WO1998027113A2 - Melanocortines - Google Patents

Melanocortines Download PDF

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Publication number
WO1998027113A2
WO1998027113A2 PCT/NL1997/000703 NL9700703W WO9827113A2 WO 1998027113 A2 WO1998027113 A2 WO 1998027113A2 NL 9700703 W NL9700703 W NL 9700703W WO 9827113 A2 WO9827113 A2 WO 9827113A2
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WO
WIPO (PCT)
Prior art keywords
msh
peptides
peptide
receptors
ala
Prior art date
Application number
PCT/NL1997/000703
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English (en)
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WO1998027113A3 (fr
WO1998027113A8 (fr
WO1998027113A9 (fr
Inventor
Roger Antonius Hendricus Adan
Johannes Peter Henri Burbach
Willem Hendrik Gispen
Original Assignee
Quadrant Holdings Cambridge Limited
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Quadrant Holdings Cambridge Limited filed Critical Quadrant Holdings Cambridge Limited
Priority to AU53480/98A priority Critical patent/AU5348098A/en
Priority to JP52756598A priority patent/JP2001506996A/ja
Priority to EP97950498A priority patent/EP0946595A2/fr
Priority to CA002275442A priority patent/CA2275442A1/fr
Publication of WO1998027113A2 publication Critical patent/WO1998027113A2/fr
Publication of WO1998027113A3 publication Critical patent/WO1998027113A3/fr
Publication of WO1998027113A8 publication Critical patent/WO1998027113A8/fr
Publication of WO1998027113A9 publication Critical patent/WO1998027113A9/fr

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Classifications

    • 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
    • C07K14/665—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin
    • C07K14/68—Melanocyte-stimulating hormone [MSH]
    • C07K14/685—Alpha-melanotropin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • 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
    • A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to the field of melanocortin peptides .
  • Melanocortins (which used to be called me1anotropines also) are peptides originally derived from a larger precursor protein named pro-opiomelanocortin.
  • the natural melanocortins share the heptapeptide core sequence Met-Glu-His-Phe-Arg-Trp- Gly.
  • These melanocortins include ⁇ -MSH ( ⁇ -melanocyte stimulating hormone), ⁇ -MSH, ⁇ -MSH, ⁇ -LPH ( ⁇ -lipotropin hormone) and ACTH ( adrenocorticotrope hormone) .
  • Melanocortins have a wide range of biological activities.
  • MCR-1 Melanocortin receptor 1
  • MCR-2 is the ACTH receptor expressed in for instance the adrenal gland.
  • the invention provides a peptide having specific binding affinity for a melanocortine receptor, preferably the mc3, mc4 or mc5 receptor comprising the sequence
  • X and Y are amino acid residues and Z is an aromatic amino acid residue.
  • the above peptides are agonists for MSH activity which are highly potent.
  • a very important contribution to the high potency can be attributed to the 7-position (counted as in the original ACTH-molecule) which should be D-2-thienyl-Ala or 3-pyridyl-D-Ala and for which only very limited and very similar residues may be substituted without losing the increase in agonist potency.
  • Another important contribution to MSH agonistic activity is the omission of residues 1-3 and/or the omission of residues 11-13.
  • a high contribution to activity is also provided by the presence of an aromatic amino acid residue at position 9.
  • Positions 4 and 5 should normally not be omitted; these residues should be present though it is far less critical which amino acid residues are present at said positions. It is clear that at least conserved substitutions are allowed for these positions, but also less conserved substitutions will histidine residue at position 6 and the arginine residue at position 8 are quite important for activity and should only be replaced by very conservative substitutions, if at all. Especially the more important residues in general should not be all replaced by substitutes in one and the same molecule.
  • the preferred residue at position is Naftyl-alanine, be it- in the D-or in the L-configuration. The presence of this residue leads to a further increase in potency.
  • amino acid residue at position 10 is not essential for the activity of the molecule, but it does seem to have some effect. If a residue is present it is preferred that this residue is glycine or lysine, whereby the latter has the additional advantage that it provides a reactive moiety which can be used to couple the peptide to other molecules or to make the peptide cyclic. In the event that a cyclic peptide is to be produced, which is preferred, since the half-life of such a cyclic peptide is improved over the half-life of the linear form, then a reactive moiety at the other end should also be provided.
  • Cyclic peptides can however also be produced by providing reactive moieties outside the essential core that enable closure of the loop, such as reactive moieties leading to a lactam.
  • the preferred residues at positions X and Y are Nle for X and Gly or Asp for Y, whereby the presence of Asp leads to a further advantage in having a reactive moiety for making a lactam.
  • the peptides according to the invention are generally more potent than MSH itself.
  • the preferred peptides have potencies of up to 100 times the potency of MSH. Less potent peptides are within the scope of the present invention, since potency is not the only criterion which is required for a successful peptide-based drug.
  • half-life and selectivity are also important parameters. the regular in vitro tests as well as an in vivo test in rats whereby the grooming behaviour is measured.
  • the results in a grooming assay are good indications that the peptides will be able to activate the receptor and thereby the G-protein cascade coupled to said receptor and thus the peptides can be used as agonists for MC-receptors .
  • Targeting the MC-receptor in particular of the MC-4 receptor for which a particularly selective peptide has been provided by the present invention in an agonistic manner is useful in the treatment of CNS- disorders, neurophathies , obesity, and in particular for diabetes related neuropathy, as well as neuropathy as a result of cytotoxic treatments (chemotherapy and the like).
  • the present invention also provides pharmaceutical compositions capable of treating the above conditions. Dosages for such treatments will usually be given once a day in doses of about 1 ⁇ q to about 100 mg per dosage unit, preferably 10 ⁇ q - 10 mg, more preferably 50 ⁇ q - 1 mg. The dosage should result in a concentration in the body of between 0,1 nm and 1 ⁇ m, preferably 1 nM - 100 nM, most preferably 10 - 50 nM.
  • the compositions may comprise the usual additives for usual dosage formats for peptide drugs or for peptide derived drugs. The format is preferably an oral formulation such as a tablet, a granulate, a powder or a liquid formulation, although enteral and parenteral administrations may find application as well. Particularly preferred are compositions wherein a peptide according to the invention is combined with a drug aiming to prevent or that leads to neuropathy, such as insulin and cytotoxic agents.
  • HEK 293 Human embryonal kidney (HEK 293) cells were stably transfected with the human MC3(Gantz et al. JBC 1993. 268:8246-8250), human MC4 (Gantz et al. 1993. JBC 268:15174015179) or human MC5 receptor constructs using the calcium phosphate precipitation method.
  • a reporter plasmid 10 ⁇ g of the pCRE- LacZ vector (Chen et al. 1995. Anal.Biochem. 226:349-354), in which a cAMP responsive element drives expression of the LacZ gene, was transfected at the beginning of each experiment. The day after pCRE-LacZ transfection, cells were split in 96-wells plates. After 48 hours cells were stimulated with varying concentrations of the MC receptor ligands in assay medium
  • DMEM + 0.1 mg/ml BSA, 0.1 mM IBMX DMEM + 0.1 mg/ml BSA, 0.1 mM IBMX
  • lysis buffer 60mM sodium phosphate, 1 mM MgCl2, 5 mM ⁇ -mercaptoethanol,
  • Rats Male Wistar rats weighing 120-130 g were implanted with cannulas into the foramen intraventriculare under hypnorm anaesthesia (Brakkee et al . , Life Science vol. 17 1979, ). Rats were allowed to recover for 3 days and used for experiments during the next 10 days. In case that rats were used for more than one grooming experiment they were allowed to recover for at least 3 days between subsequent experiments. Peptides (15 ng) dissolved in 3 ⁇ g saline (154 mM NaCI) were injected i.e.v. by means of a Hamilton syringe. Grooming tests were performed according to (Gispen et al , Lab. Ani . Sci. 29 1975). Rats were placed into the observation boxes immediately after the injection. Observation started 15 min after the 15 sec over 50 min, thus the maximal grooming score for a rat is 200.
  • Preparative HPLC was carried out using a Waters Prep 4000 .
  • liquid chromatograph equipped with a Waters RCM module with two PrepPak cartridges plus quard cartridge (25x210 mm) filled with Delta-Pak C18 material.
  • Peptides were detected at 230 nm using a Waters 486 spectrophotometer with a preparative cell. Purifications were performed in gradients using water with 0.1% trifluoroacetic acid (TFA) and acetonitrile with 0.1% TFA.
  • TFA trifluoroacetic acid
  • the Hamilton Microlab 2200 was programmed to deliver washing solvents and reagents to a rack with 40 individual 4 ml columns with filter, containing Rink ( 4- ( 2 ' , 4 ' -dimethoxyphenyl-Fmoc- aminomethy1 ) -phenoxy) resin for peptide synthesis.
  • the columns were drained automatically after each step by vacuum.
  • the coupling cycle was based on Fmoc/HBTU (2-(lH-benzotriazol-l- yl)-l,l,3,3-tetramethyluronium hexafluorophosphate) chemistry [Fields et al., Peptide Research 4, 95-101] using double coupling steps of 40 minutes. Peptides were deprotected and cleaved in 2 hrs using 1.5 ml of a mixture of trifluoroacetic acid/phenol/thioanisole/water/ethanedithiol
  • HPLC purified or crude peptides were used for cyclization via a disulfide bridge with cysteines or via a lactam bridge with the side chains of aspartic acid and lysine:
  • the peptide was dissolved in 3 ml of 40% acetic acid and purified by preparative HPLC in a gradient of 14% to 21% acetonitrile in water (containing 0.1% TFA) in 30 min. Yield after purification: 22.8 mg.
  • Lactam bridge a mixture of 20 ml of DMF (peptide grade), 26 mg of Benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP, 0.05 mmol) and 0.017 ml of DIEA (0.1 mmol) was added to crude MBJ07 (20 mg, 0.012 mmol). The cyclization reaction was followed by analytical HPLC. After 2 hours the mixture was acidified to pH 4 using 0.1 M HCI. The product was purified by preparative HPLC after dilution with 30 ml of water in a gradient of 21% to 30% acetonitrile in water, containing 0.1% TFA, in 30 min. Yield 15.4 mg.
  • Figure 1 shows the dose-response curves for the following peptides: MBU 23 *2GH6R7G# linear MBU 24 *2GH6R8G# linear MBU 27 *CGH6R8C# cyclic disulphate MBU 28 *2DH6R8K# cyclic lactam MBU 29 *2DH6R7K cyclic lactam
  • Figure lb Effect of the different aminoacids at position 7 and 9 together with MBU 23 and MBU 24. All peptides were tested at 100 nM on HEK 293 cells stably expressing the three different MC receptors; MC3, MC4 and MC5 receptors. Values activity of 100 nM NDP-MSH.
  • FIG. 1 Effect of single aminoacid substitutions at aminoacid position number 9 of NDP-MSH.
  • the aminoacids replacing the endogenous aminoacid (Trp) are depicted. Values represent the percentage activity as compared to the maximal activity of 10 nM cc-MSH. All peptides were tested at 10 nM on HEK 293 cells stably expressing the three different MC receptors ;MC3, MC4 and MC5 receptors. At this position on an NDP-MSH background an aromatic amino acid is highly preferred.
  • Figure 3 Effect of single aminoacid substitutions at aminoacid position number 4 of Nle-MSH. On the X-axis the aminoacids replacing the endogenous aminoacid (Met) are depicted. Values represent the percentage activity as compared to the maximal activity of 100 nM ⁇ -MSH. All peptides were tested at 100 nM on HEK 293 cells stably expressing the three different MC receptors; MC3, MC4 and MC5 receptors.
  • Figure 4 Effect of single aminoacid substitutions at aminoacid position number 5 of Nle-MSH. On the X-axis the aminoacids replacing the endogenous aminoacid (Glu) are depicted. Values represent the percentage activity as compared to the maximal activity of 100 nM ⁇ -MSH. All peptides were tested at 100 nM on HEK 293 cells stably expressing the three different MC receptors; MC3, MC4 and. MC5 receptors.
  • Figure 5 Effect of single aminoacid substitutions at aminoacid position number 6 of Nle-MSH.
  • aminoacids replacing the endogenous aminoacid His
  • Values represent the percentage activity as compared to the maximal activity of 100 nM ⁇ -MSH. All peptides were tested at 100 nM on HEK 293 cells stably expressing the three different MC receptors ;MC3, MC4 and MC5 receptors. aminoacid position number 7 of Nle-MSH.
  • the aminoacids replacing the endogenous aminoacid Phe
  • Values represent the percentage activity as compared to the maximal activity of 100 nM ⁇ -MSH. All peptides were tested at 100 nM on HEK 293 cells stably expressing the three different MC receptors; MC3, MC4 and MC5 receptors.
  • Figure 7 Effect of single aminoacid substitutions at aminoacid position number 8 of Nle-MSH.
  • the aminoacids replacing the endogenous aminoacid (Arg) are depicted. Values represent the percentage activity as compared to the maximal activity of 100 nM ⁇ -MSH. All peptides were tested at 100 nM on HEK 293 cells stably expressing the three different MC receptors ;MC3, MC4 and MC5 receptors. Only five aminoacid substitutions were tested.
  • Figure 8 Effect of single aminoacid substitutions at aminoacid position number 9 of Nle-MSH.
  • the aminoacids replacing the endogenous aminoacid (Trp) are depicted. Values represent the percentage activity as compared to the maximal activity of 100 nM ⁇ -MSH. All peptides were tested at 100 nM on HEK 293 cells stably expressing the three different MC-receptors ; MC3, MC4 and MC5 receptors.
  • Figure 9 Effect of single aminoacid substitutions at aminoacid position number 10 of Nle-MSH.
  • the aminoacids replacing the endogenous aminoacid (Gly) are depicted. Values represent the percentage activity as compared to the maximal activity of 100 nM ⁇ -MSH. All peptides were tested at 100 nM on HEK 293 cells stably expressing the three different MC receptors; MC3, MC4 and MC5 receptors.
  • 3 ⁇ l saline, or 3 ⁇ l saline with either 15 ng MBU peptides or 150 ng ⁇ -MSH or 1500 ng ⁇ -MSH was injected i.e.v. in rats and grooming behaviour was scored (mean ⁇ s.d.).

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Abstract

La présente invention concerne de nouveaux peptides dérivés du groupe d'hormones comprenant l'ACTH. Ces peptides, ou 'mélanocortines' (connus autrefois sous le nom de 'mélanotropines'), sont capables de cibler différents récepteurs se localisant souvent différemment sur plusieurs tissus. Les peptides de la présente invention conviennent particulièrement au ciblage agoniste de récepteurs du système nerveux. L'invention concerne également des compositions pharmaceutiques et leur utilisation.
PCT/NL1997/000703 1996-12-17 1997-12-17 Melanocortines WO1998027113A2 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
AU53480/98A AU5348098A (en) 1996-12-17 1997-12-17 Melanocortins
JP52756598A JP2001506996A (ja) 1996-12-17 1997-12-17 メラノコルチン受容体３、４又は５の特異結合のためのメラノコルチン誘導体
EP97950498A EP0946595A2 (fr) 1996-12-17 1997-12-17 Melanocortines
CA002275442A CA2275442A1 (fr) 1996-12-17 1997-12-17 Melanocortines

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EP96203567.1 1996-12-17
EP96203567 1996-12-17

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WO1998027113A2 true WO1998027113A2 (fr) 1998-06-25
WO1998027113A3 WO1998027113A3 (fr) 1998-08-06
WO1998027113A8 WO1998027113A8 (fr) 1999-09-02
WO1998027113A9 WO1998027113A9 (fr) 1999-11-04

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WO (1) WO1998027113A2 (fr)

Cited By (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998046243A2 (fr) * 1997-04-15 1998-10-22 Csir Compositions pharmaceutiques dotees d'une activite coupe-faim
WO2001030808A1 (fr) * 1999-10-27 2001-05-03 The Regents Of The University Of California Procedes et composes utiles pour moduler la liaison du recepteur de melanocortine-ligand
WO2001090140A1 (fr) * 2000-05-22 2001-11-29 Elan Drug Delivery Limited Peptoides comme liants pour recepteurs a la melanocortine
US6613874B1 (en) 1999-03-29 2003-09-02 The Procter & Gamble Company Melanocortin receptor ligands
US6693165B2 (en) 2000-01-18 2004-02-17 Merck & Co., Inc. Cyclic peptides as potent and selective melanocortin-4 receptor antagonists
WO2005030797A2 (fr) 2003-09-30 2005-04-07 Novo Nordisk A/S Nouveaux agonistes du recepteur de la melanocortine
US7033616B2 (en) 2000-06-30 2006-04-25 Phytopharm Plc Extracts, compounds and pharmaceutical compositions having anti-diabetic activity and their use
US7307063B2 (en) 2001-02-13 2007-12-11 Palatin Technologies, Inc. Melanocortin metallopeptides for treatment of sexual dysfunction
US7417027B2 (en) 2001-07-11 2008-08-26 Palatin Technologies, Inc. Linear and cyclic melanocortin receptor-specific peptides
US7501135B2 (en) 1999-10-27 2009-03-10 Conopco, Inc. Gastric acid secretion
EP2033662A1 (fr) 2004-01-21 2009-03-11 Novo Nordisk Health Care AG Conjugaison au moyen de transglutaminase de peptides
US7541430B2 (en) 2003-05-09 2009-06-02 Novo Nordisk A/S Peptides for use in treating obesity
WO2011103134A1 (fr) 2010-02-17 2011-08-25 Janssen Pharmaceutica Nv Aminothiazolones en tant que modulateurs de récepteur alpha associé aux œstrogènes
WO2011104379A1 (fr) 2010-02-26 2011-09-01 Novo Nordisk A/S Peptides pour le traitement de l'obésité
WO2011104378A1 (fr) 2010-02-26 2011-09-01 Novo Nordisk A/S Peptides de traitement de l'obésité
US8263781B2 (en) 2009-12-18 2012-09-11 Janssen Pharmaceutica Nv Substituted aminothiazolone indazoles as estrogen related receptor-alpha modulators
US8426604B2 (en) 2010-02-17 2013-04-23 Janssen Pharmaceutica Nv Aminothiazolones as estrogen related receptor-alpha modulators
US8455617B2 (en) 2009-06-08 2013-06-04 Astrazeneca Ab Melanocortin receptor-specific peptides
US8487073B2 (en) 2008-06-09 2013-07-16 Palatin Technologies, Inc. Melanocortin receptor-specific peptides for treatment of sexual dysfunction
US8492517B2 (en) 2009-11-23 2013-07-23 Palatin Technologies, Inc. Melanocortin-1 receptor-specific cyclic peptides
US8796256B2 (en) 2010-05-25 2014-08-05 Janssen Pharmaceutica Nv Substituted thiazolidinedione indazoles, indoles and benzotriazoles as estrogen-related receptor-α modulators
US8846601B2 (en) 2009-06-08 2014-09-30 Palatin Technologies, Inc. Melanocortin receptor-specific peptides
US8933194B2 (en) 2009-11-23 2015-01-13 Palatin Technologies, Inc. Melanocortin-1 receptor-specific linear peptides
WO2015162485A1 (fr) 2014-04-22 2015-10-29 Txp Pharma Gmbh Analogues peptidiques avec sonde(s) d'acide aminé ramifiée(s)
US9217023B2 (en) 2012-10-19 2015-12-22 Txp Pharma Gmbh Alpha- and gamma-MSH analogues
US9273098B2 (en) 2009-06-08 2016-03-01 Palatin Technologies, Inc. Lactam-bridged melanocortin receptor-specific peptides
WO2018167194A1 (fr) 2017-03-15 2018-09-20 Novo Nordisk A/S Composés bicycliques aptes à se lier au récepteur de mélanocortine 4
WO2019219714A1 (fr) 2018-05-15 2019-11-21 Novo Nordisk A/S Composés capables de se lier au récepteur de la mélanocortine 4
WO2020053414A1 (fr) 2018-09-14 2020-03-19 Novo Nordisk A/S Composés bicycliques aptes à se lier aux agonistes du récepteur de la mélanocortine 4

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Cited By (57)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7166611B2 (en) 1997-04-15 2007-01-23 Csir Pharmaceutical compositions having appetite suppressant activity
WO1998046243A3 (fr) * 1997-04-15 1999-02-25 Csir Compositions pharmaceutiques dotees d'une activite coupe-faim
GB2338235A (en) * 1997-04-15 1999-12-15 Csir Pharmaceutical compositions having appetite suppressant activity
GB2338235B (en) * 1997-04-15 2001-11-14 Csir Appetite suppressing plant extracts
WO1998046243A2 (fr) * 1997-04-15 1998-10-22 Csir Compositions pharmaceutiques dotees d'une activite coupe-faim
US6376657B1 (en) 1997-04-15 2002-04-23 Csir Pharmaceutical compositions having appetite suppressant activity
US6613874B1 (en) 1999-03-29 2003-09-02 The Procter & Gamble Company Melanocortin receptor ligands
US6951916B2 (en) 1999-03-29 2005-10-04 The Procter & Gamble Company Melanocortin receptor ligands
WO2001030808A1 (fr) * 1999-10-27 2001-05-03 The Regents Of The University Of California Procedes et composes utiles pour moduler la liaison du recepteur de melanocortine-ligand
US7501135B2 (en) 1999-10-27 2009-03-10 Conopco, Inc. Gastric acid secretion
US6693165B2 (en) 2000-01-18 2004-02-17 Merck & Co., Inc. Cyclic peptides as potent and selective melanocortin-4 receptor antagonists
WO2001090140A1 (fr) * 2000-05-22 2001-11-29 Elan Drug Delivery Limited Peptoides comme liants pour recepteurs a la melanocortine
US7033616B2 (en) 2000-06-30 2006-04-25 Phytopharm Plc Extracts, compounds and pharmaceutical compositions having anti-diabetic activity and their use
US7416744B2 (en) 2000-06-30 2008-08-26 Conopco, Inc. Extracts, compounds and pharmaceutical compositions having anti-diabetic activity and their use
US7307063B2 (en) 2001-02-13 2007-12-11 Palatin Technologies, Inc. Melanocortin metallopeptides for treatment of sexual dysfunction
US7417027B2 (en) 2001-07-11 2008-08-26 Palatin Technologies, Inc. Linear and cyclic melanocortin receptor-specific peptides
US7541430B2 (en) 2003-05-09 2009-06-02 Novo Nordisk A/S Peptides for use in treating obesity
WO2005030797A2 (fr) 2003-09-30 2005-04-07 Novo Nordisk A/S Nouveaux agonistes du recepteur de la melanocortine
US7517854B2 (en) 2003-09-30 2009-04-14 Novo Nordisk A/S Melanocortin receptor agonists
EP2033662A1 (fr) 2004-01-21 2009-03-11 Novo Nordisk Health Care AG Conjugaison au moyen de transglutaminase de peptides
EP2368579A1 (fr) 2004-01-21 2011-09-28 Novo Nordisk Health Care AG Conjugaison au moyen de transglutaminase de peptides
US8729224B2 (en) 2008-06-09 2014-05-20 Palatin Technologies, Inc. Melanocortin receptor-specific peptides for treatment of female sexual dysfunction
US8487073B2 (en) 2008-06-09 2013-07-16 Palatin Technologies, Inc. Melanocortin receptor-specific peptides for treatment of sexual dysfunction
US8455618B2 (en) 2009-06-08 2013-06-04 Astrazeneca Ab Melanocortin receptor-specific peptides
US8846601B2 (en) 2009-06-08 2014-09-30 Palatin Technologies, Inc. Melanocortin receptor-specific peptides
US9273098B2 (en) 2009-06-08 2016-03-01 Palatin Technologies, Inc. Lactam-bridged melanocortin receptor-specific peptides
US9458201B2 (en) 2009-06-08 2016-10-04 Palatin Technologies, Inc. Melanocortin receptor-specific heptapeptides
US10632171B2 (en) 2009-06-08 2020-04-28 Palatin Technologies, Inc. Melanocortin receptor-specific peptides
US8455617B2 (en) 2009-06-08 2013-06-04 Astrazeneca Ab Melanocortin receptor-specific peptides
US10179804B2 (en) 2009-06-08 2019-01-15 Palatin Technologies, Inc. Melanocortin receptor-specific peptides
US9040663B2 (en) 2009-06-08 2015-05-26 Astrazeneca Ab Melanocortin receptor-specific peptides
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EP0946595A2 (fr) 1999-10-06
JP2001506996A (ja) 2001-05-29
WO1998027113A3 (fr) 1998-08-06
CN1246868A (zh) 2000-03-08
WO1998027113A8 (fr) 1999-09-02
AU5348098A (en) 1998-07-15
WO1998027113A9 (fr) 1999-11-04
CA2275442A1 (fr) 1998-06-25

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