Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
  • A61K38/08—Peptides having 5 to 11 amino acids
  • A61K38/085—Angiotensins
• • 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
  • 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
  • A61P9/10—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

Definitions

• the present invention relates to angiotensin I derivatives.
• the present invention relates to angiotensin I derivatives but excluding des-aspartate-angiotensin I.
• the peptide angiotensin I is converted to angiotensin III by aminopeptidases(s) and angiotensin converting enzyme, respectively, via the intermediate molecule des-aspartate-angiotensin I.
• Des-aspartate-angiotensin I has been described for use in treatment and/or prevention of cardiac hypertrophy (United States Patent No. 5,773,415), and neointima formation or restenosis (United States Patent No. 6,100,237).
• Angiotensin Il is involved in cardiac hypertrophy and neointima formation. Exogenously-administered angiotensin Il potentiates cardiac hypertrophy (Dostal and
• angiotensin IV a secondary metabolite of angiotensin II
• Angiotensin IV has recently been shown to act on a subtype of angiotensin receptor, which is different from the known AT1 and AT2 receptors (Swanson et al,
• This receptor is named AT4 receptor and has been shown to regulate cognitive function in the brain and possibly neuronal development (von Bohlen and Halbach, Cell Tissue Res., 311 :1-9 (2003)). Its role, if any, in cardiac hypertrophy, is indeterminate.
• angiotensin IV (AT4) on cardiac hypertrophy in an intact mammalian species.
• AT4 angiotensin IV
• a study by Moeller et al reported an upregulation of AT4 receptors in the neointima and media of endothelial denuded rabbit carotid artery.
• Moeller et al reported an upregulation of AT4 receptors in the neointima and media of endothelial denuded rabbit carotid artery.
• angiotensin IV in neointima formation remains unknown.
• the present invention addresses the problems above and provides new uses and/or composition(s) of derivative(s) of angiotensin I.
• the present invention provides new uses of derivative(s) of angiotensin I, with the exclusion of des- aspartate-angiotensin I.
• the derivatives of angiotensin I, with the exclusion of des-aspartate-angiotensin I are used for the treatment and/or prevention of cardiac hypertrophy, and/or neointima formation, including restenosis, in a subject or human patient in need of such treatment or prevention.
• a method for the treatment and/or prevention of cardiac hypertrophy and/or neointima formation in a subject in need of such treatment and/or prevention comprising administering to the patient an effective amount of at least one derivative of angiotensin I, with the exclusion of des-aspartate-angiotensin I.
• compositions comprising an effective amount of at least one derivative of angiotensin I, with the exclusion of des-aspartate- angiotensin I, and at least one pharmaceutically acceptable carrier, excipient, diluent and/or adjuvant.
• the composition is preferably for use in the treatment and/or prevention of cardiac hypertrophy and/or neointima formation in a subject in need of such treatment and/or prevention comprising administering to the patient.
• the patient may be human.
• the neointima formation may comprise restenosis.
• angiotensin I there is also provided at least one derivative of angiotensin I, with the exclusion of des-aspartate-angiotensin I, for use in medicine.
• the derivative according to the invention is preferably for use in the treatment and/or prevention of cardiac hypertrophy and/or neointima formation in a subject in need of such treatment.
• the patient may be human.
• the neointima formation may comprise restenosis.
• angiotensin I angiotensin I
• des-aspartate-angiotensin I for the preparation of a medicament for the treatment and/or prevention of cardiac hypertrophy, and/or neointima formation in a subject in need of such treatment or prevention.
• the patient may be human.
• the neointima formation may comprise restenosis.
• kits comprising at least one derivative of angiotensin I with the exclusions of des-aspartate-angiotensin I, wherein the kit is for the treatment and/or prevention of cardiac hypertrophy and/or neointima formation.
• the kit may further comprise information, illustration and/or indication pertaining to the use.
• the derivative of angiotensin I may be a derivative, homologue, analogue and/or chemical equivalent of angiotensin I.
• the derivative may be a derivative, homologue, analogue and/or chemical equivalent of angiotensin IV.
• the at least one derivative is angiotensin IV.
• the derivative may be prepared, used and/or administered in an effective amount.
• the effective amount may be 10 to 500 ⁇ g/kg/day or 50 to 250 ⁇ g/kg/day.
• the derivative is prepared, used and/or administered in an effective amount of about 150 ⁇ g/kg/day for the treatment and/or prevention of cardiac hypertrophy, and in about 200 ⁇ g/kg/day for the treatment and/or prevention of neointima formation and/or restenosis.
• the derivative, medicament or the pharmaceutical composition according to the invention may be administered in solid or liquid form.
• the derivative may be administered together with a pharmaceutically acceptable carrier, excipient, diluent and/or adjuvant. Further, the derivative may be administered in conjunction with at least one pharmaceutical agent.
• the at least one pharmaceutical agent is an angiotensin converting enzyme inhibitor, an angiotensin receptor antagonist, and/or at least one type of stem cell.
• the present invention relates to a new use in medicine for at least one derivative of angiotensin I.
• the invention relates to the use in medicine of at least one derivative of angiotensin I, with the exclusion of des-aspartate-angiotensin I.
• the derivative used in the present invention may be a derivative, homologue, analogue and/or chemical equivalent of angiotensin I.
• the derivative may be angiotensin IV.
• angiotensin I at least one derivative of angiotensin I, with the exclusion of des-aspartate-angiotensin I, for the treatment and/or prevention of cardiac hypertrophy and/or neointima formation in a subject in need of such treatment and/or prevention.
• angiotensin IV which is a derivative of angiotensin I
• cardiac hypertrophy, and/or neointima formation/restenosis in a rat as an example of a mammalian subject following experimentally-induced cardiac hypertrophy and/or neointima formation or restenosis were determined.
• one aspect of the present invention relates to the use of derivatives of angiotensin I, with the exception of des-aspartate-angiotensin I, for the treatment and/or prevention of cardiac hypertrophy, and/or neointima formation or restenosis.
• the at least one derivative of angiotensin I is administered in the form of an affective amount for the treatment and/or prevention of cardiac hypertrophy, and/or neointima formation or restenosis.
• Another aspect of the present invention is the use of an effective amount of a derivative of angiotensin I, with the exception of des-aspartate-angiotensin I, for the preparation of a medicament for the treatment and/or prevention of cardiac hypertrophy, and/or neointima formation or restenosis.
• the medicament may be administered in conjunction with at least one pharmaceutically acceptable carrier, excipient, diluent and/or adjuvant.
• the medicament may also be administered in conjunction with a further pharmaceutical agent (or compound).
• kits comprising a derivative of angiotensin I other than des-aspartate-angiotensin I.
• the kit is for the treatment or prevention of cardiac hypertrophy, and/or neointima formation or restenosis.
• the kit may comprise information, illustrations and/or instructions pertaining to the use of the derivative of angiotensin I.
• the present invention also provides a pharmaceutical composition
• a pharmaceutical composition comprising an effective amount of at least one derivative of angiotensin I, with the exclusion of des- aspartate-angiotensin I, and a pharmaceutically acceptable carrier, excipient, diluent and/or carrier.
• the pharmaceutical composition may also comprise at least one pharmaceutical agent.
• a pharmaceutical agent may be, for example, at least one angiotensin converting enzyme inhibitor, at least one angiotensin receptor antagonist, at least one type of stem cell, and the like.
• the pharmaceutical composition according to the invention is for use in the treatment and/or prevention of cardiac hypertrophy and/or neointima formation in a subject in need of such treatment and/or prevention
• cardiac hypertrophy is the enlargement of the heart or any part of the heart, due to the condition of high blood pressure or any other cause.
• Neointima formation is the formation of undifferentiated or multi-types of new tissue in blood vessels due to injury or any other cause and includes restenosis.
• Restenosis is the re-narrowing, as in of a blood vessel, for example, the re-narrowing of a coronary artery after angioplasty. As used herein, restenosis can also be due to any other cause.
• cardiac hypertrophy neointima formation
• restenosis are used in the broadest sense.
• an “effective amount” refers to an amount effective, at dosages and for periods of time necessary to achieve the desired therapeutic result, such as to prevent, inhibit or delay the onset of cardiac hypertrophy, and/or neointima formation or restenosis or ameliorate the symptoms of cardiac hypertrophy, and/or neointima formation or restenosis.
• the effective amount may vary according to various factors such as the disease state, age, sex, and weight of the individual.
• the effective amount may range from 10 to 500 ⁇ g/kg/day for mammalian patients or subjects. More specifically, the effective amount may range from 50 to 250 ⁇ g/kg/day. Yet more specifically, the effective amount is about 150 ⁇ g/kg/day for cardiac hypertrophy and about 200 mg/kg/day for neointima formation in human patients.
• a “derivative of angiotensin I” refers to any mutant, fragment, part or portion of angiotensin I, with the exclusions of des-aspartate-angiotensin I 1 but including molecules comprising single or multiple amino acid substitutions, deletions and/or insertions to angiotensin I and which inhibits, reduces or interferes with the activity or function of angiotensin II, or homologue, analogue or chemical equivalent thereof which is functionally equivalent in that it inhibits, reduces or otherwise interferes with the activity or functioning of angiotensin II.
• lnsertional amino acid sequence derivatives are those that include an addition of one or more amino acid residues. The addition may be introduced into a predetermined site or by random insertion with suitable screening of the resulting products.
• An amino acid insertional derivative of angiotensin I may include amino and/or carboxyl terminal fusions as well as intra-sequence insertions of single or multiple amino acids.
• Deletional derivatives are characterized by the removal of one or more amino acids from the sequence. Substitutional amino acid derivatives are those in which at least one residue in the sequence has been removed and a different residue inserted in its place.
• a homologue of an angiotensin I derivative includes functionally, structurally or stereochemical similar polypeptides but with the exclusion of des-aspartate- angiotensin I, obtained from other species such as livestock animals and laboratory test animals, including rodents and primates.
• An analogue of an angiotensin I derivative includes a mimotope, or peptide or analogue mimetic and includes molecules which contain non-naturally occurring amino acids as well as molecules which do not contain amino acids but nevertheless behaves as a functional equivalent, with the exclusion of des-aspartate-angiotensin I.
• Analogues contemplated herein include modifications to side chains, including deglycosylation or glycosylation, incorporation of unnatural amino acids and/or their derivatives during peptide synthesis and the use of crosslinkers and other methods which impose conformational constraints on the peptide molecule.
• Analogues also include angiotensin I derivatives coupled directly or indirectly to at least one modifying group while retaining the functionality of the derivative.
• modifications are well known in the art and include, for example, a derivative modified to alter a pharmacokinetic property, such as in vivo stability, bioavailability or half-life.
• the derivative may also be coupled to an additional therapeutic moiety or to a detectable substance.
• Examples of unconventional (or unnatural) amino acids and/or their derivatives which may be incorporated during peptide synthesis include, but are not limited to, use of norleucine, 4-amino butyric acid, 4-amino-3-hydroxy-5-phenylpentanoic acid, 6- aminohexanoicacid, t-butylglycine, norvaline, phenylglycine, ornithine, sarcosine, 4- amino-3-hydroxy-6-methylheptanoic acid, 2-thienyl alanine and/or D-isomers of amino acids.
• These types of modifications may be important to stabilize a derivative of angiotensin I, excluding des-aspartate-angiotensin I and -angiotensin Il but including angiotensin IV. This may be important, for example, in the manufacture of a therapeutic composition or if angiotensin I derivative is used
• Non-conventional Code Non-conventional Code amino acid amino acid
• D-N-methylcysteine Dnmcys N-(3,3-diphenylpropyl)glycine Nbhe D-N-methylglutamine Dnmgln N-(3-guanidinopropyl)glycine Narg
• a chemical equivalent of an angiotensin I derivative as described above shares conformational or functional similarities and may not necessarily be derived from the derivative of angiotensin I.
• a chemical equivalent may be specifically designed to mimic certain physiochemical properties of a derivative of angiotensin I.
• Chemical equivalents may be chemically synthesized or may be detected following, for example, natural product screening of candidate compounds which can inhibit, reduce or otherwise interfere with the activity, or functioning of angiotensin Il using assays described below.
• a derivative of angiotensin I as defined herein may readily be made using synthetic techniques well known in the art, such as solid phase peptide synthesis and the like, or by recombinant DNA manipulations. Techniques for making substitution mutations at predetermined sites in DNA having known or partially known sequence are well known and include, for example, M13 mutagenesis. The manipulation of DNA sequence to produce variant proteins, which manifest as substitutional, insertional or deletional variants are conveniently described, for example, in Sambrook et al.
• a derivative of angiotensin I according to the invention may be readily identified, for example, by its ability to act as an agonist on an indomethacin-sensitive angiotensin receptor or its ability to induce relaxation of a pre-contracted cardiac end of a rabbit pulmonary artery or its ability to attenuate angiotensin ll-induced hypertrophy in cultured rat neonatal cardiomyocytes.
• angiotensin IV or derivative, homologue, analogue or chemical equivalent thereof.
• the term derivative in this context has the same meaning as used in the context of angiotensin I as described above.
• homologue or analogue and chemical equivalent as used in this context has the same meaning as described above for angiotensin I derivative generally. It is well known in the art that modifications and changes can be made to the structure of a peptide without substantially altering the biological function of that peptide. To this end, where angiotensin IV is derivatized by amino acid substitution, the amino acids are generally replaced by other amino acids having like properties,
• Amino acid substitutions are typically of single residues. Amino acid insertions will usually be in the order of about 1 to 6 amino acid residues and deletions will range from about 1 to 6 residues.
• angiotensin I derivative and angiotensin IV should be read as including reference to all functionally equivalent forms, including, by way of example, isoforms, monomeric, dimeric and multimeric forms.
• an effective amount of the derivative of angiotensin I such as but not limited to angiotensin IV or a derivative, homologue, analogue or chemical equivalent thereof or a medicament or pharmaceutical composition containing the same, as described below, is administered in a solid or liquid form, to a subject, such as a human patient, via any acceptable method known in the art, either singly or in combination with other pharmaceutical agents.
• “Pharmaceutical agent” means any diagnostic and/or therapeutic drug or combination of drugs that has the property of assisting the medical or pharmaceutical use of the derivative of angiotensin I according to the invention.
• pharmaceutical agent means any diagnostic and/or therapeutic drug or combination of drugs that has the property of assisting in the treatment and/or prevention of cardiac hypertrophy and/or neointima formation.
• pharmaceutical agents include angiotensin converting enzyme inhibitors such as captopril or other angiotensin receptor antagonists such as losartan, or stem cells of any types or origin.
• the compound, composition and/or medicament according to the invention may be administered orally, by suppository, or parenterally (e.g. intramuscularly, intravenously, subcutaneously or intradermally), and in the form of either solid or liquid dosage including tablets, suspensions, or solutions, as is discussed in more detail below.
• the administration may be conducted in single dosage form with continuous therapy or in single dose therapy ad libitum.
• compositions may take the form of tablets, pills, capsules, powders, enterically coated or other protected formulations, sustained release formulations, erodible formulations, implantable devices or components thereof, microsphere formulations, solutions, suspensions, elixirs, aerosols and the like.
• Water, saline, aqueous dextrose, and glycols are preferred liquid carriers, particularly (when isotonic) for injectable solutions.
• the carrier may be selected from various oils including those of petroleum, animal, vegetable or synthetic origin, for example, peanut oil, soybean oil, mineral oil, sesame oil, and the like.
• Suitable pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol, and the like.
• compositions may be subjected to conventional pharmaceutical expedients such as sterilization and may contain conventional pharmaceutical additives such as preservatives, stabilizing agents, wetting or emulsifying agents, salts for adjusting osmotic pressure, buffers and the like.
• suitable pharmaceutical carriers and their formulations are described in Martin, "Remington's Pharmaceutical Sciences", 15 th Ed.; Mack Publishing Co., Easton (1975); see, e.g. pp. 1405-1412 and pp 1461-1487.
• Such compositions will, in general, contain an effective amount of the active compound together with a suitable amount of at least one pharmaceutically acceptable carrier, excipient, diluent and/or adjuvant so as to prepare the proper dosage form for proper administration to the host.
• the particular dosage of pharmaceutical composition to be administered to the subject will depend on a variety of consideration including the stage of the disease or condition, the severity thereof, the schedule of administration, the age and physical characteristics of the subject, and so forth. Proper dosages may be established using clinical approaches familiar to the medicinal arts.
• angiotensin I derivatives according to the invention in any mammal subject including, but not limited to, humans, mice, rabbits, livestock animals and primates.
• Angiotensin IV as an example of an Angiotensin I derivative, was obtained from Bachem (Dubendorf, Switzerland). Angiotensin IV can be prepared by techniques well known in the art.
• SD rats 200-220 g for cardiac hypertrophy experiment, and 340-360 g for the neointima formation experiment) were obtained from the Animal Center, National University of Singapore.
• Example 2 Induction of Cardiac Hypertrophy
• the experimental protocol for induction of cardiac hypertrophy in rats was carried out as described by Everett et al (Hypertension, 23:587-592 (1994)).
• each rat was anaesthetized with 7% w/v chloral hydrate (0.35 g/kg, intraperitoneally).
• An incision was made in the ventral abdominal wall to access the suprarenal portion of the abdominal aorta. This portion of the abdominal aorta was dissected free and a blunt 23-guage needle was placed adjacent to the aorta.
• a ligature was placed around the blunt needle and the aorta. The blunt needle was then removed, leaving the aorta constricted to the size of the needle.
• the resulting coarctation resisted the normal flow of blood from the heart to the lower portion of the body and placed an
• Example 3 Treatment with Angiotensin IV and Measurement of Cardiac Hypertrophy Following surgery, each animal was placed in a cage. The animals had access to water and rat chow ad libitum. The animals were randomly divided into the control group and treatment group. Each group consisted of 10 animals. The treatment group was orally administered various doses of angiotensin IV (95 - 380 nmoles/kg/day or 74-294 ⁇ g/kg/day) dissolved in 0.5 ml saline for four days commencing on the day of surgery. Control animals with coarcted abdominal aorta were administered saline instead of the angiotensin IV solution. Sham animals were animals that underwent the same surgical operations but their aortas were not coarcted.
• angiotensin IV 95 - 380 nmoles/kg/day or 74-294 ⁇ g/kg/day
• Example 4 Effect of Angiotensin IV on Cardiac Hypertrophy
• Table 2 Data were expressed as mean ⁇ SEM. Significant differences were determined by one-way ANOVA and post hoc Newman Kleuf test. The accepted level of significance was p ⁇ 0.05.
• Angiotensin IV as an example of a derivative of angiotensin I, was shown to be an effective agent in attenuating the index of hypertrophy in experimentally-induced cardiac hypertrophic rats. The effect was dose-dependent and significant anti-cardiac hypertrophic action was brought about by an oral dose of 190 nmoles/kg/day (or 147 ⁇ g/kg/day).
• SD rats were subjected to left carotid artery injury by the balloon technique according to the method described by lndolfi et al (Circulation, 92:1230-1235 (1995)).
• rats were anesthetized with chloral hydrate (0.35 g/kg) and a balloon catheter (2F Fogarty, Edwards Laboratories) was introduced through the left external carotid artery into the common carotid artery.
• the balloon was inflated to a pressure of 2.2 kg/cm 2 by compressed carbogen gas mixture (95% O 2 and 5% CO 2 ) and passed three times (three cycles) along the common carotid artery.
• the catheter was removed, the left external carotid artery was ligated, and the wound was closed. Formation of neointima in the catheter-injured carotid artery occurred and slowed considerably after 14 days (Clowes and Clowes, Lab. Invest, 52:611-616 (1985)). The right common carotid artery was left intact and served as the control artery.
• Example 6 Treatment with Angiotensin IV and Quantitation of Neointima Formation. Following the surgery, each animal was placed in a cage. The animals had access to water and rat chow ad libitum. The animals were randomly divided into the control group and treatment group. Each group consisted of 6 animals. The treatment group was orally administered various doses of angiotensin IV (60-360 nmoles/kg/day or 46.5-279 ⁇ g/kg/day) dissolved in 0.5 ml saline for 13 days commencing on the day of surgery. Control animals were balloon catheterized animals that were administered saline instead of the angiotensin IV solution.
• angiotensin IV 60-360 nmoles/kg/day or 46.5-279 ⁇ g/kg/day
• Sections of 10 ⁇ m thickness were prepared and stained with toluidine blue. Twenty of such sections were cut from the midportion of the artery towards the distal end and used for morphometric evaluation of neointima formation.
• the area of the medial smooth muscle cells, lumen, and neointima of each section was morphometrically quantitated using an image analysis system consisting of a
• neointima formation was expressed as a percentage of occlusion of the lumen by the neointima.
• Example 7 Effect of Angiotensin IV on Neointima formation
• Angiotensin IV as an example of a derivative of angiotensin I, has been found to be an effective agent in preventing the formation of neointima resulting from balloon catheterization.
• the anti-neointima action is dose-dependent and its maximum action is brought about by an oral dose of 240 nmoles/kg/day (or 186 ⁇ g/kg/day) for 13 days.
• angiotensin IV has no

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