EP2066338A2 - Verwendung von wachstumshormon-sekretagogen zur sperrung oder hemmung des renin-angiotensin-systems - Google Patents
Verwendung von wachstumshormon-sekretagogen zur sperrung oder hemmung des renin-angiotensin-systemsInfo
- 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
- Authority
- EP
- European Patent Office
- Prior art keywords
- angiotensin
- growth hormone
- ace
- renin
- activity
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
Links
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/25—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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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITMI20061917 ITMI20061917A1 (it) | 2006-10-05 | 2006-10-05 | Utilizzo dei growth hormone secretagogues per bloccare o inibire l'attivit@ del sistema renina-angiotensina |
| 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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| EP07825260A Ceased EP2066338A2 (de) | 2006-10-05 | 2007-10-04 | Verwendung von wachstumshormon-sekretagogen zur sperrung oder hemmung des renin-angiotensin-systems |
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| WO2005039625A1 (en) * | 2003-10-28 | 2005-05-06 | Rheoscience A/S | Growth hormone secretagogue receptor agonists |
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| Title |
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| 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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