AU2001283938A1 - Ghrelin antagonists - Google Patents
Ghrelin antagonistsInfo
- Publication number
- AU2001283938A1 AU2001283938A1 AU2001283938A AU8393801A AU2001283938A1 AU 2001283938 A1 AU2001283938 A1 AU 2001283938A1 AU 2001283938 A AU2001283938 A AU 2001283938A AU 8393801 A AU8393801 A AU 8393801A AU 2001283938 A1 AU2001283938 A1 AU 2001283938A1
- Authority
- AU
- Australia
- Prior art keywords
- ser
- peptide
- leu
- octanoyl
- phe
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 101800001586 Ghrelin Proteins 0.000 title claims description 4
- GNKDKYIHGQKHHM-RJKLHVOGSA-N ghrelin Chemical compound C([C@H](NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)CN)COC(=O)CCCCCCC)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C1=CC=CC=C1 GNKDKYIHGQKHHM-RJKLHVOGSA-N 0.000 title claims description 4
- 239000005557 antagonist Substances 0.000 title claims description 3
- 102000012004 Ghrelin Human genes 0.000 title 1
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 37
- WCORRBXVISTKQL-WHFBIAKZSA-N Gly-Ser-Ser Chemical compound NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O WCORRBXVISTKQL-WHFBIAKZSA-N 0.000 claims description 11
- 102000018997 Growth Hormone Human genes 0.000 claims description 11
- 108010051696 Growth Hormone Proteins 0.000 claims description 11
- 239000000122 growth hormone Substances 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 11
- 125000002801 octanoyl group Chemical group C(CCCCCCC)(=O)* 0.000 claims description 11
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 8
- 241000124008 Mammalia Species 0.000 claims description 7
- 238000009472 formulation Methods 0.000 claims description 6
- 230000000694 effects Effects 0.000 claims description 5
- 102400000442 Ghrelin-28 Human genes 0.000 claims description 3
- 238000013268 sustained release Methods 0.000 claims description 3
- 239000012730 sustained-release form Substances 0.000 claims description 3
- 230000015572 biosynthetic process Effects 0.000 claims description 2
- 230000037396 body weight Effects 0.000 claims description 2
- 238000007911 parenteral administration Methods 0.000 claims 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- 241000700159 Rattus Species 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 239000002904 solvent Substances 0.000 description 2
- 229940122853 Growth hormone antagonist Drugs 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229920002988 biodegradable polymer Polymers 0.000 description 1
- 239000004621 biodegradable polymer Substances 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- -1 octanoyl ester Chemical class 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 238000012261 overproduction Methods 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 125000003607 serino group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C(O[H])([H])[H] 0.000 description 1
- 238000010532 solid phase synthesis reaction Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
- C07K14/60—Growth hormone-releasing factor [GH-RF], i.e. somatoliberin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/02—Drugs for disorders of the endocrine system of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin
- A61P5/04—Drugs for disorders of the endocrine system of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin for decreasing, blocking or antagonising the activity of the hypothalamic hormones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/06—Drugs for disorders of the endocrine system of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/10—Tetrapeptides
- C07K5/1002—Tetrapeptides with the first amino acid being neutral
- C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
- C07K5/1008—Tetrapeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Endocrinology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Toxicology (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Diabetes (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
- Peptides Or Proteins (AREA)
- Materials For Photolithography (AREA)
- Steroid Compounds (AREA)
Description
GHRELIN ANTAGONISTS
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of provisional application serial no. 60/220,178 filed July 13, 2000.
TECHNICAL FIELD
The invention relates to new growth hormone antagonists that can be administered to mammals to decrease the level of circulating growth hormone therein.
BACKGROUND
Ghrelin is a name for a family of related peptides of 27 or 28 amino acids which have been isolated in the stomach (M. Kojima et al., Nature, 402, 656- 660, 1999; H. Hosoda et al., J. Biol. Chem., May 8, 2000) by a distinct cell type in rats and humans. It is further characterized by having an essential octanoyl ester attached to a serine residue. Ghrelins are known to be potent releasers of growth hormone (GH) in animals and man.
Synthetic variations of these peptides were investigated to determine whether improvements can be made on them, and the present invention results from that investigation.
SUMMARY OF THE INVENTION
It has surprisingly been found that novel peptides of the general formula: Gly-Ser-Ser(Octanoyl)-Phe-A where A is -OH, NH2, Leu-Ser-Pro-Glu-X or -Ala-Lys-Leu-Gln-Pro-Arg-B where B is -OH or NH2 decrease, rather than increase the level of circulating
GH in mammals, presumably because these peptides antagonize the effect of the ghrelins. For this reason, these peptides are of value in normalizing or reducing elevated levels of growth hormone such as those found in acromegalic patients or in other tumor related overproduction GH.
DETAILED DESCRIPTION OF THE INVENTION
The instant peptides can be prepared by a number of synthetic methods such as exemplified in "Chemical Approaches to the Synthesis of Peptides and Proteins" by P. Lloyd- Williams et al., CRC Press, New York 1997, and similar works well known to peptide chemists.
These peptides are administered in aqueous solutions subcutaneously at doses of about 1 to lOmg/kg of body weight by bolus injection or by slow parenteral infusions. Also, these peptides may be administrated intranasally or intrapulmonary or via a sustained release formulation that includes a biodegradable polymer incorporating the peptide, or by other means well known to those of ordinary skill in the art, such as implantable osmotic pumps and the like.
EXAMPLES The following examples illustrate the effectiveness of these novel peptides.
Example 1
By solid phase synthesis the following peptide was prepared: Gly-Ser-Ser(Octanoyl)-Phe-Leu-Ser-Pro-Glu
Theoretical MW: 948.9 Found 948.9
Solubility in water: 0.7mg/ml Purity by HPLC analysis: 97.8%
The peptide was injected subcutaneously in 10-day old rats at a dose of 300mg/kg along with a solvent control and Gliielin, and the circulating GH determined at 15 minutes, as described in R. Deghenghi et al, Life Sciences 54, 1321-1328 (1994). The results were as follows:
This demonstrates that the present peptide antagonizes the effect of the ghrelins by reducing GH release to a level that is almost nil and much lower than the solvent control
Example 2 By the same method of Example 1, the following tetradecapeptide was prepared:
Gly-Ser-Ser(Octanoyl)-Phe-Leu-Ser-Pro-Glu-Ala-Lys-Leu-Gln-PiO-Arg
Theoretical MW: 1642.7 Found: 1642.7 Solubility in water: 0.9 mg/ml
Purity by HPLC analysis: 95.0%
The peptide was administered to rats as described above in Example 1. The results were as follows:
Again the inventive peptide is seen to antagonize the effect of the ghrelins by significantly reducing GH release to a level that is below that of the control.
Example 3
By the same method of Example 1, the following peptide was prepared:
Gly-Ser-Ser(Octanoyl)-Phe
Theoretical MW: 522.4 Found: 522.4
Solubility in water: insoluble
Purity by HPLC analysis: 95.6%
The peptide was administered to rats as described above in Example 1. The results were as follows:
Yet again the inventive peptide antagonizes the effect of the ghrelins by significantly reducing GH release to a level that is below that of the control.
Claims (18)
- THE CLAIMSWhat is claimed is:L A Ghrelin antagonist peptide of the formula:Gly-Ser-Ser(Octanoyl)-Phe-A where A is -OH, NH2, Leu-Ser-Pro-Glu-B, or -Ala-Lys-Leu-Gln-Pro-Arg-B, where B is -OH or NH2, wherein said peptide antagonizes the effect of ghrelins when administered to a mammal.
- 2. The peptide of claim 1 specifically asGly-Ser-Ser(Octanoyl)-Phe-Leu-Ser-PiO-Glu.
- 3. The peptide of claim 1 specifically as:Gly-Ser-Ser(Octanoyl)-Phe-Leu-Ser-PiO-Glu-Ala-Lys-Leu-Gln-PiO-Arg.
- 4. The peptide of claim 1 specifically as:Gly-Ser-Ser(Octanoyl)-Phe
- 5. A pharmaceutical composition comprising peptide of claim 1 in the form of a pharmaceutically acceptable salt.
- 6. The composition of claim 5 which further comprises a carrier.
- 7. The composition of claim 5 in the form of a sustained release formation or device for parenteral administration.
- 8. The peptide of claim 5 in the form of a pharmaceutically acceptable intranasal formulation.
- 9. The peptide of claim 5 in the form of a pharmaceutically acceptable inhalation formulation.
- 10. A method of normalizing elevated growth hormone levels in a mammal by administering to a mammal in need of such treatment an effective dose of at least one of the peptides of claim 1.
- 11. The method of claim 10 wherein the peptide is :Gly-Ser-Ser(Octanoyl)-Phe-Leu-Ser-Pro-Glu.
- 12. The method of claim 1 1 wherein the peptide is:Gly-Ser-Ser(Octanoyl)-Phe-Leii-Ser-PiO-Glu-Ala-Lys-Leu-Gln-Pro-Arg.
- 13. The method of claim 12 wherein the peptide is:Gly-Ser-Ser(Octanoyl)-Phe.
- 14. The method of claim 10 wherein the peptide is administered as a sustained release formulation or through a device used for parenteral administration.
- 15. The method of claim 10 wherein the peptide is administered as a pharmaceutically acceptable intranasal formulation.
- 16. The method of claim 10 wherein the peptide is administered in a pharmaceutically acceptable inhalation formulation.
- 17. The method of claim 10 wherein the peptide is administered at a dosage of between about 1 and 10 mg/kg of body weight of the mammal
- 18. The method of claim 10 wherein the peptide is administered to a mammal that is acromegalic.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US22017800P | 2000-07-24 | 2000-07-24 | |
| US60220178 | 2000-07-24 | ||
| PCT/EP2001/007929 WO2002008250A2 (en) | 2000-07-24 | 2001-07-10 | Ghrelin antagonists |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| AU2001283938A1 true AU2001283938A1 (en) | 2002-02-05 |
Family
ID=22822394
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU2001283938A Abandoned AU2001283938A1 (en) | 2000-07-24 | 2001-07-10 | Ghrelin antagonists |
Country Status (9)
| Country | Link |
|---|---|
| US (1) | US20020187938A1 (en) |
| EP (1) | EP1303538A2 (en) |
| JP (1) | JP2004504406A (en) |
| KR (1) | KR20030033002A (en) |
| CN (1) | CN1443198A (en) |
| AU (1) | AU2001283938A1 (en) |
| CA (1) | CA2416643A1 (en) |
| MX (1) | MXPA03000738A (en) |
| WO (1) | WO2002008250A2 (en) |
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| US20070275877A1 (en) * | 2003-08-29 | 2007-11-29 | Amylin Pharmaceuticals, Inc. | Methods for Treating or Ameliorating Ghrelin-Associated Diseases and Disorders |
| CN1902177A (en) | 2003-09-22 | 2007-01-24 | 万有制药株式会社 | Novel piperidine derivative |
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| US9724396B2 (en) | 2013-03-15 | 2017-08-08 | Massachusetts Institute Of Technology | Use of antagonists of growth hormone or growth hormone receptor to prevent or treat stress-sensitive psychiatric illness |
| PT3004138T (en) | 2013-06-05 | 2024-06-18 | Bausch Health Ireland Ltd | Ultra-pure agonists of guanylate cyclase c, method of making and using same |
| WO2015051496A1 (en) | 2013-10-08 | 2015-04-16 | Merck Sharp & Dohme Corp. | Antidiabetic tricyclic compounds |
| EP3065757A4 (en) | 2013-10-09 | 2017-08-23 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for downregulation of pro-inflammatory cytokines |
| US9119832B2 (en) | 2014-02-05 | 2015-09-01 | The Regents Of The University Of California | Methods of treating mild brain injury |
| CA2959208C (en) | 2014-08-29 | 2023-09-19 | Tes Pharma S.R.L. | Pyrimidine derivatives and their use as inhibitors of alpha-amino-beta-carboxymuconate-epsilon-semialdehyde decarboxylase |
| WO2016138099A1 (en) | 2015-02-24 | 2016-09-01 | Massachusetts Institute Of Technology | Use of ghrelin or functional ghrelin receptor agonists to prevent and treat stress-sensitive psychiatric illness |
| EP3526199B1 (en) | 2016-10-14 | 2022-04-13 | Tes Pharma S.r.l. | Inhibitors of alpha-amino-beta-carboxymuconic acid semialdehyde decarboxylase |
| US11072602B2 (en) | 2016-12-06 | 2021-07-27 | Merck Sharp & Dohme Corp. | Antidiabetic heterocyclic compounds |
| US10968232B2 (en) | 2016-12-20 | 2021-04-06 | Merck Sharp & Dohme Corp. | Antidiabetic spirochroman compounds |
| CA3119509A1 (en) | 2018-11-20 | 2020-05-28 | Tes Pharma S.R.L | Inhibitors of alpha-amino-beta-carboxymuconic acid semialdehyde decarboxxylase |
| US11098029B2 (en) | 2019-02-13 | 2021-08-24 | Merck Sharp & Dohme Corp. | 5-alkyl pyrrolidine orexin receptor agonists |
| EP4010314B1 (en) | 2019-08-08 | 2024-02-28 | Merck Sharp & Dohme LLC | Heteroaryl pyrrolidine and piperidine orexin receptor agonists |
| TW202227417A (en) | 2020-08-18 | 2022-07-16 | 美商默沙東藥廠 | Bicycloheptane pyrrolidine orexin receptor agonists |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ATE449174T1 (en) * | 1999-07-23 | 2009-12-15 | Kenji Kangawa | NEW PEPTIDES |
| US6967237B2 (en) * | 2000-05-30 | 2005-11-22 | Merck & Co., Inc. | Ghrelin analogs |
-
2001
- 2001-07-10 WO PCT/EP2001/007929 patent/WO2002008250A2/en not_active Application Discontinuation
- 2001-07-10 US US09/902,556 patent/US20020187938A1/en not_active Abandoned
- 2001-07-10 KR KR10-2003-7000982A patent/KR20030033002A/en not_active Application Discontinuation
- 2001-07-10 AU AU2001283938A patent/AU2001283938A1/en not_active Abandoned
- 2001-07-10 MX MXPA03000738A patent/MXPA03000738A/en unknown
- 2001-07-10 EP EP01962848A patent/EP1303538A2/en not_active Withdrawn
- 2001-07-10 JP JP2002514154A patent/JP2004504406A/en active Pending
- 2001-07-10 CN CN01813240A patent/CN1443198A/en active Pending
- 2001-07-10 CA CA002416643A patent/CA2416643A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| CA2416643A1 (en) | 2002-01-31 |
| US20020187938A1 (en) | 2002-12-12 |
| WO2002008250A3 (en) | 2002-08-22 |
| MXPA03000738A (en) | 2003-06-04 |
| WO2002008250A2 (en) | 2002-01-31 |
| JP2004504406A (en) | 2004-02-12 |
| CN1443198A (en) | 2003-09-17 |
| EP1303538A2 (en) | 2003-04-23 |
| KR20030033002A (en) | 2003-04-26 |
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