as well as other metabolic disorders. Amylin is a 37 amino acid peptide that shows about 46% identity in amino acid sequence on comparison with the calcitonin gene-related peptides (CGRPs). Cooper, G. J. S. et al., Progress in Growth Factor Research 1:99-105 (1989). CGRP shares limited sequence identity, about 30%, with calcitonin and common parentage in that alternate processing of a primary mRNA transcript leads to the generation of the two distinct peptides. Amara, S. G. et al., Science 229:1094-1097 (1985). Compounds that inhibit the effects of amylin and its agonists (i.e., mimics of one or more of the effects of amylin) are referred to as amylin "antagonists." Amylin antagonist compounds and uses therefor are the subject of commonly owned U.S. application Ser. No. 07/794,288, filed Nov. 19, 1992, for "Novel Amylin Antagonist Peptides and Uses Therefor," the disclosure of which is hereby incorporated by reference. Amylin antagonist peptides may or may not be selective for amylin receptors. More selective antagonists may exhibit less side effects than those which might be associated with more non-selective antagonists. For example, non-selective amylin antagonists may bind to calcitonin or CGRP receptors and could thereby produce unwanted effects related to calcium homeostasis or blood pressure regulation. It is an object of the invention to provide further novel and potent amylin antagonists, including antagonists which are more selective for amylin receptors than for calcitonin and CGRP receptors. SUMMARY OF THE INVENTION In one aspect, the invention provides novel compounds which are potent amylin antagonist peptides that are more selective for amylin receptors than calcitonin and CGRP receptors. Described and claimed are amylin antagonist peptides having the formula: X-R.sub.1 ThrGlnR.sub.2 LeuAlaAsnR.sub.3 LeuValArgLeuGlnThrTyr-ProArgThrAsnValGlyR.sub.4 AsnThrTyr--NH.sub.2 wherein R.sub.1 is the amino acid residue Ala or a bond; R.sub.2 is an amino acid residue selected from the group consisting of Arg, Gln, Lys, Asn and Leu; R.sub.3 is an amino acid residue selected from the group consisting of Gln, Glu, Asn, Asp and Phe; R.sub.4 is an amino acid residue selected from the group consisting of Ala and Ser; and X is hydrogen or an acetyl group. Additionally the valine residue at position 20 may be substituted for threonine, and the threonine residue at position 24 may be substituted for serine. Also provided are preferred antagonists of the above formula, where: R.sub.1 is Ala, R.sub.2 is Arg, R.sub.3 is Glu, R.sub.4 is Ser, and X is an acetyl group; R.sub.1 is Ala, R.sub.2 is Arg, R.sub.3 is Gln, R.sub.4 is Ser, and X is an acetyl group; R.sub.1 is Ala, R.sub.2 is Leu, R.sub.3 is Glu, R.sub.4 is Ser, and X is an acetyl group; R.sub.1 is Ala, R.sub.2 is Gln, R.sub.3 is Glu, R.sub.4 is Ser, and X is an acetyl group; R.sub.1 is Ala, R.sub.2 is Leu, R.sub.3 is Gln, R.sub.4 is Ser, and X is hydrogen; and, R.sub.1 is Ala, R.sub.2 is Gln, R.sub.3 is Gln, R.sub.4 is Ser, and X is hydrogen. In another aspect, the invention provides pharmaceutical compositions comprising therapeutically effective amounts of the above amylin antagonist peptides and a pharmaceutically acceptable carrier, and methods of using these pharmaceutical compositions for the treatment of Type 2 diabetes mellitus and other disorders, including obesity, insulin resistance, impaired glucose tolerance, hypertension, disorders associated with renin secretion, and other disorders where amylin activity is beneficially reduced. Other features and advantages of the invention will be apparent from the following detailed description of the invention and from the claims. |
| PATENT PHOTOCOPY | available on request |
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