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WO2012013597A1 - Substances et utilisation desdites substances pour influer sur les récepteurs peptidiques natriurétiques - Google Patents

Substances et utilisation desdites substances pour influer sur les récepteurs peptidiques natriurétiques Download PDF

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Publication number
WO2012013597A1
WO2012013597A1 PCT/EP2011/062655 EP2011062655W WO2012013597A1 WO 2012013597 A1 WO2012013597 A1 WO 2012013597A1 EP 2011062655 W EP2011062655 W EP 2011062655W WO 2012013597 A1 WO2012013597 A1 WO 2012013597A1
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WO
WIPO (PCT)
Prior art keywords
natriuretic
prevention
rezeptoragonisten
receptor agonists
peptide
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.)
Ceased
Application number
PCT/EP2011/062655
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German (de)
English (en)
Inventor
Thomas Walther
Anja Schwiebs
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Justus Liebig Universitaet Giessen
Original Assignee
Justus Liebig Universitaet Giessen
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 DE102010032482A external-priority patent/DE102010032482A1/de
Priority claimed from DE102010047582A external-priority patent/DE102010047582A1/de
Application filed by Justus Liebig Universitaet Giessen filed Critical Justus Liebig Universitaet Giessen
Publication of WO2012013597A1 publication Critical patent/WO2012013597A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K38/2242—Atrial natriuretic factor complex: Atriopeptins, atrial natriuretic protein [ANP]; Cardionatrin, Cardiodilatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • C07K14/58—Atrial natriuretic factor complex; Atriopeptin; Atrial natriuretic peptide [ANP]; Cardionatrin; Cardiodilatin

Definitions

  • the present invention relates to peptidic and non-peptidic receptor agonists of the natriuretic system, preferably NPRA and NPRB receptor agonists for the prevention and / or treatment of disease states associated with increased extracellular fluid volume, in particular for the prevention and / or treatment of congestive heart disease coronary artery disease, organic and functional vascular disorders, nephrotic syndrome, high blood pressure disorder or to improve arterial, venous and capillary blood flow.
  • the present invention relates to peptidic and non-peptidic receptor agonists of the natriuretic system, preferably NPRA and NPRB receptor agonists for the prevention and / or treatment of disease states in which the second messenger cGMP develops protective properties, in particular for the prevention and / or treatment of hypertrophic Cardiomyopathy, myocardial infarction, acute lung injury or erectile dysfunction.
  • the present invention relates to peptidic and non-peptidic receptor agonists of the natriuretic system, preferably NPRA and NPRB receptor agonists for the prevention and / or treatment of disease states in which an antihypertrophic (antifibrotic) effect is desired, in particular for the prevention and / or therapy of a primary or secondary fibrosis, liver cirrhosis or pulmonary fibrosis.
  • NPRA and NPRB receptor agonists for the prevention and / or treatment of disease states in which an antihypertrophic (antifibrotic) effect is desired, in particular for the prevention and / or therapy of a primary or secondary fibrosis, liver cirrhosis or pulmonary fibrosis.
  • ACNP natriuretic peptide of the invention, also referred to as ANP / CNP; Chimera of ANP and CNP
  • Atrial Natriuretic Peptide Atrial Natriuretic Peptide
  • Atrial Natriuretic Peptide also referred to as Atrial Natriuretic Factor, Atriopeptin, Natriuretic Peptide Type A, Cardionatrine, Cardiodilatin, Atrial Natriuretic Factor, Urodilatin
  • BNP Brain Natriuretic Peptide; also referred to as B-type Natriuretic Peptides
  • BNP / CNP chimera of BNP and CNP
  • cGMP cyclic guanosine mono phosphates, cyclic guanosine monophosphate
  • Chimera Combination of two or more pieces of peptide to a new peptide that does not occur in the wild type. Chimera also means those nucleic acid sequences which code for the chimeric peptides
  • CNP C-type Natriuretic Peptide, C-type Natriuretic Peptide
  • DNA deoxyribonucleic acid, deoxyribonucleic acid
  • HEK cells human embryonic kidney cells, human embryonic kidney cells; human cell line
  • Lusitropy, lusitrop ability of the heart muscles for fast and complete relaxation
  • Natriurese, natriuretic excretion of sodium ions with the urine
  • Non-peptidic receptor hormone receptor agonist consisting of a non-peptidic substance, for example a low-molecular substance
  • NP Natriuretic peptide containing the body's own natriuretic peptides ANP, BNP and CNP, as well as parts thereof, variants thereof or chimeras thereof
  • NPRA A-type Natriuretic Receptor, Natriuretic Peptide Receptor A
  • NPRB B-type Natriuretic Receptor, Natriuretic Peptide Receptor B
  • Nucleic acid sequence Sequence of the nucleotides of any nucleic acid, for example DNA or RNA
  • Peptidic receptor agonist consisting of a protein or peptide or a compound of a protein or peptide with a non-peptide Receptor: substance with the ability to activate a receptor and thus trigger a reaction of the receptor
  • RNA ribonucleic acid, ribonucleic acid
  • Vasodilatation, vasodilatory dilation of blood vessels, thereby lowering blood pressure
  • natriuretic peptides are structurally related endogenous molecules which have essentially natriuretic, diuretic and vasodilatory activities and thus play an important role in the homeostasis of the fluid balance as well as the control of the blood pressure.
  • the natriuretic peptides affect the release of cGMP and thus have a direct cardioprotective effect.
  • natriuretic peptides have an antihypertrophic (antifibrotic) effect.
  • the individual naturally occurring natriuretic peptides bind to different receptors (natriuretic peptide receptors) and can therefore develop different effects.
  • ANP selectively binds to the receptor NPRA and thereby unfolds a direct natriuretic effect and an increase in diuresis and by the vasodilatory effect a reduction in blood pressure. Similarly, ANP reduces the release of renin and aldosterone, thereby inhibiting the renin-angiotensin-aldosterone system.
  • BNP binds to the receptor NPRA and thus unfolds a direct natriuretic effect and an increase in diuresis and by the vasodilatory effect a reduction in blood pressure.
  • BNP also has a renin inhibitor and positive lusitropic effect.
  • BNP and the N-terminal fragment of proBNP can also be used to diagnose and predict heart disease by measuring the plasma level of BNP or the N-terminal fragment of proBNP in patients.
  • the naturally occurring BNP consists of 32 amino acids and is therefore also referred to as BNP 1 -32.
  • CNP binds to the receptor NPRB and acts as a vasodilatory and growth-inhibiting peptide, but has no natriuretic activity. CNP also promotes bone growth.
  • ANP, BNP and CNP each have an amino acid loop formed by an intramolecular disulfide bridge between two cysteine amino acids, with ANP, BNP and CNP each having different lengths of C- and N-terminal ends.
  • the receptor NPRA and the receptor NPRB are stimulated by different natriuretic peptides, with the stimulation of both receptors simultaneously showing a therapeutic effect in a large number of diseases and thus being extremely positive.
  • amino acid sequences of the naturally occurring natriuretic peptides and the nucleic acid sequences coding therefor are known.
  • natriuretic peptides for the treatment of a variety of diseases is known.
  • BNP and the N-terminal fragment of proBNP are used to diagnose cardiac diseases.
  • BNP 1 -32 under the trade name Natrecor ® (Neseritide) Available in USA.
  • Natrecor ® Neseritide
  • the art describes the production of natriuretic and vasodilatory peptides which correspond to the amino acid structure of the BNP and can be used to treat disease states associated with an elevated extracellular fluid state.
  • a recombinantly produced human BNP and its use as a medicament are described (US 5,1 14,923, US 5,674,710).
  • Nucleic acid sequences are known which code for peptides having natriuretic activity (for example for cardiodilatin), as well as the corresponding amino acid sequences (EP 0224676 A1).
  • the use of natriuretic peptides for the diagnosis or treatment of diseases which are associated with an elevated extracellular fluid state is known (US 5,114,923, US 5,674,710, EP 0224676 A1, US 0,170,756 A1).
  • natriuretic peptides or peptide chimeras which bind only to one of the known natriuretic peptide receptors.
  • NPRA natriuretic peptide receptor A
  • a natriuretic peptide used as a drug loses its effectiveness because the corresponding receptor via which it exerts its effect is no longer available in sufficient quantity or quality.
  • NPRA natriuretic peptides
  • NPRB natriuretic peptides receptors
  • the object of the invention is therefore the provision of substances which bind to both the natriuretic peptide receptor A and B and thereby trigger the desired effects, without a down-regulation of one of the two receptors reduces the effect of the substances of the invention, and their use as medicines.
  • the object of the invention is therefore to provide substances which can act more efficiently on the NPRA than the native BNP. Furthermore, it is an object of the invention to provide substances which simultaneously bind to the two natriuretic peptide receptors A and B and thus allow the desired effects of such binding in an improved form.
  • natriuretic peptide ACNP, ANP / CNP
  • SEQ ID NO: 1 SEQ ID NO: 1
  • a receptor agonist of the natriuretic peptide receptors is available which offers a solution to the disadvantages in the prior art.
  • the natriuretic peptide ACNP binds to both the natriuretic peptide receptor A and the natriuretic peptide receptor B on the basis of its amino acid sequence.
  • novel natriuretic peptides hBNP 1 -30, mBNP 1 -30 and pBNP 1 -30 and their derivatives, homologues and analogs, receptor agonists of the natriuretic peptide receptors are available which are active both on the natriuretic peptide receptor A and on the natriuretic peptide receptor B and thus allow simultaneous stimulation of both natriuretic peptide receptors.
  • the peptides hBNP 1-30, mBNP 1-30 and pBNP 1-30 stimulate the natriuretic peptide receptor A significantly more potent than the naturally occurring BNP 1-32, so that the use of the receptor agonists hBNP 1-30, mBNP 1 - 30 and pBNP 1 -30 leads to a greater blood pressure reduction and relief of the heart at the same dosage. It has been shown that hBNP 1 -30 is more potent than BNP 1 -32 in in vitro and in vivo experiments and results in greater blood pressure reduction and cardiac relief at the same dose.
  • receptor agonists of the natriuretic peptide receptors are available which bind to both the natriuretic peptide receptor A and the natriuretic peptide receptor B and thus to a Stimulation of both natriuretic peptide receptors simultaneously.
  • Exemplary Embodiments The exemplary embodiments emerge from the attached sequence listing SEQ ID NO: 1 -6.
  • Embodiment 1 is a diagrammatic representation of Embodiment 1:
  • natriuretic peptide hBNP 1 -30 with the amino acid sequence SPKMV QGSGC FGRKM DRISS SSGLG CKVLR and a disulphide bridge between the two cysteine amino acids at positions 10 and 26 as well as its derivatives, homologues and analogues.
  • Embodiment 3 is a diagrammatic representation of Embodiment 3
  • natriuretic peptide mBNP 1 -30 with the amino acid sequence NSKVT HISSC FGHKI DRIGS VSRLG CNALK and a disulphide bridge between the two cysteine amino acids at positions 10 and 26 as well as its derivatives, homologues and analogues.
  • Embodiment 4 is a diagrammatic representation of Embodiment 4:
  • natriuretic peptide pBNP 1 -30 with the amino acid sequence SPKTM RDSGC FGRRL DRIGS LSG LG CNVLR and a disulfide bridge between the two cysteine amino acids at positions 10 and 26 as well as its derivatives, homologues and analogues.
  • Embodiment 5 :
  • natriuretic peptide hBNP 1 -29 with the amino acid sequence SPKMV QGSGC FGRKM DRISS SSGLG CKVL and a disulphide bridge between the two cysteine amino acids at positions 10 and 26 as well as its derivatives, homologues and analogues.
  • Embodiment 6 is a diagrammatic representation of Embodiment 6
  • natriuretic peptide mBNP 1 -29 with the amino acid sequence NSKVT HISSC FGHKI DRIGS VSRLG CNAL and a disulphide bridge between the two cysteine amino acids at positions 10 and 26 as well as its derivatives, homologues and analogues.
  • FIG. 1 shows the amino acid sequence of a peptidic receptor agonist ACNP according to the invention (ANP / CNP) according to SEQ ID NO: 1 with a disulphide bridge between the two cysteine amino acids at positions 7 and 23.
  • FIG. 2 shows the generation of the second messenger cGMP in HEK cells transfected with the natriuretic peptide receptor A (NPRA) or the natriuretic peptide receptor B (NPRB) after stimulation with various natriuretic peptides.
  • the upper diagram shows that ACNP stimulates the NPRA in the same way as the native receptor agonists ANP and BNP.
  • the lower diagram shows that ACNP stimulates the natriuretic peptide receptor B in the same way as the native receptor agonist CNP.
  • FIG. 3 shows the generation of the second messenger cGMP in HEK cells transfected with the natriuretic peptide receptor A (upper diagram) or the natriuretic peptide receptor B (lower diagram) after stimulation with different natriuretic peptides.
  • the figure shows that shortening the C- or N-terminal ends of the BNP leads to a significant reduction in the stimulability of the NPRA and to an increase in the stimulability of the NPRB.
  • FIG. 4 shows the result of the blood pressure measurements from 3 groups of mice to which saline, BNP 1 -32 or BNP 1 -30 were injected in each case.
  • the y-axis shows the change in blood pressure in mmHg.
  • the graph shows that the blood pressure at the injection of BNP 1 -32 and BNP 1 -30 decreases compared to the control group that received only saline. BNP 1 -30 reduces blood pressure to a higher degree than BNP 1 -32, which is statistically significant.
  • the cGMP values in the plasma of these animals were measured, which is shown in the second graph.
  • cGMP arises from the stimulation of natriuretic petid receptors by natriuretic peptides and is significantly involved in vascular relaxation by natriuretic peptides.
  • the generation of cGMP is a measure of the biological activity of the peptides.
  • the y-axis shows the concentration of cGMP in pmol / ml.
  • FIG. 5 shows the activity measurement of various natriuretic peptides against natriuretic peptide receptors in cells.
  • the y-axis shows the concentration of cGMP in pmol / ml.
  • cGMP is caused by stimulation of receptors by natriuretic peptides.
  • the generation of cGMP is a measure of the biological activity of the peptides.
  • human embryonic kidney (HEK293) cells were transfected with the NPRA or NPRB so that these cells overexpress the respective receptor. After stimulation with the respective peptide, the cGMP concentration was measured.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
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  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
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  • Proteomics, Peptides & Aminoacids (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract

L'invention concerne des agonistes des récepteurs peptidiques ou non peptidiques du système natriurétique, de préférence des agonistes des récepteurs NPRA et NPRB, pour la prévention et/ou le traitement d'états pathologiques qui s'accompagnent d'une augmentation du volume de liquide extracellulaire, dans lesquels le second messager cGMP développe des propriétés protectrices et dans lesquels un effet antihypertrophique (antifibrotique) est souhaité. L'invention concerne en particulier des agonistes des récepteurs peptidiques ou non peptidiques du système natriurétique destinés au traitement d'une maladie cardiaque congestive, d'une maladie cardiaque coronarienne, de troubles vasculaires organiques et vasculaires, d'un syndrome néphrotique, d'un trouble de l'hypertension artérielle, d'un infarctus du myocarde, d'une lésion pulmonaire aiguë, d'un dysfonctionnement érectile, d'une fibrose primaire ou secondaire, d'une cirrhose du foie, d'une fibrose pulmonaire, ou à l'amélioration de la circulation sanguine artérielle, veineuse et capillaire.
PCT/EP2011/062655 2010-07-28 2011-07-22 Substances et utilisation desdites substances pour influer sur les récepteurs peptidiques natriurétiques Ceased WO2012013597A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
DE102010032482A DE102010032482A1 (de) 2010-07-28 2010-07-28 Stoffe zur Beeinflussung der natriuretischen Peptid-Rezeptoren A und B und deren Verwendung
DE102010032482.5 2010-07-28
DE102010047582.3 2010-10-07
DE102010047582A DE102010047582A1 (de) 2010-10-07 2010-10-07 Stoffe und deren Verwendung zur Beeinflussung natriuretischer Peptidrezeptoren

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WO2012013597A1 true WO2012013597A1 (fr) 2012-02-02

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Citations (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0224676A1 (fr) 1985-10-08 1987-06-10 Bissendorf Peptide GmbH Médicament contenant de la cardiodilatine préparée par fermentation et procédé pour sa production
US4851349A (en) 1984-04-12 1989-07-25 Mitsubishi Chemical Industries Limited Expression vectors encoding cardionatrin and cardiodilatin
US5114923A (en) 1988-05-31 1992-05-19 California Biotechnology Inc. Recombinant techniques for production of novel natriuretic and vasodilator peptides
EP0497368A1 (fr) * 1991-01-31 1992-08-05 Suntory Limited Peptides analogues de CNP et leur utilisation
WO1994020534A1 (fr) * 1993-03-03 1994-09-15 Mayo Foundation For Medical Education And Research Peptide vasonatrine et analogues de ce dernier
US5674710A (en) 1988-05-31 1997-10-07 Scios, Inc. Recombinant techniques for production of human brain natriuretic peptide
WO2004011498A2 (fr) 2002-07-31 2004-02-05 Conjuchem Inc. Derives de peptide natriuretique de longue duree
WO2004047871A2 (fr) * 2002-11-26 2004-06-10 Nobex Corporation Composes natriuretiques modifies, leurs conjugues et leur utilisation
WO2005077042A2 (fr) * 2004-02-09 2005-08-25 Human Genome Sciences, Inc. Proteines hybrides d'albumine
US20060051825A1 (en) * 2004-09-09 2006-03-09 Buechler Kenneth F Methods and compositions for measuring canine BNP and uses thereof
WO2007003594A1 (fr) * 2005-07-01 2007-01-11 Solvay Pharmaceuticals Gmbh Utilisation de meprine de metalloprotease et d'inhibiteurs de celle-ci
WO2008030901A2 (fr) * 2006-09-07 2008-03-13 Abbott Laboratories Fragments de biomarqueurs pour la détection du bnp humain
US20090170756A1 (en) 1999-12-17 2009-07-02 Mayo Foundation For Medical Education And Research Chimeric natriuretic peptides
WO2009086126A2 (fr) * 2007-12-21 2009-07-09 Mayo Foundation For Medical Education And Research Polypeptides natriurétiques
WO2010078325A2 (fr) * 2008-12-29 2010-07-08 Mayo Foundation For Medical Education And Research Polypeptides natriurétiques pour réduire ou prévenir une resténose

Patent Citations (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4851349A (en) 1984-04-12 1989-07-25 Mitsubishi Chemical Industries Limited Expression vectors encoding cardionatrin and cardiodilatin
EP0224676A1 (fr) 1985-10-08 1987-06-10 Bissendorf Peptide GmbH Médicament contenant de la cardiodilatine préparée par fermentation et procédé pour sa production
US5114923A (en) 1988-05-31 1992-05-19 California Biotechnology Inc. Recombinant techniques for production of novel natriuretic and vasodilator peptides
US5674710A (en) 1988-05-31 1997-10-07 Scios, Inc. Recombinant techniques for production of human brain natriuretic peptide
EP0497368A1 (fr) * 1991-01-31 1992-08-05 Suntory Limited Peptides analogues de CNP et leur utilisation
WO1994020534A1 (fr) * 1993-03-03 1994-09-15 Mayo Foundation For Medical Education And Research Peptide vasonatrine et analogues de ce dernier
US5583108A (en) 1993-03-03 1996-12-10 Mayo Foundation For Medical Education And Research Vasonatrin peptide and analogs thereof
US20090170756A1 (en) 1999-12-17 2009-07-02 Mayo Foundation For Medical Education And Research Chimeric natriuretic peptides
WO2004011498A2 (fr) 2002-07-31 2004-02-05 Conjuchem Inc. Derives de peptide natriuretique de longue duree
WO2004047871A2 (fr) * 2002-11-26 2004-06-10 Nobex Corporation Composes natriuretiques modifies, leurs conjugues et leur utilisation
WO2005077042A2 (fr) * 2004-02-09 2005-08-25 Human Genome Sciences, Inc. Proteines hybrides d'albumine
US20060051825A1 (en) * 2004-09-09 2006-03-09 Buechler Kenneth F Methods and compositions for measuring canine BNP and uses thereof
WO2007003594A1 (fr) * 2005-07-01 2007-01-11 Solvay Pharmaceuticals Gmbh Utilisation de meprine de metalloprotease et d'inhibiteurs de celle-ci
WO2008030901A2 (fr) * 2006-09-07 2008-03-13 Abbott Laboratories Fragments de biomarqueurs pour la détection du bnp humain
WO2009086126A2 (fr) * 2007-12-21 2009-07-09 Mayo Foundation For Medical Education And Research Polypeptides natriurétiques
WO2010078325A2 (fr) * 2008-12-29 2010-07-08 Mayo Foundation For Medical Education And Research Polypeptides natriurétiques pour réduire ou prévenir une resténose

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