EP2066338A2 - Use of growth hormone secretagogues to block or inhibit the renin-angiotensin system - Google Patents

Use of growth hormone secretagogues to block or inhibit the renin-angiotensin system

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Publication number
EP2066338A2
EP2066338A2 EP07825260A EP07825260A EP2066338A2 EP 2066338 A2 EP2066338 A2 EP 2066338A2 EP 07825260 A EP07825260 A EP 07825260A EP 07825260 A EP07825260 A EP 07825260A EP 2066338 A2 EP2066338 A2 EP 2066338A2
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EP
European Patent Office
Prior art keywords
angiotensin
growth hormone
ace
renin
activity
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Ceased
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EP07825260A
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German (de)
French (fr)
Inventor
Vittorio Locatelli
Antonio Biagio Torsello
Elena Bresciani
Ilaria Bulgarelli
Laura Tamiazzo
Monica Ravelli
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Universita degli Studi di Milano Bicocca
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Universita degli Studi di Milano Bicocca
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Publication of EP2066338A2 publication Critical patent/EP2066338A2/en
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    • 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
    • A61K38/25—Growth hormone-releasing factor [GH-RF], i.e. somatoliberin

Definitions

  • the present invention relates to the use of natural and synthetic ghrelin analogues and growth hormone secretagogue (GHS) receptor agonists and antagonists for the treatment of disorders wherein it is desirable to inhibit the activity of the renin-angiotensin system, such as hypertension and other cardiovascular disorders, hypertension in pregnancy, and in some medical conditions in which it has been suggested that ACE inhibitors may have favourable effects, such as glucose metabolism disorders, dyslipidaemia, appetite and energy metabolism disorders, and inflammatory states.
  • GRS growth hormone secretagogue
  • ACE angiotensin-converting enzyme
  • ARB angiotensin Il receptor blockers
  • the mechanisms whereby the block of the RAS system leads to an increase in insulin sensitivity are multifactorial.
  • Activation of the bradykinin- nitric oxide system is involved in this process, and leads to increased translocation of glucose transporter 4 (GLUT4) and increased plasma levels of adiponectin (a cytokine of adipocyte origin that reduces insulin resistance) as a result of the reduction in angiotensin Il levels (7, 20).
  • adiponectin a cytokine of adipocyte origin that reduces insulin resistance
  • telmisartan is an ARB whose antihyperglycaemic effect goes beyond the antagonist activity on the angiotensin Il receptor. This effect is mediated by an action on PPAR- ⁇ , and is not shared to the same extent by other ARBs.
  • the activity of telmisartan and irbesartan on PPAR- ⁇ indicates that these compounds may provide better control of insulin sensitivity than other ARBs and ACE-inhibitors (2).
  • ACE-inhibitors are known to cause an increase in the circulating levels of N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP; goralatide) in humans and rats (1). This increase may in turn be responsible for some favourable effects of treatment with ACE-inhibitors, such as inhibition of cell proliferation stimulated by angiotensin II, inhibition of macrophage and mast- cell infiltration, and inhibition of collagen deposition in the left cardiac ventricle (15, 17).
  • thiazide diuretics only slightly increase the risks, in the low dose range, whereas ⁇ -blockers are only indicated in patients with coronary cardiovascular disease or thyreotoxicosis, or in cases of arterial hypertension which are difficult to control.
  • ACE-inhibitors and ARBs have favourable effects on glucose metabolism, and can be considered the first- choice antihypertensive treatment in obese patients.
  • GHS Growth hormone secretagogues
  • GHSs exhibit endocrine activity only, others extraendocrine activity only, and others a combination of some endocrine and extraendocrine activities.
  • the first evidence of the vasoactive effects of ghrelin is represented by the report that intravenous administration of ghrelin to humans generates a significant reduction in blood pressure without altering the heart rate (13).
  • Specific binding sites for GHS, especially GHS-RIa and CD36 are expressed in the human and rat cardiovascular system (11 , 13).
  • the administration of peptidyl GHS has proved effective in protecting the myocardium against post-ischaemic damage in the rat (12, 21).
  • Ghrelin and other GHSs also stimulate the appetite in both humans and laboratory animals.
  • the present invention relates to the use of natural and synthetic analogues of ghrelin and synthetic compounds with agonist and antagonist activity on the growth hormone secretagogue receptors which blocks or inhibits the renin-angiotensin system in man, in particular by interfering with the activity of the circulating and/or tissue ACE enzyme (and its isotypes) and/or with the angiotensin Il receptors and/or with the breakdown of peptide Ac-SDKP, to prepare drugs useful for the treatment of disorders wherein it is desirable to reduce the activity of the renin-angiotensin system, such as hypertension, hypertension in pregnancy, glucose metabolism disorders, dyslipidaemia, appetite and energy metabolism disorders, cardiovascular disease and inflammatory states.
  • the present invention relates to the use of peptides, pseudopeptides
  • the invention relates to the use of natural and synthetic ghrelin analogues and growth hormone secretagogue receptor agonists and antagonists to prepare medicinal products which block or inhibit the renin-angiotensin system.
  • These medicinal products could be advantageously used to treat hypertension, hypertension in pregnancy, glucose metabolism disorders, dyslipidaemia, appetite and energy metabolism disorders, cardiovascular disease and inflammatory states.
  • Examples of compounds which can be used according to this invention are the hexapeptide hexarelin and analogues thereof, disclosed in WO 91/18016, WO 96/10040, WO 01/96300, WO 02/08250 and WO 03/004518.
  • Non-peptide ghrelin antagonists are described in WO 2005/30734.
  • Examples of peptidomimetic growth hormone secretagogues are described in WO 96/15148, while pseudopeptides are known from WO 2005/105828.
  • Hexarelin and its derivatives or analogues are particularly preferred.
  • the structural formulas of said analogues or derivatives are reported in the Table.
  • the GHS receptor agonists or antagonists will typically be administered orally or parenterally, depending on the pharmacokinetic characteristics of each specific compound.
  • the effective therapeutic doses may be determined by one skilled in the art on the basis of the pharmacokinetic, pharmacodynamic and toxicology data. Said doses may be equal to, lower or higher than those already known or under study for the known indications of natural and synthetic ghrelin analogue compounds and growth hormone secretagogue receptor agonists and antagonists. Broadly speaking, the effective doses will presumably be of at least the same order of magnitude as for the traditional indications.
  • ACE activity in serum and tissue was determined by the spectophotometric method, (14) using commercial reagents (Sigma-Aldrich, St Louis, USA). Briefly, the method is based on the ability of the ACE enzyme to convert the compound hippuryl-histidyl-leucine (Hip-His-Leu) into histidyl-leucine (His-Leu). In the presence of orthophthalaldehyde, hydrolysis of the tripeptide Hip-His-Leu into His-Leu leads to increased fluorescence (excitation 365 nm, emission 495 nm). The human serum used for the tests was obtained from non-hypertensive male subjects not undergoing treatment with ACE- inhibitors. The samples were maintained at -80 0 C until the time of use for the ACE activity determination procedures.
  • the experiments on animals were conducted in Sprague-Dawley rats weighing 175-200 g.
  • the ACE activity in the serum was determined on 10 ⁇ l of human or rat serum.
  • the tissue samples were homogenised in 10 volumes of PBS.
  • the determinations of ACE activity were performed with 100 ⁇ l of tissue homogenate.
  • Example 1 Study of the effects of GHS on human and rat ACE The results of this experiment, reported in the annexed Figure, demonstrate that some peptide GHSs inhibit ACE activity in human plasma in vitro. This effect is qualitatively comparable with the effect observed with the classic ACE-inhibitor enalapril.
  • the ACE-inhibiting activity of GHSs proved to be independent of their ability to stimulate GH secretion.
  • Example 2 Study of the dose-effect relationship in the inhibitory effect of some GHSs on human or rat serum ACE.
  • hexarelin, EP80317, EP71563, EP70905, EP70555, EP80279, JMV2214, JMV2096 and JMV2097 tested in a concentration range between 1 and 100 ⁇ M, significantly inhibited the ACE activity present in the sample.
  • ACE-inhibiting activity is not correlated with the peptide nature of GHS, as it is also shared by peptidomimetic molecules.
  • Example 3 Study of the effects of GHS on ACE activity in rat tissue samples

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Endocrinology (AREA)
  • Immunology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Zoology (AREA)
  • Medicinal Chemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The invention relates to the preparation of drugs useful in the treatment of hypertension and cardiovascular disease, glucose metabolism disorders, dyslipidaemia, appetite and energy metabolism disorders and inflammatory states, through the administration of compounds which are natural and/or synthetic ghrelin analogues and growth hormone secretagogue receptor agonists and antagonists which block or inhibit the renin-angiotensin system in humans by interfering with the activity of the circulating and tissue ACE enzyme and/or with the angiotensin Il receptors and/or with the breakdown of peptide Ac-SDKP.

Description

USE QF GROWTH HORMONE SECRETAGOGUES TO BLOCK OR INHIBIT THE RENIN-ANGIOTENSIN SYSTEM
The present invention relates to the use of natural and synthetic ghrelin analogues and growth hormone secretagogue (GHS) receptor agonists and antagonists for the treatment of disorders wherein it is desirable to inhibit the activity of the renin-angiotensin system, such as hypertension and other cardiovascular disorders, hypertension in pregnancy, and in some medical conditions in which it has been suggested that ACE inhibitors may have favourable effects, such as glucose metabolism disorders, dyslipidaemia, appetite and energy metabolism disorders, and inflammatory states. BACKGROUND TO THE INVENTION
Arterial hypertension is a very common disorder among the general population, and in the Western world it is a frequent complication of excess weight and obesity. It is well known that both obesity and hypertension are important components of insulin-resistance syndrome (3). Many hypertensive patients develop type 2 diabetes, which in turn increases the cardiovascular risk. Thiazide diuretics and β-blockers were used for decades as first-choice drugs in the treatment of hypertension, but although they effectively controlled the blood pressure, their use was often associated with the appearance of glucose intolerance. (9). Moreover, treatment with β-blockers is associated with weight increase, which is an important factor in glucose intolerance and diabetes. Conversely, the functional block of the renin-angiotensin system (17) by administering angiotensin-converting enzyme (ACE) inhibitors or angiotensin Il receptor blockers (ARB) has led to a significant improvement in sensitivity to insulin (6). In view of the possible adverse effects of antihypertensive agents on glucose metabolism, the initial choice of antihypertensive treatment is important for limiting the onset of further cardiovascular risk factors.
Studies carried out on animals and humans demonstrate that an excessive weight increase is associated with an increase in renal sympathetic tone, and leads to an increase in sodium retention (16). Activation of the RAS system contributes to an increase in oxidative stress, vascular remodelling, and the blood pressure response to physical exercise. The activation of the sympathetic nervous system which is observed in obesity is partly mediated by leptin, a hormone secreted by adipocytes, which increases in circulation in proportion to adiposity. An increase in the circulating levels of leptin in hypertensive patients is associated with an increase in plasma renin activity, and in aldosterone and angiotensin Il levels (19).
The mechanisms whereby the block of the RAS system leads to an increase in insulin sensitivity are multifactorial. Activation of the bradykinin- nitric oxide system is involved in this process, and leads to increased translocation of glucose transporter 4 (GLUT4) and increased plasma levels of adiponectin (a cytokine of adipocyte origin that reduces insulin resistance) as a result of the reduction in angiotensin Il levels (7, 20). Several clinical trials have proved that blocking the RAS system by administering ACE-inhibitors or ARB can significantly reduce the incidence of onset of diabetes. The LIFE (6) and VALUE (10) studies have demonstrated that two ACE-inhibitors, losartan and valsartan, reduce the incidence of onset of diabetes more than treatment with β-blockers and Ca-antagonists. Telmisartan is an ARB whose antihyperglycaemic effect goes beyond the antagonist activity on the angiotensin Il receptor. This effect is mediated by an action on PPAR-γ, and is not shared to the same extent by other ARBs. The activity of telmisartan and irbesartan on PPAR-γ indicates that these compounds may provide better control of insulin sensitivity than other ARBs and ACE-inhibitors (2).
Reportedly, during the onset of diabetes mellitus a correlated increase in the inflammatory biomarker levels takes place, a finding which supports a possible role of inflammation in diabetogenesis. The levels of C-reactive protein, the classic marker for systemic inflammation, are substantially higher in overweight and obese than thin individuals (22). Inhibition of the angiotensin receptors seems to correlate with a reduction in systemic inflammation markers (8), an effect which could explain the favourable effects of ACE-inhibitors and ARBs in preventing diabetes mellitus in obese and overweight patients.
Some ACE-inhibitors are known to cause an increase in the circulating levels of N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP; goralatide) in humans and rats (1). This increase may in turn be responsible for some favourable effects of treatment with ACE-inhibitors, such as inhibition of cell proliferation stimulated by angiotensin II, inhibition of macrophage and mast- cell infiltration, and inhibition of collagen deposition in the left cardiac ventricle (15, 17).
It is known that obese and hypertensive patients are often insulin-resistant, with a high risk of developing type 2 diabetes. This risk is exacerbated by treatment with thiazide diuretics and β-blockers. In general, thiazide diuretics only slightly increase the risks, in the low dose range, whereas β-blockers are only indicated in patients with coronary cardiovascular disease or thyreotoxicosis, or in cases of arterial hypertension which are difficult to control. However, ACE-inhibitors and ARBs have favourable effects on glucose metabolism, and can be considered the first- choice antihypertensive treatment in obese patients.
Conversely, it is well known that neither ACE-inhibitors nor ARBs should be taken during pregnancy. It has been reported that both ACE-inhibitors and ARBs can cause permanent, and sometimes lethal foetotoxic effects if administered in the 2nd or 3rd trimester of pregnancy, and there is good reason to suspect teratogenicity if they are used during the first trimester (18).
Growth hormone secretagogues (GHS) are a group of natural and synthetic molecules whose archetype, synthesised in the early 1980s, exhibited a potent GH-secretagogue activity (5). These compounds act synergically with GHRH in vivo, and additively in vitro on GH secretion through interaction with a specific receptor, GHS-RIa. Ghrelin is an endogenous peptide of 28 amino acids which binds specifically to GHS-RIa and effectively stimulates GH release and appetite. In addition to its ability to modify GH secretion, and to a lesser extent of PRL and Cortisol, different GHSs seem to have other extraendocrine activities. Some GHSs exhibit endocrine activity only, others extraendocrine activity only, and others a combination of some endocrine and extraendocrine activities. The first evidence of the vasoactive effects of ghrelin is represented by the report that intravenous administration of ghrelin to humans generates a significant reduction in blood pressure without altering the heart rate (13). The cardiovascular effects of hexarelin, a synthetic GHS, had already been demonstrated (4). Specific binding sites for GHS, especially GHS-RIa and CD36, are expressed in the human and rat cardiovascular system (11 , 13). The administration of peptidyl GHS has proved effective in protecting the myocardium against post-ischaemic damage in the rat (12, 21). Ghrelin and other GHSs also stimulate the appetite in both humans and laboratory animals.
DESCRIPTION OF THE INVENTION
The present invention relates to the use of natural and synthetic analogues of ghrelin and synthetic compounds with agonist and antagonist activity on the growth hormone secretagogue receptors which blocks or inhibits the renin-angiotensin system in man, in particular by interfering with the activity of the circulating and/or tissue ACE enzyme (and its isotypes) and/or with the angiotensin Il receptors and/or with the breakdown of peptide Ac-SDKP, to prepare drugs useful for the treatment of disorders wherein it is desirable to reduce the activity of the renin-angiotensin system, such as hypertension, hypertension in pregnancy, glucose metabolism disorders, dyslipidaemia, appetite and energy metabolism disorders, cardiovascular disease and inflammatory states.
The present invention relates to the use of peptides, pseudopeptides
(peptoids), peptidomimetic compounds, peptidyl derivatives and non-peptidyl compounds with a GHS receptor agonist, endowed with partial agonist or antagonist activity to prepare medicinal products which block or inhibit the renin- angiotensin system.
In particular the invention relates to the use of natural and synthetic ghrelin analogues and growth hormone secretagogue receptor agonists and antagonists to prepare medicinal products which block or inhibit the renin-angiotensin system. These medicinal products could be advantageously used to treat hypertension, hypertension in pregnancy, glucose metabolism disorders, dyslipidaemia, appetite and energy metabolism disorders, cardiovascular disease and inflammatory states.
Examples of compounds which can be used according to this invention are the hexapeptide hexarelin and analogues thereof, disclosed in WO 91/18016, WO 96/10040, WO 01/96300, WO 02/08250 and WO 03/004518. Non-peptide ghrelin antagonists are described in WO 2005/30734. Examples of peptidomimetic growth hormone secretagogues are described in WO 96/15148, while pseudopeptides are known from WO 2005/105828.
Hexarelin and its derivatives or analogues (especially those known by the codes EP 71563, EP 80317, EP 70905, EP 70555, EP 80279, EP 80874, EP 255, EP 256, EP 71180, EP 80089, EP 70760, EP 92440 and EP 930497) are particularly preferred. The structural formulas of said analogues or derivatives are reported in the Table.
The GHS receptor agonists or antagonists will typically be administered orally or parenterally, depending on the pharmacokinetic characteristics of each specific compound. The effective therapeutic doses may be determined by one skilled in the art on the basis of the pharmacokinetic, pharmacodynamic and toxicology data. Said doses may be equal to, lower or higher than those already known or under study for the known indications of natural and synthetic ghrelin analogue compounds and growth hormone secretagogue receptor agonists and antagonists. Broadly speaking, the effective doses will presumably be of at least the same order of magnitude as for the traditional indications.
The invention is illustrated in greater detail in the following examples. ACE activity in serum and tissue was determined by the spectophotometric method, (14) using commercial reagents (Sigma-Aldrich, St Louis, USA). Briefly, the method is based on the ability of the ACE enzyme to convert the compound hippuryl-histidyl-leucine (Hip-His-Leu) into histidyl-leucine (His-Leu). In the presence of orthophthalaldehyde, hydrolysis of the tripeptide Hip-His-Leu into His-Leu leads to increased fluorescence (excitation 365 nm, emission 495 nm). The human serum used for the tests was obtained from non-hypertensive male subjects not undergoing treatment with ACE- inhibitors. The samples were maintained at -800C until the time of use for the ACE activity determination procedures.
The experiments on animals were conducted in Sprague-Dawley rats weighing 175-200 g. The blood, from which the serum was subsequently separated, and samples of lung, kidneys, heart, muscle, adipose tissue, testicles and abdominal aorta, were removed from each rat.
The ACE activity in the serum was determined on 10 μl of human or rat serum. The tissue samples were homogenised in 10 volumes of PBS. The determinations of ACE activity were performed with 100 μl of tissue homogenate.
The standard curve was prepared with known concentrations (6.2-100 μM) of His-Leu. The fluorescence of the samples and the standard curve were measured with a Wallace Victor2 multifunction spectrophotometer. Example 1 : Study of the effects of GHS on human and rat ACE The results of this experiment, reported in the annexed Figure, demonstrate that some peptide GHSs inhibit ACE activity in human plasma in vitro. This effect is qualitatively comparable with the effect observed with the classic ACE-inhibitor enalapril.
Similar results were obtained with rat plasma.
Surprisingly, the ACE-inhibiting activity of GHSs proved to be independent of their ability to stimulate GH secretion.
Example 2: Study of the dose-effect relationship in the inhibitory effect of some GHSs on human or rat serum ACE.
In this study, numerous synthetic GHSs among those tested were found to inhibit the ACE activity present in human and rat serum, to a concentration-dependent extent.
By way of example, hexarelin, EP80317, EP71563, EP70905, EP70555, EP80279, JMV2214, JMV2096 and JMV2097, tested in a concentration range between 1 and 100 μM, significantly inhibited the ACE activity present in the sample. ACE-inhibiting activity is not correlated with the peptide nature of GHS, as it is also shared by peptidomimetic molecules.
Once again, the ACE-inhibiting activity of GHSs proved to be entirely unrelated to their GH-stimulating activity.
Example 3: Study of the effects of GHS on ACE activity in rat tissue samples
In this study hexarelin, EP80317 and various other GHSs tested in the concentration range of 1-100 μM were found to significantly inhibit the ACE activity present in rat lung, kidney and testicle samples. REFERENCES
1. Azizi, M., Rousseau, A., Ezan, E., et al., Acute angiotensin-converting enzyme inhibition increases the plasma level of the natural stem cell regulator N-acetyl-seryl-aspartyl-lysyl-proline. J Clin Invest, 1996. 97: 839-44.
2. Benson, S. C, Pershadsingh, H.A., Ho, C. I., et al., Identification of telmisartan as a unique angiotensin Il receptor antagonist with selective PPARgamma-modulating activity. Hypertension, 2004. 43: 993-1002. 3. Bergman, R.N., Van Citters, G.W., Mittelman, S. D., et al., Central role of the adipocyte in the metabolic syndrome. J Investig Med, 2001. 49: 119-26.
4. Bisi, G., Podio, V., Valetto, M. R., et al., Acute cardiovascular and hormonal effects of GH and hexarelin, a synthetic GH-releasing peptide, in humans. J Endocrinol Invest, 1999. 22: 266-72.
5. Bowers, C. Y., Momany, F., Reynolds, G.A., Chang, D., Hong, A., and Chang, K., Structure-activity relationships of a synthetic pentapeptide that specifically releases growth hormone in vitro. Endocrinology, 1980. 106: 663-7. 6. Dahlof, B., Devereux, R. B., Kjeldsen, S. E., et al., Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet, 2002. 359: 995-1003.
7. Furuhashi, M., Ura, N., Higashiura, K., et al., Blockade of the renin-angiotensin system increases adiponectin concentrations in patients with essential hypertension. Hypertension, 2003. 42: 76-81.
8. Graninger, M., Reiter, R., Drucker, C, Minar, E., and Jilma, B., Angiotensin receptor blockade decreases markers of vascular inflammation. J Cardiovasc Pharmacol, 2004. 44: 335-9.
9. Gress, T.W., Nieto, F.J., Shahar, E., Wofford, M. R., and Brancati, F. L., Hypertension and antihypertensive therapy as risk factors for type 2 diabetes mellitus. Atherosclerosis Risk in Communities Study. N Engl J Med, 2000. 342: 905-12.
10. Julius, S., Kjeldsen, S. E., Weber, M., et al., Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet, 2004. 363: 2022-31.
11. Katugampola, S. D., Pallikaros, Z., and Davenport, A.P., [125l-His(9)]- ghrelin, a novel radioligand for localizing GHS orphan receptors in human and rat tissue: up-regulation of receptors with athersclerosis. Br J Pharmacol, 2001. 134: 143-9.
12. Locatelli, V., Rossoni, G., Schweiger, F., et al., Growth hormone-independent cardioprotective effects of hexarelin in the rat. Endocrinology, 1999. 140: 4024-31.
13. Nagaya, N., Kojima, M., Uematsu, M., et al., Hemodynamic and hormonal effects of human ghrelin in healthy volunteers. Am J Physiol Regul lntegr Comp Physiol, 2001. 280: R1483-1487.
14. Paula, R.D., Lima, C.V., Britto, R.R., Campagnole-Santos, M.J., Khosla, M. C, and Santos, R.A., Potentiation of the hypotensive effect of bradykinin by angiotensin-(1-7)-related peptides. Peptides, 1999. 20: 493-500.
15. Peng, H., Carretero, O. A., Vuljaj, N., et al., Angiotensin-converting enzyme inhibitors: a new mechanism of action. Circulation, 2005. 112: 2436-45.
16. Rahmouni, K., Correia, M. L., Haynes, W. G., and Mark, A.L., Obesity-associated hypertension: new insights into mechanisms. Hypertension, 2005. 45: 9-14. 17. Rasoul, S., Carretero, O. A., Peng, H., et al., Antifibrotic effect of Ac-SDKP and angiotensin-converting enzyme inhibition in hypertension. J Hypertens, 2004. 22: 593-603.
18. Schaefer, C, Angiotensin ll-receptor-antagonists: further evidence of fetotoxicity but not teratogenicity. Birth Defects Res A Clin MoI Teratol, 2003.
67: 591-4.
19. Schorr, U., Blaschke, K., Turan, S., Distler, A., and Sharma, A.M., Relationship between angiotensinogen, leptin and blood pressure levels in young normotensive men. J Hypertens, 1998. 16: 1475-80. 20. Shiuchi, T., Cui, T.X., Wu, L., et al., ACE inhibitor improves insulin resistance in diabetic mouse via bradykinin and NO. Hypertension, 2002. 40: 329-34.
21. Tivesten, A., Bollano, E., Caidahl, K., et al., The growth hormone secretagogue hexarelin improves cardiac function in rats after experimental myocardial infarction. Endocrinology, 2000. 141 : 60-6.
22. Visser, M., Bouter, L.M., McQuillan, G. M., Wener, M. H., and Harris, T. B., Elevated C-reactive protein levels in overweight and obese adults. Jama, 1999. 282: 2131-5.

Claims

1. Use of natural and synthetic analogues of ghrelin and growth hormone secretagogue receptor agonists and antagonists for the preparation of drugs able to block or inhibit the renin-angiotensin system by inhibiting the circulating and tissue ACE enzyme and/or the angiotensin Il receptors and/or the breakdown of peptide Ac-SDKP.
2. Use as claimed in claim 1 for the preparation of drugs for the prevention and treatment of hypertension and cardiovascular disease, glucose metabolism disorders, dyslipidaemia, appetite and energy metabolism disorders, and inflammatory states.
3. Use of growth hormone secretagogue receptor agonists as claimed in claim 1 or 2.
4. Use of growth hormone secretagogue receptor antagonists as claimed in claim 1 or 2.
5. Use as claimed in claim 3 or 4 wherein the ghrelin analogues or derivatives are selected from hexarelin and its analogues or derivatives.
EP07825260A 2006-10-05 2007-10-04 Use of growth hormone secretagogues to block or inhibit the renin-angiotensin system Ceased EP2066338A2 (en)

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PCT/IB2007/002934 WO2008041106A2 (en) 2006-10-05 2007-10-04 Use of growth hormone secretagogues to block or inhibit the renin-angiotensin system

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CN114984223B (en) * 2022-05-31 2023-06-20 中国人民解放军陆军军医大学第二附属医院 Use of growth hormone secretagogue receptor antagonists for the preparation of inhalation anesthetic resuscitation formulations

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EP1536817A1 (en) * 2002-08-23 2005-06-08 Gestion Univalor Société en Commandite Growth hormone-releasing peptides in the treatment of prevention of atherosclerosis and hypercholesterolemia
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Non-Patent Citations (1)

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Title
TORSELLO ANTONIO ET AL: "Novel domain-selective ACE-inhibiting activity of synthetic growth hormone secretagogues.", PHARMACOLOGICAL RESEARCH : THE OFFICIAL JOURNAL OF THE ITALIAN PHARMACOLOGICAL SOCIETY OCT 2012, vol. 66, no. 4, October 2012 (2012-10-01), pages 317 - 324, ISSN: 1096-1186 *

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