WO2000030674A1 - Agents neuropeptide y-y4 utilises dans le traitement des troubles de la reproduction - Google Patents

Agents neuropeptide y-y4 utilises dans le traitement des troubles de la reproduction Download PDF

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Publication number
WO2000030674A1
WO2000030674A1 PCT/GB1999/003963 GB9903963W WO0030674A1 WO 2000030674 A1 WO2000030674 A1 WO 2000030674A1 GB 9903963 W GB9903963 W GB 9903963W WO 0030674 A1 WO0030674 A1 WO 0030674A1
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WO
WIPO (PCT)
Prior art keywords
npy
treatment
composition
receptor
administration
Prior art date
Application number
PCT/GB1999/003963
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English (en)
Inventor
Pierre Broqua
Karen Akinsanya
Amanda Hayward
Original Assignee
Ferring Bv
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
Priority claimed from GB9825969A external-priority patent/GB2344050A/en
Priority claimed from GBGB9911178.3A external-priority patent/GB9911178D0/en
Application filed by Ferring Bv filed Critical Ferring Bv
Publication of WO2000030674A1 publication Critical patent/WO2000030674A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—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

Definitions

  • the present invention relates to pharmaceutical agents that can be used in the treatment of disorders of the human reproductive system.
  • H-P-G hypothalamic-pituitary-gonadal
  • GnRH gonadotropin releasing hormone
  • LHRH luteinizing hormone releasing hormone
  • FSH follicle stimulating hormone
  • LH luteinizing hormone
  • steroids such as oestradiol and testosterone
  • leptin ob protein
  • leptin ob protein
  • NPY neuropeptide Y
  • NPY is one of a family of neuropeptides. Other members of this family include peptide YY (PYY) and pancreatic polypeptide (PP). The sequences of these three peptides in humans (h) and of PP in rats (r) are listed below.
  • NPY exerts its effects by interacting with a membrane-bound receptor that relays a signal to cytoplasmic second messengers.
  • a number of NPY receptors have been identified. Together, they form a family within the superfamily of heptahelical receptors, also called the seven-transmembrane domain receptors. At least five such receptors (designated NPY-Y1 to NPY-Y5) have been characterised at the DNA level and the proteins have been expressed in transformed cells.
  • NPY analogues have been described, and their affinities for the various NPY receptors have been reported.
  • the particular receptor that is responsible for the effects of NPY on the H-P-G axis has eluded positive identification.
  • the invention comprises a pharmaceutical composition for the treatment of reproductive disorders, which composition is characterised in that it comprises a compound with high affinity for the NPY-Y4 receptor.
  • the compound may be either a peptide or a non-peptide, and may act as an agonist or antagonist at the NPY-Y4 receptor.
  • the invention comprises a method of treatment of various reproductive disorders wherein a pharmaceutical composition comprising an NPY-Y4 receptor ligand is administered to an individual in need of such treatment.
  • the present invention is based on our novel finding that the effects of NPY on the reproductive system of mammals are mediated by the NPY-Y4 receptor.
  • the experimental evidence is described in detail in the Examples (below). Briefly, it has been found that the administration of selective NPY-Y4 agonists (compounds that activate the NPY-Y4 receptor) to experimental animals causes an increase in the circulating levels of LH. These compounds also improve the fertility of animals with compromised reproductive function. Based on these findings, we disclose herein the use of NPY-Y4 ligands in the treatment of reproductive disorders.
  • NPY-Y4 ligand includes peptide and non-peptide agonists and antagonists at the Y4 subtype of neuropeptide Y receptor.
  • NPY-Y4 ligands are known in the art. NPY is an agonist at this receptor, but is not selective for this subtype. PP is a very selective NPY-Y4 agonist. A synthetic analogue of NPY, known variously as GR231118 and 12229U91 , was originally described as an NPY-Y1 antagonist, but has more recently been shown to be an NPY-Y4 agonist. Non-peptide NPY receptor ligands have also been reported, although the receptor subtype specificity is not generally discussed in these reports.
  • the invention disclosed herein comprises a pharmaceutical composition for the treatment of reproductive disorders, which composition is characterised in that at least one of the active agents is an NPY-Y4 ligand.
  • Such compositions will also include one or more excipients, such as diluents, preservatives and the like. These excipients are well known in the art.
  • the composition is formulated as appropriate for the intended route of administration. In general, peptides are not well suited to oral administration.
  • the composition according to the present invention should be formulated for injection (for example, intravenous, subcutaneous or intramuscular injection) or for transmucosal delivery (for example, by intranasal, vaginal or rectal administration).
  • One particularly preferred composition is a sterile solution of the NPY-Y4 ligand in isotonic saline, optionally buffered to pH 4-7 with citrate and/or phosphate.
  • Such a composition is suitable for injection or for intranasal administration.
  • Another particularly preferred composition is this solution microencapsulated in a biodegradable polymer such as copoly(lactide-glycolide).
  • a formulation is appropriate for intramuscular injection when a slow release of the active agent is required.
  • Non-peptide ligands may also be formulated in these ways, but may preferably be formulated as tablets, capsules and the like, for oral administration.
  • the NPY-Y4 ligand is an NPY-Y4 agonist and the composition is for the treatment of a decreased reproductive function.
  • Examples of conditions resulting in decreased reproductive function include delayed puberty and amenorrhea (for example related to intensive exercise).
  • the NPY-Y4 ligand is an NPY-Y4 antagonist and the composition is for the treatment of supranormal function of the reproductive organs.
  • examples of such conditions include precocious puberty, polycystic ovary syndrome, endometriosis and benign prostatic hyperplasia.
  • the invention disclosed herein comprises a method for the treatment of reproductive disorders wherein an effective amount of a pharmaceutical composition comprising at least one NPY-Y4 ligand is administered to a person in need of such treatment.
  • the administration may be by injection (for example, intravenous, subcutaneous or intramuscular injection) or by any other appropriate route (for example, by oral, intranasal, vaginal or rectal administration).
  • a particularly preferred method of administration is by intramuscular injection of a controlled-release formulation of the composition.
  • the precise quantity of the composition to be administered will be determined by the supervising physician, but will generally be an amount corresponding to between 5 ⁇ g and 50mg of the active agent per day for an average adult, given as a single dose or divided into multiple doses.
  • the method is a method of treatment of impaired reproductive function, such as delayed puberty or amenorrhea, by the administration of a composition comprising an NPY-Y4 agonist.
  • This embodiment also includes the administration of such compositions in the context of assisted reproduction regimes.
  • the method is a method of treatment of supranormal function of the reproductive axis and organs, such as precocious puberty, polycystic ovary syndrome, endometriosis and benign prostatic hyperplasia, by the administration of a composition comprising an NPY-Y4 antagonist.
  • Implantation of intracerebroventricular cannula Rats were weighed and anaesthetised with ketamin/xylazin (3 and 7mg/kg, i.p., respectively). Canulae, aimed at the right lateral ventricle, were placed 1 mm posterior and 2mm lateral to bregma and extended 2mm below the outer surface of the skull. The injection canula extended beyond the guide canula 4mm ventrally to the skull surface. Rats were allowed to recover for 7 days.
  • Implantation of a jugular catheter Under the same anaesthetic, the ventral side of the throat was shaved and an incision was made down the centre of the throat. The right jugular vein was exposed and canulated using a polythene tubing (OD 1.0mm) connected to a medical grade silicone tubing (OD 0.94mm) (siiicone side in the jugular vein). The tubing was secured and the polythene side was externalised through an incision made on the dorsal side of the neck. The catheter was rinsed with 300 ⁇ L of a ringer solution containing 0.1% heparin. Rats were allowed to recover for at least 24 hours in individual cages with food and water available ad libitum.
  • GR231118 is a mixed Y4 agonist/Y1 antagonist (Schober et al., 1998; Parker ef a/., 1998). Intracerebroventricular injection of GR231118 (1.2-12nmol/rat) dose-dependently increased plasma LH levels (Table 1).
  • rPP is a Y4 agonist with very weak or no affinity for other NPY-receptor subtypes (Gerald ef al., 1996). Intracerebroventricular injection of rPP (3-30nmol/rat) dose-dependently increased plasma LH levels (Table 2).
  • NPY-Y4 agonists are capable of increasing the level of LH in the circulation and of promoting the growth of the reproductive organs. Therefore it can be predicted that such compounds will be useful in the restoration of fertility in humans. It also follows that NPY-Y4 antagonists will decrease the levels of circulating LH, hence decreasing the activity of the target organs of this hormone. Hence, such antagonists are predicted to be useful in pathologies arising from a supranormal function of these organs. Such pathologies include (but are not limited to) precocious puberty, endometriosis, benign prostatic hyperplasia, polycystic ovary syndrome and hormone-dependent neoplasias (including breast and prostate cancer).
  • the neuropeptide Y Y1 antagonist 1229U91 a potent agonist for the human pancreatic polypeptide preferring (NPY Y4) receptor.
  • Orn is ornithine.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Endocrinology (AREA)
  • General Health & Medical Sciences (AREA)
  • Immunology (AREA)
  • Epidemiology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Diabetes (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne une composition pharmaceutique pour traiter les troubles de la reproduction chez l'homme. Cette composition comprend une quantité efficace d'un ligand du récepteur NPY-Y4.
PCT/GB1999/003963 1998-11-26 1999-11-26 Agents neuropeptide y-y4 utilises dans le traitement des troubles de la reproduction WO2000030674A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB9825969.0 1998-11-26
GB9825969A GB2344050A (en) 1998-11-26 1998-11-26 Agents useful in the treatment of reproductive disorders.
GBGB9911178.3A GB9911178D0 (en) 1999-05-13 1999-05-13 Agents useful in the treatment of reproductive disorders
GB9911178.3 1999-05-13

Publications (1)

Publication Number Publication Date
WO2000030674A1 true WO2000030674A1 (fr) 2000-06-02

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Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1362926A1 (fr) * 2002-05-15 2003-11-19 Integragen Gène humain de susceptibilité à l'obésité et leurs utilisations
WO2003097683A2 (fr) * 2002-05-15 2003-11-27 Integragen Gene humain de predisposition a l'obesite et utilisations dudit gene
EP1403380A1 (fr) * 2002-09-27 2004-03-31 Integragen Gène humain de susceptibilité à l'obésité et leurs utilisations
WO2004098591A2 (fr) 2003-05-05 2004-11-18 Probiodrug Ag Inhibiteurs de glutaminyl-cyclase
WO2005075436A2 (fr) 2004-02-05 2005-08-18 Probiodrug Ag Nouveaux inhibiteurs de la glutaminyl-cyclase
WO2008055945A1 (fr) 2006-11-09 2008-05-15 Probiodrug Ag Dérivés 3-hydr0xy-1,5-dihydr0-pyrr0l-2-one utiles en tant qu' inhibiteurs de la glutaminyl-cyclase dans le traitement des ulcères, du cancer et d'autres maladies
WO2008065141A1 (fr) 2006-11-30 2008-06-05 Probiodrug Ag Nouveaux inhibiteurs de glutaminylcyclase
WO2008104580A1 (fr) 2007-03-01 2008-09-04 Probiodrug Ag Nouvelle utilisation d'inhibiteurs de la glutaminyl cyclase
WO2011029920A1 (fr) 2009-09-11 2011-03-17 Probiodrug Ag Dérivés hétérocycliques en tant qu'inhibiteurs de glutaminyle cyclase
EP2338490A2 (fr) 2003-11-03 2011-06-29 Probiodrug AG Combinaisons utiles pour le traitement de désordres neuronales
WO2011107530A2 (fr) 2010-03-03 2011-09-09 Probiodrug Ag Nouveaux inhibiteurs
WO2011110613A1 (fr) 2010-03-10 2011-09-15 Probiodrug Ag Inhibiteurs hétérocycliques de la glutaminyl cyclase (qc, ec 2.3.2.5)
WO2011131748A2 (fr) 2010-04-21 2011-10-27 Probiodrug Ag Nouveaux inhibiteurs
WO2012123563A1 (fr) 2011-03-16 2012-09-20 Probiodrug Ag Dérivés de benzimidazole en tant qu'inhibiteurs de la glutaminyl cyclase
EP2865670A1 (fr) 2007-04-18 2015-04-29 Probiodrug AG Dérivés de thio-urée utilisés comme inhibiteurs de la glutaminyl cyclase
EP3461819A1 (fr) 2017-09-29 2019-04-03 Probiodrug AG Inhibiteurs de la glutaminyl-cyclase

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994000486A1 (fr) * 1992-06-20 1994-01-06 The Wellcome Foundation Limited Antagonistes du neuropeptide y
WO1998018481A1 (fr) * 1996-10-31 1998-05-07 Merck & Co., Inc. Therapie par combinaison d'agents pour le traitement du diabete et de l'obesite
EP0908515A2 (fr) * 1997-09-16 1999-04-14 Smithkline Beecham Plc Polypeptide pancréatique

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994000486A1 (fr) * 1992-06-20 1994-01-06 The Wellcome Foundation Limited Antagonistes du neuropeptide y
WO1998018481A1 (fr) * 1996-10-31 1998-05-07 Merck & Co., Inc. Therapie par combinaison d'agents pour le traitement du diabete et de l'obesite
EP0908515A2 (fr) * 1997-09-16 1999-04-14 Smithkline Beecham Plc Polypeptide pancréatique

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
JAIN M R ET AL.: "Evidence that stimulation of two modalities of pituitary luteinising hormone release in ovarian steroid-primed ovariectomized rats may involve neuropeptide Y Y1 and Y4 receptors", ENDOCRINOLOGY, vol. 140, no. 11, November 1999 (1999-11-01), pages 5171 - 5177, XP000876932 *
KALRA S P: "Mandatory neuropeptide-steroid signaling for the preovulatry luteinizing hormone-releasing hormone discharge", ENDOCRINE REVIEWS, vol. 14, no. 5, October 1993 (1993-10-01), pages 507 - 538, XP000876938 *
RAPOSINHO P D ET AL.: "Evidence that the inhibition of luteinizing hormone release hormone secretion exerted by central administration of neuropeptide Y (NPY) in the rat is predominantly mediated by the NPY-Y5 receptor subtype", ENDOCRINOLOGY, vol. 140, no. 9, September 1999 (1999-09-01), pages 4046 - 4055, XP000876933 *

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1995331A1 (fr) * 2002-05-15 2008-11-26 Integragen Gène de susceptibilité d'obésité humaine et utilisations associées
WO2003097683A2 (fr) * 2002-05-15 2003-11-27 Integragen Gene humain de predisposition a l'obesite et utilisations dudit gene
WO2003097683A3 (fr) * 2002-05-15 2004-04-01 Integragen Sa Gene humain de predisposition a l'obesite et utilisations dudit gene
EP1362926A1 (fr) * 2002-05-15 2003-11-19 Integragen Gène humain de susceptibilité à l'obésité et leurs utilisations
EP1997913A1 (fr) * 2002-05-15 2008-12-03 Integragen Gène de susceptibilité d'obésité humaine et utilisations associées
EP1403380A1 (fr) * 2002-09-27 2004-03-31 Integragen Gène humain de susceptibilité à l'obésité et leurs utilisations
WO2004098591A2 (fr) 2003-05-05 2004-11-18 Probiodrug Ag Inhibiteurs de glutaminyl-cyclase
EP2338490A2 (fr) 2003-11-03 2011-06-29 Probiodrug AG Combinaisons utiles pour le traitement de désordres neuronales
WO2005075436A2 (fr) 2004-02-05 2005-08-18 Probiodrug Ag Nouveaux inhibiteurs de la glutaminyl-cyclase
US7897633B2 (en) 2004-02-05 2011-03-01 Probiodrug Ag Inhibitors of glutaminyl cyclase
WO2008055945A1 (fr) 2006-11-09 2008-05-15 Probiodrug Ag Dérivés 3-hydr0xy-1,5-dihydr0-pyrr0l-2-one utiles en tant qu' inhibiteurs de la glutaminyl-cyclase dans le traitement des ulcères, du cancer et d'autres maladies
WO2008065141A1 (fr) 2006-11-30 2008-06-05 Probiodrug Ag Nouveaux inhibiteurs de glutaminylcyclase
WO2008104580A1 (fr) 2007-03-01 2008-09-04 Probiodrug Ag Nouvelle utilisation d'inhibiteurs de la glutaminyl cyclase
EP2481408A2 (fr) 2007-03-01 2012-08-01 Probiodrug AG Nouvelle utilisation d'inhibiteurs glutaminyle cyclase
EP2865670A1 (fr) 2007-04-18 2015-04-29 Probiodrug AG Dérivés de thio-urée utilisés comme inhibiteurs de la glutaminyl cyclase
WO2011029920A1 (fr) 2009-09-11 2011-03-17 Probiodrug Ag Dérivés hétérocycliques en tant qu'inhibiteurs de glutaminyle cyclase
WO2011107530A2 (fr) 2010-03-03 2011-09-09 Probiodrug Ag Nouveaux inhibiteurs
WO2011110613A1 (fr) 2010-03-10 2011-09-15 Probiodrug Ag Inhibiteurs hétérocycliques de la glutaminyl cyclase (qc, ec 2.3.2.5)
WO2011131748A2 (fr) 2010-04-21 2011-10-27 Probiodrug Ag Nouveaux inhibiteurs
WO2012123563A1 (fr) 2011-03-16 2012-09-20 Probiodrug Ag Dérivés de benzimidazole en tant qu'inhibiteurs de la glutaminyl cyclase
EP3461819A1 (fr) 2017-09-29 2019-04-03 Probiodrug AG Inhibiteurs de la glutaminyl-cyclase

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