EP1233774A1 - Urotensin-ii analogs - Google Patents

Urotensin-ii analogs

Info

Publication number
EP1233774A1
EP1233774A1 EP00980842A EP00980842A EP1233774A1 EP 1233774 A1 EP1233774 A1 EP 1233774A1 EP 00980842 A EP00980842 A EP 00980842A EP 00980842 A EP00980842 A EP 00980842A EP 1233774 A1 EP1233774 A1 EP 1233774A1
Authority
EP
European Patent Office
Prior art keywords
cys
lys
phe
seq
val
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.)
Withdrawn
Application number
EP00980842A
Other languages
German (de)
French (fr)
Other versions
EP1233774A4 (en
Inventor
Dashyant Dhanak
Steven D. Knight
Gregory L. Warren
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.)
SmithKline Beecham Corp
Original Assignee
SmithKline Beecham Corp
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 SmithKline Beecham Corp filed Critical SmithKline Beecham Corp
Publication of EP1233774A1 publication Critical patent/EP1233774A1/en
Publication of EP1233774A4 publication Critical patent/EP1233774A4/en
Withdrawn legal-status Critical Current

Links

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
    • C07K14/575—Hormones
    • C07K14/57509—Corticotropin releasing factor [CRF] (Urotensin)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P25/22—Anxiolytics
    • 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
    • A61P25/24—Antidepressants
    • 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
    • A61P25/26—Psychostimulants, e.g. nicotine, cocaine
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • 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
    • 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
    • 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
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • 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
    • A61P9/06—Antiarrhythmics
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • A61P9/12—Antihypertensives
    • 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 generally Urotensin-II analogs and pharmaceutical compositions containing them.
  • cardiovascular homeostasis The integrated control of cardiovascular homeostasis is achieved through a combination of both direct neuronal control and systemic neurohormonal activation. Although the resultant release of both contractile and relaxant factors is normally under stringent regulation, an aberration in this status quo can result in cardiohemodynamic dysfunction with pathological consequences.
  • the principal mammalian vasoactive factors that comprise this neurohumoral axis namely angiotensin-II, endothelin-1, norepinephrine, all function via an interaction with specific G-protein coupled receptors (GPCR).
  • GPCR G-protein coupled receptors
  • this peptide has significant hemodynamic and endocrine actions in diverse end-organ systems and tissues:
  • osmoregulation effects which include the modulation of transepithelial ion (Na + , Cl " ) transport. Although a diuretic effect has been described, such an effect is postulated to be secondary to direct renovascular effects (elevated GFR)
  • Human Urotensin-II was assessed for contractile activity in the rat-isolated aorta and was shown to be the most potent contractile agonist identified to date. Based on the in vitro pharmacology and in vivo hemodynamic profile of human Urotensin-II it plays a pathological role in cardiovascular diseases characterized by excessive or abnormal vasoconstriction and myocardial dysfunction. (Ames et. al. Nature 1999, 401, 282)
  • Urotensin-II analogs are useful for identifying agonists and antagonists/inhibitors of urotensin II, and for treating conditions associated with Human Urotensin II imbalance. For example, facilitating the actions of the U-II system, either by mimicking the agonist activity of U-II at its cognate receptor(s) or by attenuating the uptake/metabolism of U-II.
  • These compounds may be useful in the treatment of congestive heart failure, stroke, ischemic heart disease (angina, myocardial ischemia), cardiac arrhythmia, hypertension (essential and pulmonary), COPD, restenosis, asthma, (Hay DWP, Luttmann MA, Douglas SA: 2000, Br J Pharmacol: volume 131 , pages 10-12) neurogenic inflammation and metabolic vasculopathies all of which are characterized by abnormal vasoconstriction and/or myocardial dysfunction. Since U-II and GPR14 are both expressed within the mammalian CNS (Ames et. al. Nature 1999, 401, 282), they also may be useful in the treatment of addiction, schizophrenia, impulsivity, anxiety, stress, depression, and neuromuscular function.
  • U-II receptors are expressed in rhabdomyosarcomas cell lines and therefore may have oncological indications. Urotensin may also be implicated in various metabolic diseases such as diabetes (Ames et. al. Nature 1999, 401, 282, Nothacker et al., Nature Cell Biology 1 : 383-385, 1999).
  • this invention provides for urotensin II analogs and pharmaceutical compositions containing them.
  • this invention provides for the use of urotensin analogs for identifying agonists and antagonists of urotensin II, and as inhibitors of urotensin II. In another aspect, this invention provides for the use of urotensin analogs for treating conditions associated with urotensin II imbalance.
  • this invention provides for the use of urotensin analogs for the treatment of congestive heart failure, stroke, ischemic heart disease (angina, myocardial ischemia), cardiac arrhythmia, hypertension (essential and pulmonary), COPD, restenosis, asthma, neurogenic inflammation and metabolic vasculopathies, addiction, schizophrenia, impulsivity, anxiety, stress, depression, neuromuscular function, and diabetes.
  • the present invention provides for the following urotension II analogs and pharmaceutical compositions containing them : H-Glu-Thr-Pro-Asp-Cys-Phe-D-Trp-Lys-Tyr-Cys-Val-OH (cyclic disulfide); (SEQ ID NO: 1)
  • H-Asp-Cys-Phe-D-Trp-Lys-Tyr-Cys-Val-OH (cyclic disulfide); (SEQ ID NO: 4) H-Asp-Cys-Cha-Trp-Lys-Cha-Cys-Val-OH (cyclic disulfide); (SEQ ID NO: 5) H-Asp-Cys-Phe-Trp-Lys-Cha-Cys-Val-OH (cyclic disulfide); (SEQ ID NO: 6) H-Asp-Cys-Phe-Trp-Lys-Phe-Cys-Val-OH (cyclic disulfide); (SEQ ID NO: 7) H-Asp-Cys-Cha-Trp-Lys-Tyr-Cys-Val-OH (cyclic disulfide); (SEQ ID NO: 8) H-Asp-Cys-Phe-Tr
  • the compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active form. All of these compounds and their diastereoisomers are contemplated to be within the scope of the present invention.
  • the resin was treated with 50% TFA in methylene chloride (two to three times resin volume), stirred at room temperature for 30 min and drained. The resin was washed once with an equal volume of isopropanol for 1 min, then washed twice with an equal volume of methanol for 1 min.
  • Resin from (a) above was washed with an equal volume of 10% triethylamine in methylene chloride twice for 1 min, then washed with an equal volume of methanol twice for 1 min, and finally washed with an equal volume of methylene chloride twice for 1 min.
  • To the resin was added three equivalents of terf-butoxycarbonyl amino acid (dissolved in methylene chloride or methylene chloride/N,N-dimethylformamide mixture), three equivalents of 1 -hydroxybenzotriazole hydrate (1 M solution in N,N-dimethylformamide) and the resultant suspension was stirred for one min.
  • HPLC column Vydac C-18 RP silica, 15-20 uM, 2" diameter
  • the crude peptides were loaded onto reverse phase HPLC column. A linear gradient was used over 30 min (100% water containing 0.1 % trifluoroacetic acid to 80% acetonitrile containing 0.1 % trifluoroacetic acid /20% water containing 0.1 % trifluoroacetic acid).
  • Compounds of Formula (I) and their pharmaceutically acceptable salts may be administered in a standard manner for the treatment of the indicated diseases, for example orally, parenterally, sub-lingually, transdermally, rectally, via inhalation or via buccal administration.
  • a syrup formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier for example, ethanol, peanut oil, olive oil, glycerin or water with a flavoring or coloring agent. Where the composition is in the form of a tablet, any pharmaceutical carrier routinely used for preparing solid formulations may be used.
  • any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be considered, for example aqueous gums, celluloses, silicates or oils and are inco ⁇ orated in a soft gelatin capsule shell.
  • Typical parenteral compositions consist of a solution or suspension of the compound or salt in a sterile aqueous or non-aqueous carrier optionally containing a parenterally acceptable oil, for example polyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil, or sesame oil.
  • Typical compositions for inhalation are in the form of a solution, suspension or emulsion that may be administered as a dry powder or in the form of an aerosol using a conventional propellant such as dichlorodifluoromethane or trichlorofluoromethane.
  • a typical suppository formulation comprises a compound of Formula (1) or a pharmaceutically acceptable salt thereof which is active when administered in this way, with a binding and/or lubricating agent, for example polymeric glycols, gelatins, cocoa- butter or other low melting vegetable waxes or fats or their synthetic analogues.
  • a binding and/or lubricating agent for example polymeric glycols, gelatins, cocoa- butter or other low melting vegetable waxes or fats or their synthetic analogues.
  • Typical transdermal formulations comprise a conventional aqueous or non-aqueous vehicle, for example a cream, ointment, lotion or paste or are in the form of a medicated plaster, patch or membrane.
  • a conventional aqueous or non-aqueous vehicle for example a cream, ointment, lotion or paste or are in the form of a medicated plaster, patch or membrane.
  • the composition is in unit dosage form, for example a tablet, capsule or metered aerosol dose, so that the patients may administer to themselves a single dose.
  • urotensin analogs may be used for the treatment of congestive heart failure, stroke, ischemic heart disease (angina, myocardial ischemia), cardiac arrhythmia, hypertension (essential and pulmonary), COPD, restenosis, asthma, neurogenic inflammation and metabolic vasculopathies, addiction, schizophrenia, impulsivity, anxiety, stress, depression, neuromuscular function, and diabetes.
  • HEK-293 cell membranes containing stable cloned human and rat GPR-14 (20 ug/assay) were incubated with 200 pM [1251] h-U-II (200 Ci/mmol "1 in the presence of increasing concentrations of test compounds in DMSO (0.1 nM to 10 uM), in a final incubation volume of 200 ul (20 mM Tris-HCl, 5 mM MgC12). Incubation was done for 30 minutes at room temperature followed by filtration GF/B filters with Brandel cell harvester.
  • ⁇ 2 ⁇ labeled U-II binding was quantitated by gamma counting. Nonspecific binding was defined by *25 ⁇ T J.JJ binding in the presence of 100 nM of unlabeled human U-II. Analysis of the data was performed by nonlinear least square fitting.
  • a microtitre plate based Ca 2+ -mobilization FLIPR assay (Molecular Devices, Sunnyvale, CA) was used for the functional identification of the ligand activating HEK-293 cells expressing (stable) recombinant GPR-14.
  • the day following transfection cells were plated in a poly-D-lysine coated 96 well black/clear plates. After 18-24 hours the media was aspirated and Fluo 3AM-loaded cells were exposed to various concentrations (10 nM to 30 uM) of test compounds followed by h-U-II. After initiation of the assay, fluorescence was read every second for one minute and then every 3 seconds for the following one minute. The inhibitory concentration at 50% (IC50) was calculated for various test compounds.
  • HEK-293-GPR14 cells in T 150 flask were prelabeled overnight with 1 uCi myo- H] inositol per ml of inositol free Dulbecco's modified Eagel's medium. After labeling, the cells were washed twice with Dulbecco's phosphate-buffered saline (DPBS) and then incubated in DPBS containing 10 mM LiCl for 10 min at 37°C.
  • DPBS Dulbecco's phosphate-buffered saline
  • the experiment was initiated by the addition of increasing concentrations of h-U-II ( 1 pM to 1 ⁇ M ) in the absence and presence of three different concentrations (0.3, 1 and 10 uM) of test compounds and the incubation continued for an additional 5 min at 37°C after which the reaction was terminated by the addition of 10% (final concentration) trichloroacetic acid and centrifugation.
  • the supernatants were neutralized with lOOul of 1M Trizma base and the inositol phosphates were separated on AG 1-X8 columns (0.8 ml packed, 100-200 mesh) in formate phase. Inositol monophosphate was eluted with 8 ml of 200 mM ammonium formate.
  • Rats are surgically prepared with guide cannulae directed towards the lateral ventricle (verified by an intense drinking response to angiotensin II; lOOng i.e. v.). Following a two week recovery period, rats receive human urotensin-II, putative agonist ligand (1-10 ug, i.e. v.) or vehicle (0.9% saline solution) over min (allowing 90 sec for diffusion) in order to detect any neuroendocrine plasma changes.
  • anesthetized rats are prepared for acute systemic exposure to human urotensin-II, putative agonist ligand (100 ug, bolus i.v.) or vehicle (0.9% saline solution) via an i.v. cannula placed in the left femoral of jugular vein.
  • i.v. cannula placed in the left femoral of jugular vein.
  • RIAs radioimmunoassays
  • Neuroendocrine markers include but are not limited to:
  • Pituitary hormones both anterior ⁇ e.g. ADH, OCT, ACTH) and posterior (e.g. GH, TSH,
  • Thyroid/parathyroid hormones T4, T3, rT3, calcitonin, PTH
  • Sex hormones including releasing hormones
  • Vasoactive neurohormones ET, Angiotensin II, aldosterone, NE
  • EXAMPLE 27 Formulations for pharmaceutical use inco ⁇ orating compounds of the present invention can be prepared in various forms and with numerous excipients. Examples of such formulations are given below.
  • a compound of Formula I (1 mg to 100 mg) is aerosolized from a metered dose inhaler to deliver the desired amount of drug per use.
  • Tablets/Ingredients Per Tablet 1. Active ingredient 40 mg (Cpd of Form. I) 2.Corn Starch 20 mg 3.Alginic acid 20 mg 4.Sodium Alginate 20 mg 5.Mg stearate 1.3 mg
  • Step l Blend ingredients No. 1 , No. 2, No. 3 and No. 4 in a suitable mixer/blender.
  • Step 2 Add sufficient water portion-wise to the blend from Step 1 with careful mixing after each addition. Such additions of water and mixing until the mass is of a consistency to permit its conversion to wet granules.
  • Step 4 The wet granules are then dried in an oven at 140°F (60°C) until dry.
  • Step 5 The dry granules are lubricated with ingredient No. 5.
  • Step 6 The lubricated granules are compressed on a suitable tablet press.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Cardiology (AREA)
  • Diabetes (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Psychiatry (AREA)
  • Endocrinology (AREA)
  • Pain & Pain Management (AREA)
  • Pulmonology (AREA)
  • Urology & Nephrology (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Emergency Medicine (AREA)
  • Addiction (AREA)
  • Vascular Medicine (AREA)
  • Rheumatology (AREA)
  • Toxicology (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)

Abstract

The present invention relates generally Urotensin-II analogs and pharmaceutical compositions containing them.

Description

UROTENSIN-II ANALOGS
FIELD OF THE INVENTION
The present invention relates generally Urotensin-II analogs and pharmaceutical compositions containing them.
BACKGROUND OF THE INVENTION
The integrated control of cardiovascular homeostasis is achieved through a combination of both direct neuronal control and systemic neurohormonal activation. Although the resultant release of both contractile and relaxant factors is normally under stringent regulation, an aberration in this status quo can result in cardiohemodynamic dysfunction with pathological consequences.
The principal mammalian vasoactive factors that comprise this neurohumoral axis, namely angiotensin-II, endothelin-1, norepinephrine, all function via an interaction with specific G-protein coupled receptors (GPCR). Urotensin-II, represents a novel member of this neurohumoral axis.
In the fish, this peptide has significant hemodynamic and endocrine actions in diverse end-organ systems and tissues:
• smooth muscle contraction both vascular and non-vascular in origin including smooth muscle preparations from the gastrointestinal tract, respiratory, and genitourinary tract. Both pressor and depressor activity has been described upon systemic administration of exogenous peptide
• osmoregulation: effects which include the modulation of transepithelial ion (Na+, Cl") transport. Although a diuretic effect has been described, such an effect is postulated to be secondary to direct renovascular effects (elevated GFR)
• metabolism: urotensin-II influences prolactin secretion and exhibits a lipolytic effect in fish (activating triacylglycerol lipase resulting in the mobilization of non-esterified free fatty acids)
(Pearson, et. al. Proc. Natl. Acad. Sci. (U.S.A.) 1980, 77, 5021 ; Conlon, et. al. J. Exp. Zool. 1996, 275, 226.) In studies with human Urotensin-II it was found that it:
• was an extremely potent and efficacious vasoconstrictor • exhibited sustained contractile activity that was extremely resistant to wash out
• had detrimental effects on cardiac performance (myocardial contractility)
Human Urotensin-II was assessed for contractile activity in the rat-isolated aorta and was shown to be the most potent contractile agonist identified to date. Based on the in vitro pharmacology and in vivo hemodynamic profile of human Urotensin-II it plays a pathological role in cardiovascular diseases characterized by excessive or abnormal vasoconstriction and myocardial dysfunction. (Ames et. al. Nature 1999, 401, 282)
Urotensin-II analogs are useful for identifying agonists and antagonists/inhibitors of urotensin II, and for treating conditions associated with Human Urotensin II imbalance. For example, facilitating the actions of the U-II system, either by mimicking the agonist activity of U-II at its cognate receptor(s) or by attenuating the uptake/metabolism of U-II.
These compounds may be useful in the treatment of congestive heart failure, stroke, ischemic heart disease (angina, myocardial ischemia), cardiac arrhythmia, hypertension (essential and pulmonary), COPD, restenosis, asthma, (Hay DWP, Luttmann MA, Douglas SA: 2000, Br J Pharmacol: volume 131 , pages 10-12) neurogenic inflammation and metabolic vasculopathies all of which are characterized by abnormal vasoconstriction and/or myocardial dysfunction. Since U-II and GPR14 are both expressed within the mammalian CNS (Ames et. al. Nature 1999, 401, 282), they also may be useful in the treatment of addiction, schizophrenia, impulsivity, anxiety, stress, depression, and neuromuscular function. Functional U-II receptors are expressed in rhabdomyosarcomas cell lines and therefore may have oncological indications. Urotensin may also be implicated in various metabolic diseases such as diabetes (Ames et. al. Nature 1999, 401, 282, Nothacker et al., Nature Cell Biology 1 : 383-385, 1999).
SUMMARY OF THE INVENTION
In one aspect this invention provides for urotensin II analogs and pharmaceutical compositions containing them.
In a second aspect, this invention provides for the use of urotensin analogs for identifying agonists and antagonists of urotensin II, and as inhibitors of urotensin II. In another aspect, this invention provides for the use of urotensin analogs for treating conditions associated with urotensin II imbalance.
In and yet another aspect, this invention provides for the use of urotensin analogs for the treatment of congestive heart failure, stroke, ischemic heart disease (angina, myocardial ischemia), cardiac arrhythmia, hypertension (essential and pulmonary), COPD, restenosis, asthma, neurogenic inflammation and metabolic vasculopathies, addiction, schizophrenia, impulsivity, anxiety, stress, depression, neuromuscular function, and diabetes.
Other aspects and advantages of the present invention are described further in the following detailed description of the preferred embodiments thereof.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides for the following urotension II analogs and pharmaceutical compositions containing them : H-Glu-Thr-Pro-Asp-Cys-Phe-D-Trp-Lys-Tyr-Cys-Val-OH (cyclic disulfide); (SEQ ID NO: 1)
H-Asp-Cys-Phe-Trp-Lys-Tyr-Cys-OH (cyclic disulfide); (SEQ ID NO: 2) Ac-Cys-Phe-Trp-Lys-Tyr-Cys-NH (cyclic disulfide); (SEQ ID NO: 3)
H-Asp-Cys-Phe-D-Trp-Lys-Tyr-Cys-Val-OH (cyclic disulfide); (SEQ ID NO: 4) H-Asp-Cys-Cha-Trp-Lys-Cha-Cys-Val-OH (cyclic disulfide); (SEQ ID NO: 5) H-Asp-Cys-Phe-Trp-Lys-Cha-Cys-Val-OH (cyclic disulfide); (SEQ ID NO: 6) H-Asp-Cys-Phe-Trp-Lys-Phe-Cys-Val-OH (cyclic disulfide); (SEQ ID NO: 7) H-Asp-Cys-Cha-Trp-Lys-Tyr-Cys-Val-OH (cyclic disulfide); (SEQ ID NO: 8) H-Asp-Cys-Phe-Trp-Arg-Tyr-Cys-Val-OH (cyclic disulfide); (SEQ ID NO: 9) H-Asp-Cys-Phe-Trp-Orn-Tyr-Cys-Val-OH (cyclic disulfide); (SEQ ID NO: 10) H-Ala-Cys-Phe-Trp-Lys-Tyr-Cys-Val-OH (cyclic disulfide); (SEQ ID NO: 1 1) H-Asn-Cys-Phe-Trp-Lys-Tyr-Cys-Val-OH (cyclic disulfide); (SEQ ID NO: 12) H-Gly-Cys-Phe-Trp-Lys-Tyr-Cys-Val-OH (cyclic disulfide); (SEQ ID NO: 13) H-Asp-Cys-(α-Me)Phe-Trp-Lys-Tyr-Cys-Val-OH (cyclic disulfide); (SEQ ID NO: 14) H-Asp-Cys-(N-Me)Phe-Trp-Lys-Tyr-Cys-Val-OH (cyclic disulfide); (SEQ ID NO: 15) H-Asp-Cys-(α-Me)Phe-Trp-Lys-(α-Me)Phe-Cys-Val-OH (cyclic disulfide); (SEQ ID NO: 16)
H-Asp-Cys-Phe-Tφ-Lys-(α-Me)Phe-Cys-Val-OH (cyclic disulfide); (SEQ ID NO: 17) H-Glu-Thr-Pro-Asp-Cys-Ala-Trp-Lys-Tyr-Cys-Val-OH (cyclic disulfide); (SEQ ID NO: 18)
H-Leu-Ser-Leu-Ser-Gln-Ser-Lys-Val-Leu-Pro-Asp-Cys-Phe-Trp-Lys-Tyr-Cys-Val-OH (cyclic disulfide); (SEQ ID NO: 19)
H-Leu-Ser-Leu-Ser-Gln-Ser-Lys-Val-Leu-Pro-Asn-Cys-Phe-Trp-Lys-Tyr-Cys-Val-OH (cyclic disulfide); (SEQ ID NO: 20) H-Arg-Arg-Arg-Leu-Ser-Leu-Ser-Gln-Ser-Lys-Val-Leu-Pro-Asn-Cys-Phe-Tφ-Lys-Tyr-
Cys-Val-OH (cyclic disulfide); (SEQ ID NO: 21)
H-Asp-Cys-Phe-Tφ-Lys-Tyr-Cys-Lys-OH (cyclic disulfide); (SEQ ID NO: 22)
H-Asp-Cys-Phe-Tφ-Lys-Tyr-Cys-Asp-OH (cyclic disulfide); (SEQ ID NO: 23) H-Asp-Cys-Phe-Tφ-Lys-Tyr-Cys-Asn-OH (cyclic disulfide); (SEQ ID NO: 24)
H-Gln-Arg-Lys-Gln-His-Gly-Thr-Ala-Pro-Glu-Cys-Phe-Tφ-Lys-Tyr-Cys-Val-OH (cyclic disulfide); (SEQ ID NO: 25) and
H- Gln-His-Gly-Thr-Ala-Pro-Glu Cys-Phe-Tφ-Lys-Tyr-Cys-Val-OH (cyclic disulfide);
(SEQ ID NO:26) or a pharmaceutically acceptable salt thereof. The preferred compounds are:
H-Glu-Thr-Pro-Asp-Cys-Phe-D-Tφ-Lys-Tyr-Cys-Val-OH (cyclic disulfide);
(SEQ ID NO: 1)
H-Asp-Cys-Phe-Tφ-Lys-Phe-Cys-Val-OH (cyclic disulfide); (SEQ ID NO: 7) H-Asp-Cys-Phe-Tφ-Lys-Cha-Cys-Val-OH (cyclic disulfide); (SEQ ID NO: 6)
H-Asp-Cys-Phe-Tφ-Arg-Tyr-Cys-Val-OH (cyclic disulfide); (SEQ ID NO: 9)
H-Ala-Cys-Phe-Tφ-Lys-Tyr-Cys-Val-OH (cyclic disulfide); (SEQ ID NO: 1 1) and
H-Asp-Cys-(N-Me)Phe-Tφ-Lys-Tyr-Cys-Val-OH (cyclic disulfide). (SEQ ID NO: 15)
The compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active form. All of these compounds and their diastereoisomers are contemplated to be within the scope of the present invention.
Preparation Peptides were synthesized on rert-Butoxycarbonyl-L-cysteine(S-p-methoxybenzyl)-
O-Resin (loading = 0.84 mole equiv/g). Preparation of the peptides consisted of the synthesis cycle, hydrofluoric acid cleavage, cyclization, and purification. All amino acids were used as alpha rt-butoxycarbonyl derivatives. Sidechain protecting groups were as follows:
Tryptophan none
Tyrosine Br-Z
Lysine 2-CIZ
Cysteine p-methoxybenzyl
Aspartic acid cyclohexyl Experimental
Each synthesis cycle consisted of:
a) Trifluoroacetic acid deblock
The resin was treated with 50% TFA in methylene chloride (two to three times resin volume), stirred at room temperature for 30 min and drained. The resin was washed once with an equal volume of isopropanol for 1 min, then washed twice with an equal volume of methanol for 1 min.
b) Coupling
Resin from (a) above was washed with an equal volume of 10% triethylamine in methylene chloride twice for 1 min, then washed with an equal volume of methanol twice for 1 min, and finally washed with an equal volume of methylene chloride twice for 1 min. To the resin was added three equivalents of terf-butoxycarbonyl amino acid (dissolved in methylene chloride or methylene chloride/N,N-dimethylformamide mixture), three equivalents of 1 -hydroxybenzotriazole hydrate (1 M solution in N,N-dimethylformamide) and the resultant suspension was stirred for one min. To the mixture was added three equivalents of dicyclohexylcarbodiimid (1 M solution in methylene chloride) and the reaction was stirred for 60-120 min. The resin was then washed with equal volume of methanol twice and washed with equal volume of methylene chloride twice. A small sample was taken for ninhydrin test: upon incomplete coupling, subcycle b) was repeated; upon complete coupling, the synthesis was continued with subcycle c).
c) Capping
To the resin from (b) above was added an equal volume of acetic anhydride (20% in methylene chloride) and the mixture was stirred for 5 min at room temperature. The resin was then washed with an equal volume of methanol twice and an equal volume of methylene chloride twice.
HF Cleavage:
To 1.0 g of resin from (c) above in a teflon reaction vessel was added 1 ml of anhydrous anisole. The vessel was cooled with liquid nitrogen and charged with 10 ml hydrofluoric acid (anhydrous, distilled). The temperature was raised with ice water to 0° C and the reaction stirred for 1 h. The hydrofluoric acid was distilled off at 0° C and the residue was washed with anhydrous ether, extracted with 1 : 1 acetonitrile/water and lyophylized to furnish the cleaved linear peptide.
Cyclization: After, the crude linear peptide was extracted from the cleaved resin, it was diluted to approx. 1 g/L with water. The pH was adjusted to 7.5 -8.0 with ammonium hydroxide. The cloudy reaction mixture was stirred until no more shift was detected by HPLC and/or the mixture become weak/negative by Ellman test (2-3 days). The mixture was acidified to pH 4.0 and filtered to provide the crude cyclic disulfide peptides.
Purification:
HPLC: column Vydac C-18 RP silica, 15-20 uM, 2" diameter
The crude peptides were loaded onto reverse phase HPLC column. A linear gradient was used over 30 min (100% water containing 0.1 % trifluoroacetic acid to 80% acetonitrile containing 0.1 % trifluoroacetic acid /20% water containing 0.1 % trifluoroacetic acid).
Fractions showing better than 95% purity were pooled and lyophylized to furnish the desired peptides.
Mass Spec, and Amino Acid Analysis were used to confirm the peptide sequence.
In order to use a compound of the Formula (I) or a pharmaceutically acceptable salt thereof for the treatment of humans and other mammals it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
Compounds of Formula (I) and their pharmaceutically acceptable salts may be administered in a standard manner for the treatment of the indicated diseases, for example orally, parenterally, sub-lingually, transdermally, rectally, via inhalation or via buccal administration.
Compounds of Formula (I) and their pharmaceutically acceptable salts, which are active when given orally, can be formulated as syrups, tablets, capsules and lozenges. A syrup formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier for example, ethanol, peanut oil, olive oil, glycerin or water with a flavoring or coloring agent. Where the composition is in the form of a tablet, any pharmaceutical carrier routinely used for preparing solid formulations may be used.
Examples of such carriers include magnesium stearate, terra alba, talc, gelatin, agar, pectin, acacia, stearic acid, starch, lactose and sucrose. Where the composition is in the form of a capsule, any routine encapsulation is suitable, for example using the aforementioned carriers in a hard gelatin capsule shell. Where the composition is in the form of a soft gelatin shell capsule any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be considered, for example aqueous gums, celluloses, silicates or oils and are incoφorated in a soft gelatin capsule shell.
Typical parenteral compositions consist of a solution or suspension of the compound or salt in a sterile aqueous or non-aqueous carrier optionally containing a parenterally acceptable oil, for example polyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil, or sesame oil. Typical compositions for inhalation are in the form of a solution, suspension or emulsion that may be administered as a dry powder or in the form of an aerosol using a conventional propellant such as dichlorodifluoromethane or trichlorofluoromethane.
A typical suppository formulation comprises a compound of Formula (1) or a pharmaceutically acceptable salt thereof which is active when administered in this way, with a binding and/or lubricating agent, for example polymeric glycols, gelatins, cocoa- butter or other low melting vegetable waxes or fats or their synthetic analogues.
Typical transdermal formulations comprise a conventional aqueous or non-aqueous vehicle, for example a cream, ointment, lotion or paste or are in the form of a medicated plaster, patch or membrane. Preferably the composition is in unit dosage form, for example a tablet, capsule or metered aerosol dose, so that the patients may administer to themselves a single dose.
No unacceptable toxicological effects are expected when compounds of the invention are administered in accordance with the present invention.
These urotensin analogs may be used for the treatment of congestive heart failure, stroke, ischemic heart disease (angina, myocardial ischemia), cardiac arrhythmia, hypertension (essential and pulmonary), COPD, restenosis, asthma, neurogenic inflammation and metabolic vasculopathies, addiction, schizophrenia, impulsivity, anxiety, stress, depression, neuromuscular function, and diabetes.
The biological activity of the compounds of Formula (I) are demonstrated by the following tests:
Radioligand binding:
HEK-293 cell membranes containing stable cloned human and rat GPR-14 (20 ug/assay) were incubated with 200 pM [1251] h-U-II (200 Ci/mmol"1 in the presence of increasing concentrations of test compounds in DMSO (0.1 nM to 10 uM), in a final incubation volume of 200 ul (20 mM Tris-HCl, 5 mM MgC12). Incubation was done for 30 minutes at room temperature followed by filtration GF/B filters with Brandel cell harvester. Ϊ2 ι labeled U-II binding was quantitated by gamma counting. Nonspecific binding was defined by *25τ TJ.JJ binding in the presence of 100 nM of unlabeled human U-II. Analysis of the data was performed by nonlinear least square fitting.
Ca2+-mobilization:
A microtitre plate based Ca2+-mobilization FLIPR assay (Molecular Devices, Sunnyvale, CA) was used for the functional identification of the ligand activating HEK-293 cells expressing (stable) recombinant GPR-14. The day following transfection, cells were plated in a poly-D-lysine coated 96 well black/clear plates. After 18-24 hours the media was aspirated and Fluo 3AM-loaded cells were exposed to various concentrations (10 nM to 30 uM) of test compounds followed by h-U-II. After initiation of the assay, fluorescence was read every second for one minute and then every 3 seconds for the following one minute. The inhibitory concentration at 50% (IC50) was calculated for various test compounds.
Inositol phosphates assays:
HEK-293-GPR14 cells in T 150 flask were prelabeled overnight with 1 uCi myo- H] inositol per ml of inositol free Dulbecco's modified Eagel's medium. After labeling, the cells were washed twice with Dulbecco's phosphate-buffered saline (DPBS) and then incubated in DPBS containing 10 mM LiCl for 10 min at 37°C. The experiment was initiated by the addition of increasing concentrations of h-U-II ( 1 pM to 1 μM ) in the absence and presence of three different concentrations (0.3, 1 and 10 uM) of test compounds and the incubation continued for an additional 5 min at 37°C after which the reaction was terminated by the addition of 10% (final concentration) trichloroacetic acid and centrifugation. The supernatants were neutralized with lOOul of 1M Trizma base and the inositol phosphates were separated on AG 1-X8 columns (0.8 ml packed, 100-200 mesh) in formate phase. Inositol monophosphate was eluted with 8 ml of 200 mM ammonium formate. Combined inositol di and tris phosphate was eluted with 4ml of 1M ammonium formate/ 0.1 M formic acid. Eluted fractions were counted in beta scintillation counter. Based on shift from the control curve KB was calculated. Modulation of neuroendocrine factors
Adult Sprague Dawley rats are surgically prepared with guide cannulae directed towards the lateral ventricle (verified by an intense drinking response to angiotensin II; lOOng i.e. v.). Following a two week recovery period, rats receive human urotensin-II, putative agonist ligand (1-10 ug, i.e. v.) or vehicle (0.9% saline solution) over min (allowing 90 sec for diffusion) in order to detect any neuroendocrine plasma changes. Alternatively, anesthetized rats are prepared for acute systemic exposure to human urotensin-II, putative agonist ligand (100 ug, bolus i.v.) or vehicle (0.9% saline solution) via an i.v. cannula placed in the left femoral of jugular vein. After a period of 20 min, is blood collected for subsequent assay of the neuroendocrine markers using suitable radioimmunoassays (RIAs). Neuroendocrine markers include but are not limited to:
Pituitary hormones, both anterior {e.g. ADH, OCT, ACTH) and posterior (e.g. GH, TSH,
LH, GSH, Prolactin) Hypothalamic facors (SST, GHRH, TRH, CRH)
Thyroid/parathyroid hormones (T4, T3, rT3, calcitonin, PTH)
Insulin, leptin, glucose
Lipids
Sex hormones (including releasing hormones) Vasoactive neurohormones (ET, Angiotensin II, aldosterone, NE)
Examples
Examples 1-26 were prepared following the general procedure outlined above using the appropriate starting materials:
EXAMPLE 27 Formulations for pharmaceutical use incoφorating compounds of the present invention can be prepared in various forms and with numerous excipients. Examples of such formulations are given below.
Inhalant Formulation
A compound of Formula I, (1 mg to 100 mg) is aerosolized from a metered dose inhaler to deliver the desired amount of drug per use. Tablets/Ingredients Per Tablet 1. Active ingredient 40 mg (Cpd of Form. I) 2.Corn Starch 20 mg 3.Alginic acid 20 mg 4.Sodium Alginate 20 mg 5.Mg stearate 1.3 mg
2.3 mg
Procedure for tablets:
Step l :Blend ingredients No. 1 , No. 2, No. 3 and No. 4 in a suitable mixer/blender.
Step 2:Add sufficient water portion-wise to the blend from Step 1 with careful mixing after each addition. Such additions of water and mixing until the mass is of a consistency to permit its conversion to wet granules. Step :The wet mass is converted to granules by passing it through an oscillating granulator using a No. 8 mesh (2.38 mm) screen.
Step 4:The wet granules are then dried in an oven at 140°F (60°C) until dry.
Step 5:The dry granules are lubricated with ingredient No. 5.
Step 6:The lubricated granules are compressed on a suitable tablet press.
The above specification and Examples fully disclose how to make and use the compounds of the present invention. However, the present invention is not limited to the particular embodiments described hereinabove, but includes all modifications thereof within the scope of the following claims. The various references to journals, patents and other publications which are cited herein comprise the state of the art and are incorporated herein by reference as though fully set forth.

Claims

What is claimed is:
1. A compound selected from: H-Glu-Thr-Pro-Asp-Cys-Phe D-Trp-Lys-Tyr-Cys-Val-OH (cyclic disulfide); (SEQ ID NO: 1)
H-Asp-Cys-Phe-Tφ-Lys-Tyr-Cys-OH (cyclic disulfide); (SEQ ID NO: 2) Ac-Cys-Phe-Tφ-Lys-Tyr-Cys-NH2 (cyclic disulfide); (SEQ ID NO: 3)
H-Asp-Cys-Phe-D-Tφ-Lys-Tyr-Cys-Val-OH (cyclic disulfide); (SEQ ID NO: 4) H-Asp-Cys-Cha-Tφ-Lys-Cha-Cys-Val-OH (cyclic disulfide); (SEQ ID NO: 5) H-Asp-Cys-Phe-Tφ-Lys-Cha-Cys-Val-OH (cyclic disulfide); (SEQ ID NO: 6) H-Asp-Cys-Phe-Tφ-Lys-Phe-Cys-Val-OH (cyclic disulfide); (SEQ ID NO: 7) H-Asp-Cys-Cha-Tφ-Lys-Tyr-Cys-Val-OH (cyclic disulfide); (SEQ ID NO: 8) H-Asp-Cys-Phe-Tφ-Arg-Tyr-Cys-Val-OH (cyclic disulfide); (SEQ ID NO: 9) H-Asp-Cys-Phe-Tφ-Orn-Tyr-Cys-Val-OH (cyclic disulfide); (SEQ ID NO: 10) H-Ala-Cys-Phe-Tφ-Lys-Tyr-Cys-Val-OH (cyclic disulfide); (SEQ ID NO: 1 1) H-Asn-Cys-Phe-Tφ-Lys-Tyr-Cys-Val-OH (cyclic disulfide); (SEQ ID NO: 12) H-Gly-Cys-Phe-Tφ-Lys-Tyr-Cys-Val-OH (cyclic disulfide); (SEQ ID NO: 13) H-Asp-Cys-( -Me)Phe-Tφ-Lys-Tyr-Cys-Val-OH (cyclic disulfide); (SEQ ID NO: 14) H-Asp-Cys-(N-Me)Phe-Tφ-Lys-Tyr-Cys-Val-OH (cyclic disulfide); (SEQ ID NO: 15) H-Asp-Cys-(α-Me)Phe-Tφ-Lys-(oc-Me)Phe-Cys-VaI-OH (cyclic disulfide); (SEQ ID NO: 16)
H-Asp-Cys-Phe-Tφ-Lys-( -Me)Phe-Cys-Val-OH (cyclic disulfide); (SEQ ID NO: 17) H-Glu-Thr-Pro-Asp-Cys-Ala-Tφ-Lys-Tyr-Cys-Val-OH (cyclic disulfide); (SEQ ID NO: 18) H-Leu-Ser-Leu-Ser-Gln-Ser-Lys-Val-Leu-Pro-Asp-Cys-Phe-Tφ-Lys-Tyr-Cys-Val-OH (cyclic disulfide); (SEQ ID NO: 19)
H-Leu-Ser-Leu-Ser-Gln-Ser-Lys-Val-Leu-Pro-Asn-Cys-Phe-Trp-Lys-Tyr-Cys-Val-OH (cyclic disulfide); (SEQ ID NO: 20) H-Arg-Arg-Arg-Leu-Ser-Leu-Ser-Gln-Ser-Lys-Val-Leu-Pro-Asn-Cys-Phe-Tφ-Lys-Tyr- Cys-Val-OH (cyclic disulfide); (SEQ ID NO: 21)
H-Asp-Cys-Phe-Tφ-Lys-Tyr-Cys-Lys-OH (cyclic disulfide); (SEQ ID NO: 22) H-Asp-Cys-Phe-Trp-Lys-Tyr-Cys-Asp-OH (cyclic disulfide); (SEQ ID NO: 23) H-Asp-Cys-Phe-Tφ-Lys-Tyr-Cys-Asn-OH (cyclic disulfide); (SEQ ID NO: 24) H-Gln-Arg-Lys-Gln-His-Gly-Thr-Ala-Pro-Glu-Cys-Phe-Tφ-Lys-Tyr-Cys-Val-OH (cyclic disulfide); (SEQ ID NO: 25) and H- Gln-His-Gly-Thr-Ala-Pro-Glu Cys-Phe-Tφ-Lys-Tyr-Cys-Val-OH (cyclic disulfide);
(SEQ ID NO:26) or a pharmaceutically acceptable salt thereof.
2. A compound of claim 1 selected from:
H-Glu-Thr-Pro-Asp-Cys-Phe-D-Tφ-Lys-Tyr-Cys-Val-OH (cyclic disulfide); (SEQ ID NO: 1)
H-Asp-Cys-Phe-Tφ-Lys-Phe-Cys-Val-OH (cyclic disulfide); (SEQ ID NO: 7)
H-Asp-Cys-Phe-Tφ-Lys-Cha-Cys-Val-OH (cyclic disulfide); (SEQ ID NO: 6) H-Asp-Cys-Phe-Tφ-Arg-Tyr-Cys-Val-OH (cyclic disulfide); (SEQ ID NO: 9)
H-Ala-Cys-Phe-Tφ-Lys-Tyr-Cys-Val-OH (cyclic disulfide); (SEQ ID NO: 1 1 ) and H-Asp-Cys-(N-Me)Phe-Tφ-Lys-Tyr-Cys-Val-OH (cyclic disulfide). (SEQ ID NO: 15)
3. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
4. A method for treating conditions associated with Human Urotensin II imbalance by administering to a subject in need thereof an effective amount of a compound of claim 1.
5. A method for treating stroke by adiministering to a subject in need thereof an effective amount of a compound of claim 1.
EP00980842A 1999-11-29 2000-11-29 Urotensin-ii analogs Withdrawn EP1233774A4 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US16814199P 1999-11-29 1999-11-29
US168141P 1999-11-29
PCT/US2000/032408 WO2001037780A2 (en) 1999-11-29 2000-11-29 Urotensin-ii analogs

Publications (2)

Publication Number Publication Date
EP1233774A1 true EP1233774A1 (en) 2002-08-28
EP1233774A4 EP1233774A4 (en) 2004-06-16

Family

ID=22610297

Family Applications (1)

Application Number Title Priority Date Filing Date
EP00980842A Withdrawn EP1233774A4 (en) 1999-11-29 2000-11-29 Urotensin-ii analogs

Country Status (3)

Country Link
EP (1) EP1233774A4 (en)
JP (1) JP2003527341A (en)
WO (1) WO2001037780A2 (en)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PT1355940E (en) * 2000-10-20 2007-11-08 Sod Conseils Rech Applic Urotensin-ii agonists and antagonists
EP1557430A4 (en) * 2002-10-25 2006-02-08 Takeda Pharmaceutical ANTIBODIES AND USE OF SAID ANTIBODIES
ITFI20030238A1 (en) 2003-09-11 2005-03-12 Paolo Grieco UROTENSIN ANTAGONIST CYCLIC PEPTIDES-II
ITFI20070032A1 (en) * 2007-02-09 2008-08-10 Alfredo Budillon LIGANDS OF PEPTIDIC AND NON-PEPTIDIC NATURE OF THE UT RECEIVER OF UROTENSIN-II, PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM AND THEIR USE.
EP2729184A4 (en) * 2011-05-03 2015-06-24 Inst Nat Rech Scient NEW AGONISTS AND ANTAGONISTS OF THE UROTENSINERGIC SYSTEM
FR2982488B1 (en) * 2011-11-10 2013-12-27 Univ Rouen UROTENSIN II FOR USE IN THE TREATMENT AND / OR PREVENTION OF PATHOLOGIES INVOLVING GASTRIC MOTILITY

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
BEHM D J ET AL: "PHARMACOLOGICAL CHARACTERIZATION OF SB-710411 (CPA-C[D-CYS-PAL-D-TRP-LYS-VAL-CYS]-CPA-AM IDE), A NOVEL PEPTIDIC UROTENSIN-II RECEPTOR ANTAGONIST" BRITISH JOURNAL OF PHARMACOLOGY, BASINGSTOKE, HANTS, GB, vol. 137, no. 4, October 2002 (2002-10), pages 449-458, XP001153544 ISSN: 0007-1188 *
CONLON J M ET AL: "ISOLATION AND PRIMARY STRUCTURE OF UROTENSIN II FROM THE BRAIN OF A TETRAPOD, THE FROG RANA RIDIBUNDA" BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, ACADEMIC PRESS INC. ORLANDO, FL, US, vol. 188, no. 2, 30 October 1992 (1992-10-30), pages 578-583, XP000311226 ISSN: 0006-291X *
COULOUARN Y ET AL: "Cloning of the cDNA encoding the Urotensin II precursor in frog and human reveals intense expression of the Urotensin II gene in motoneurons of the spinal cord" PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF USA, NATIONAL ACADEMY OF SCIENCE. WASHINGTON, US, vol. 95, no. 26, 22 December 1998 (1998-12-22), pages 15803-15808, XP002110994 ISSN: 0027-8424 *
COY D H ET AL: "Novel urotensin II (UII) antagonists point to multiple receptor involvement in UII bioactivity" REGULATORY PEPTIDES, vol. 94, no. 1-3, 25 October 2000 (2000-10-25), page 48, XP002267294 13th International Symposium on Regulatory Peptides;Cairns, Queensland, Australia; October 22-26, 2000 ISSN: 0167-0115 *
DOUGLAS S A ET AL: "HUMAN UROTENSIN-II, THE MOST POTENT MAMMALIAN VASOCONSTRICTOR IDENTIFIED TO DATE, AS A THERAPEUTIC TARGET FOR THE MANAGEMENT OF CARDIOVASCULAR DISEASE" TRENDS IN CARDIOVASCULAR MEDICINE, ELSEVIER SCIENCE, NEW YORK, NY, US, vol. 10, no. 6, August 2000 (2000-08), pages 229-237, XP001153538 ISSN: 1050-1738 *
PERKINS T D J ET AL: "Molecular modelling and design of analogues of the peptide hormone Urotensin II" BIOCHEMICAL SOCIETY TRANSACTIONS, COLCHESTER, ESSEX, GB, vol. 18, no. PART 5, October 1990 (1990-10), pages 918-919, XP002110993 ISSN: 0300-5127 *

Also Published As

Publication number Publication date
WO2001037780A2 (en) 2001-05-31
JP2003527341A (en) 2003-09-16
WO2001037780A8 (en) 2001-11-08
EP1233774A4 (en) 2004-06-16

Similar Documents

Publication Publication Date Title
CN104395338B (en) human amylin analog
EP1246807B1 (en) Novel hydantoin, thiohydantoin, pyrimidinedione and thioxopyrimidinone derivatives, preparation method and use as medicines
JP2013511554A (en) Melanocortin-1 receptor-specific linear peptide
US8173643B2 (en) N-substituted thiomorpholine derivatives as the inhibitors of dipeptidyl peptidase IV and the pharmaceutical uses thereof
EA018000B1 (en) Peptidomimetics with glucagon antagonistic and glp-1 agonistic activities
NO300977B1 (en) Novel 8-substituted purines as selective adenosine receptor agents
EP1244452A1 (en) Urotensin-ii receptor antagonists
US20040152692A1 (en) Pyrrolidine sulfonamides
EP2177533A1 (en) Multiple N-methylated cyclic hexapeptides for treatment of neurogenic inflammation
EP1233774A1 (en) Urotensin-ii analogs
GB2263639A (en) Substituted pyrimidinones as neurotensin antagonists
US20040039017A1 (en) Urotensin-II receptor antagonists
US20040053963A1 (en) Urotensin-II receptor antagonists
EP0005658A1 (en) Peptide derivatives analogue to encephalines, process for their preparation and their therapeutical application
EP1233776A1 (en) Urotensin-ii cyclic analogs
DE60015187T2 (en) UROTENSIN-II RECEPTOR ANTAGONISTS
EP2585486B1 (en) New octapeptidic compounds and their use in therapy
US7358342B2 (en) Preparation derived from shark cartilage for treatment of diseased related to excessive PHF or excessive intracellular calcium
US20040142923A1 (en) Pyrrolidine sulfonamides
US20050197345A1 (en) Pyrrolidine sulfonamides
US20040082566A1 (en) Pyrrolidine sulfonamides
JP2004524355A (en) Pyrrolidine sulfonamide
US20040152895A1 (en) Sulfonamides

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20020521

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR

RIC1 Information provided on ipc code assigned before grant

Ipc: 7C 07K 7/06 A

A4 Supplementary search report drawn up and despatched

Effective date: 20040423

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20040715