 oxintomodulin peptide analog, its use as well as pharmaceutical composition
专利摘要:
patent: "oxintomodulin peptide analog". The present invention relates to a useful oxytomodulin peptide analogue in the treatment of diabetes and / or obesity. 公开号:BR112012017348B1 申请号:R112012017348 申请日:2010-12-15 公开日:2019-11-05 发明作者:Alsina-Fernandez Jorge；David Kohn Wayne 申请人:Lilly Co Eli； IPC主号:
专利说明:
Descriptive Report of the Invention Patent for OXINTOMODULIN PEPTIDE ANALOG, ITS USE, AS WELL AS A PHARMACEUTICAL COMPOSITION. The present invention relates to oxintomodulin peptide analogs and their PEguilated derivatives for use in the treatment of diabetes and / or obesity. Oxytomodulin (OXM) is a peptide hormone with 37 amino acids that is released along with the Glucagon-like Peptide (GLP-1) by L cells of the small intestine in proportion to the intake of nutrients. It is composed of the complete sequence of 29 glucagon residues (Gcg) with an extension of the C-terminated octapeptide as a result of alternative processing specific to the preproglucagon tissue. Endogenous XM is rapidly degraded in vivo by dipeptidyl peptidase IV and other peptidases. Distinct receptors for OXM have not yet been identified. OXM binds and fully activates the GLP-1 receptor (GLP-1 R) and the glucagon receptor (GcgR) in vitro with similar potencies at the two receptors. OXM is involved in regulating food intake and body weight. Acute administration of OXM to normal-weight human subjects reduces hunger and decreases meal size by 19%. In a 4-week study of overweight and obese subjects, subcutaneous preprandial administration of OXM three times a day produced a weight loss of 2.3 kg compared to 0.5 kg in the placebo group. In that test, nausea, the most common side effect associated with GLP-1-based therapy (such as exenatide and liraglutide), was significantly less prevalent. OXM increased energy use by promoting increased physical activity in overweight and obese humans, although the mechanism of the effect is unclear. OXM presents several challenges for the development of a commercially viable therapeutic agent. As mentioned above, it is rapidly degraded in vivo as well as undergoing rapid renal clearance due to its small size. Therefore, it is desirable to identify OXM peptide analogues with improved metabolic stability and reduced clearance rate. Additionally, the GcgR agonist activity inherent in OXM presents a risk of negatively impacting blood glucose control. Therefore, it is also desirable to optimize the potency of a 15 OXM-like peptide designed for therapeutic use while maintaining an appropriate balance between GLP-1R and GcgR activities. The activation of GLP-1R is responsible for an insulinotropic effect, whereas! activation of GLP-1R and GcgR may play a role in the effects on weight loss. Therefore, it is desirable to produce an OXM 'θ 10 peptide analog that has potent insulinotropic activity and promotes weight loss such that it can be used for the treatment of non-insulin dependent diabetes and / or obesity. I OXM peptides with amino acid substitutions to improve stability and with additional modifications to delay clearance, such as PEGylation or lipidation are described in WO 2008101017, WO 2006134340, W02007100535 and Pocai et al., Diabetes i 58: 2258-2266, 2009. Although these OXM-derived peptides may represent a potential improvement over the wild-type peptide, the doses required to achieve a measurable weight reduction in a mouse model with diet-induced obesity (DIO) are typically larger than they could be considered feasible for pharmaceutical marketing. For example, Pocai et al. (2009) reported a weight loss of 11 g (-25%) on average after 13 days of administration of 1900 nmol / kg (~ 8 mg / kg) on alternate days (QOD). Despite the availability of several OXM peptides and their i I analogs, there is still a need for more potent, stable, long-lasting and well-tolerated OXM peptide analogs that have an optimized proportion of GcgR / GLP-1R activity such that the potency and insulinotropic activity of peptides provide effective treatments for diabetes, preferably type 2 diabetes and related disorders. It is also desirable to provide OXM peptide analogs that provide effective treatments for reducing body weight. Consequently, the present invention seeks to provide effective treatments for diabetes and / or obesity. The present invention comprises an OXM peptide analog with amino acid substitutions introduced to optimize metabolic stability and modulate the relative activities of GcgR / GLP-1R while optimizing overall potency. In addition, the OXM peptide analog of the present invention is PEGylated at selected positions to enhance the time of action, thereby allowing for less frequent dosing. The present invention provides an oxintomodulin peptide analogue that comprises the amino acid sequence: 510 His- (Aib) -Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr15 2025 Leu-Asp-Ser-Lys-Lys-Ala-Gln-Glu-Phe-Val-Gln-Trp-Leu-Leu-Asn3035 (Aib) -Gly-Arg ~ Asn-Arg-Asn-Asn-Ile-Ala-Xaa38 3 Xaa 9 (SEQ ID NO: 5) wherein Xaa 38 is Cys or Cys-PEG is absent, Xaa 39 is Cys, Cys-PEG or is absent and wherein the C - terminal amino acid is optionally amidated. The present invention provides an oxin15 tomodulin peptide analogue that comprises the amino acid sequence: 510 His- (Aib) -Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr15 2025 Leu-Asp-Ser-Lys-Lys-Ala-Gln-Glu-Phe-Val-Gln-Trp-Leu-Leu-Asn3035 (Aib) -Gly-Arg-Asn-Arg-Asn-Asn-Ile-Ala (SEQ ID NO: 1). In addition, the present invention provides an oxintomodulin peptide analog that comprises the amino acid sequence: 510 His- (Aib) -Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr15 2025 Leu-Asp-Ser-Lys-Lys-Ala-Gln-Glu-Phe-Val-Gln-Trp-Leu-Leu-Asn3035 (Aib) -Gly-Arg-Asn-Arg-Asn-Asn-Ile-Ala-Cys -Cys (SEQ ID NO: 2) I 4/34 where the Cys residue at position 38 is optionally PEGylated and where the Cys residue at position 39 is optionally PEGylated and the carboxyl group of Cys at position 39 is optionally amidated. Preferably, the oxintomodulin peptide analog of SEQ ID No.: 2 is PEGylated at the Cys residue at position 38 of Cys or N po sition 39 1 or both with a 40 kDa PEG molecule covalently attached to thiol groups of each Cys residue in these positions. More preferably, the oxintomodulin peptide analog is PEGylated at each Cys residue at position 38 and at position 39 with a PEG θ 10 20 kDa molecule, covalently attached to the thiol group of each Cys residue at those positions. Optionally, the Cys residue at position 39 may be absent from SEQ ID NO: 2, leaving a unique site for PEGylation at position 38. , The most preferred oxintomodulin peptide analog with 1 comprises the amino acid sequence: 510 His- (Aib) -Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr15 2025 Leu-Asp-Ser-Lys-Lys-Ala-Gln-Glu-Phe-Val-Gln-Trp-Leu-Leu-Asn3035 (Aib) -Gly-Arg-Asn-Arg-Asn-Asn-Ile-Ala-Cys (20kDa PEG) -Cys (20 kDa PEG) (SEQ ID NO: 3) in which the carboxyl group of Cys PEGylated at position 39 is optionally amidated. The most preferred oxintomodulin peptide analog comprises the amino acid sequence of SEQ ID NO: 3, wherein the Cys PEGylated carboxyl group at position 39 is amidated. The PEG molecule used in the present invention can be linear or branched and is preferably a linear PEG molecule. The present invention provides a pharmaceutical composition comprising the oxintomodulin peptide analog as defined above and a pharmaceutically acceptable carrier, diluent or excipient. In addition, the present invention provides a pharmaceutical composition comprising the oxintomodulin peptide analog as defined above 5/34 together with a pharmaceutically acceptable carrier, diluent or excipient and, optionally, other therapeutic ingredients. In addition, the present invention provides a method for treating non-insulin dependent (type 2) diabetes in a needy individual, comprising administering to the needy individual an effective amount of an oxintomodulin peptide analog as defined above. In addition, the present invention provides a method for treating insulin dependent (type 1) diabetes in a needy individual, comprising administering to the needy individual an effective amount of an oxintomodulin peptide analog as defined above. The present invention includes a method of treating obesity in an individual in need, comprising administering to the individual in need an effective amount of an oxintomodulin peptide analog as defined above. In addition, the present invention includes a method for treating non-insulin-dependent diabetes and obesity in a needy individual, comprising administering to the needy individual an effective amount of an oxintomodulin peptide analog as defined above. The present invention provides an oxintomodulin peptide analog as defined above for use as a medicament. In addition, the present invention provides an oxintomodulin peptide analog as defined above for use in the treatment of non-insulin dependent diabetes. In addition, the present invention provides an oxintomodulin peptide analog as defined above for use in the treatment of insulin-dependent diabetes. In addition, the present invention provides an oxintomodulin peptide analog as defined above for use in the treatment of obesity. The present invention includes an oxintomodulin peptide analog as defined above for use in the treatment of non-insulin-dependent diabetes and obesity. 6/34 The present invention provides the use of an oxintomodulin peptide analog as defined above in the manufacture of a medicament for the treatment of non-insulin-dependent diabetes. In addition, the present invention includes the use of an oxintomodulin peptide analog as defined above in the manufacture of a medicament for the treatment of insulin-dependent diabetes. In addition, the present invention provides the use of an oxintomodulin peptide analog as defined above in the manufacture of a medicament for the treatment of obesity. In addition, the present invention provides the use of an oxintomodulin peptide analog as defined above in the manufacture of a medicament for the treatment of non-insulin dependent diabetes and obesity. The OXM peptide analogs of the present invention effectively bind and activate both the GLP-1 receptor (GLP-1R) and the glucagon receptor (GcgR). It has also been found that the OXM peptide analogs of the present invention are more resistant to degradation by peptidases, in particular dipeptidyl peptidase IV, than native human OXM. As a result, the OXM peptide analogs of the present invention have improved stability in vivo versus native human OXM. Various embodiments in accordance with the present invention are capable of causing a reduction in food intake in overweight and obese individuals. A particular advantage of the present invention is that the frequency of side effects, such as nausea, which are commonly associated with GLP-1 based therapy, such as exenatide and liraglutide, is reduced or eliminated. Therefore, the present invention has reduced side effects compared to GLP-1 based therapy. The OXM peptide analogs of the present invention provide superior weight loss effect versus human wild-type OXM. 7/34 In accordance with an embodiment of the present invention, the oxintomodulin peptide analog provides improved glucose tolerance and lipid profile in individuals with type 2 diabetes and / or related metabolic disorders and does so more effectively than wild-type human OXM. Oxytomodulin (OXM) is a weak coagonist with complete efficacy and balanced potency in hGLP-1R and hGcgR, with EC 50 values of 6.7 + 2.7 nM and 4.1 + 1.7 nM, respectively, in cells HEK293 that stably overexpress their respective receptors. The sequence of native human OXM is given below: His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-AspSer-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu- Met-Asn-Thr-Lys-Arg-AsnArg-Asn-Asn-lle-Ala (SEQ ID NO: 4). The OXM peptide analog of SEQ ID NO: 3, where Cys (PEG20k) at position 39 is amidated, is a fully effective and potent Oxintomodulin peptide analog with an EC 5 of 59.9 + 4.14 nM and 2.75 + 0.55 nM against hGcgR and hGLP-1R, respectively. Therefore, the OXM peptide analog of SEQ ID NO: 3, in which the Cys (Peg20k) at position 39 is amidated, has a balance of functional activities in vitro that is ~ 22 times more selective for hGLP-1R when compared with hGcgR. Comparable results are observed for the binding affinity, Ki, where the OXM peptide analog of SEQ ID NO: 3, where the Cys (Peg20k) at position 39 is amidated, is 28 times more selective for hGLP-1R when compared to hGcgR, with Ki values of 73 + 23 nM and 2050 + 70 nM, respectively. Covalent coupling of one or more PEG molecules to particular residues of the OXM peptide analog results in a PEGylated OXM peptide analog with a prolonged half-life and reduced clearance rate when compared to those of the OXM peptide analog non-PEGylated and the in vitro potency in GLP-1R similar to that of native human OXM. Due to the small size of the OXM peptide analog and the relatively large size of the molecule (s) of 8/34 PEG, the OXM peptide analog, once PEGylated, could be expected to lose activity as a result of steric hindrance. However, it has been found that if placed at the end of the oxintomodulin peptide analog instead of the medium, the activity of the peptide analog is maintained to a greater extent. Several substitutions in the sequence intensify the power, thus compensating for the loss of power due to PEGylation while maintaining an appropriate rate of activities in GLP1R and GcgR. In addition, it has been found that the presence of two PEG molecules at the C terminal end of the oxintomodulin peptide analog is preferable to a single PEG molecule. The sequences of the present invention contain the standard single letter or three letter codes for the twenty naturally occurring amino acids. The other codes used are as defined below: Aib = alpha isobutyric amino acid PEG = polyethylene glycol PEG20k = PEG molecule with an average molecular weight of 20,000 Da The term PEG as used here means a polyethylene glycol molecule. In its typical form, PEG is a linear polymer with hydroxyl terminal groups and has the formula HO-CH2CH 2 - (CH2CH2O) n-CH2CH2-OH, where n is between about 8 to about 4000. Typically, n is not a discontinuous value, but it constitutes a range with approximately the Gaussian distribution around an average value. The terminal hydrogen can be replaced by a coating group such as an alkyl or alkanol group. Preferably, PEG has at least one hydroxyl group, more preferably a terminal hydroxyl group. This hydroxy group is preferably coupled to a linker that can react with the peptide to form a covalent bond. There are numerous PEG derivatives in the art. (See, e.g., U.S. Patent Nos: 5,445,090; 5,900,461; 5,932,462; 6,436,386; 6,448,369; 6,437,025; 6,448,369; 6,495,659; 6,515,100 and 6,514. 491 and Zalipsky, S. Bioconjugate Chem. 6: 150-165, 1995). The PEG molecule covalently coupled to the preX OXM peptide 9/34 This invention can be approximately 10,000, 20,000, 30,000 or 40,000 daltons of average molecular weight. The PEG molecule is preferably 18,000 to 22,000 daltons. Most preferably, it has 19,000 to 21,000 daltons. Most preferably, it has 20,000 to 21,000 daltons. It is, more preferably, approximately 20,000 daltons. PEGylation reagents can be linear or branched molecules and can be present alone or in tandem. The PEGylated OXM peptide analog of the present invention preferably has PEG molecules coupled to the C-terminus of the peptide. The PEG molecules are preferably coupled to two cysteine residues of the C-terminal end of the peptide by a maleimide mPEG-20kDa (Figure 1) or iodoacetamide mPEG-20kDa (Figure 2). In Figure 1 and Figure 2, n is 10 to 2500. Preferably, n is 350 to 600. More preferably, n is 425 to 475. o 7 ^ o CH 3 Figure 1 Figure 2 In particular, the PEG molecules are mPEG-20kDa maleimide (CH3O (CH2CH 2 O) n “(CH2) 3NHCO (CH2) 2-maleimide) (NOF Sunbright ME200MA) and are coupled to the two cysteine residues at the C-terminus of the peptide . The most preferred oxintomodulin peptide analog comprises the amino acid sequence of SEQ ID NO: 3, where the PEG molecules are mPEG-20kDa maleimide (ΟΗ 3 0 (ΟΗ2θΗ 2 0) η- (ΟΗ 2 ) 3ΝΗΟΟ (ΟΗ2 ) 2maleimide) (NOF Sunbright ME-200MA) and in which the Cys PEGylated carboxyl group at position 39 is amidated (Figure 3). Figure 3 contains the standardized single letter amino acid code with the exception of the framed areas where the structures for these amino acid residues have been expanded. 10/34 n = 425-475 Figure 3 The term PEGylation as used herein means the covalent coupling of one or more PEG molecules, as described above, to a molecule such as the OXM peptide analogs of the present invention. Insulinotropic activity refers to the ability to stimulate insulin secretion in response to elevated glucose levels, thereby inducing the absorption of glucose by cells and a decrease in plasma glucose levels. Insulinotropic activity can be assessed by methods known in the art, including in vitro experiments that measure insulin secretion by insulinoma or islet cell lines or in vivo experiments such as intravenous glucose tolerance test (IVGTT), tolerance test to intraperitoneal glucose (IPGTT) and the oral glucose tolerance test (OGTT). Insulinotropic activity is routinely measured in humans by measuring insulin levels or C-peptide levels. The OXM peptide analogs of the present invention have robust insulinotropic activity. In vitro potency as used here is a measure of the ability of the OXM peptide analog to activate GLP-1R or GcgR in a cell-based assay. In vitro potency is expressed as EC 5 which is the effective concentration of a compound that results in half the maximum increase in the measured response (in this case, cyclic AMP production) in a dose-response experiment. The expression plasma half-life refers to the time required for half of the relevant molecules to be cleared from the plasma. An expression used alternatively is elimination half-life. The extended or extended expression used in the context of half-life 11/34 plasma or elimination half-life indicates that there is a significant increase in the half-life of a PEGylated OXM peptide analog compared to that of the reference molecule (for example, the non-PEGylated form of the peptide or the native peptide) as determined under comparable conditions. The half-life of native OXM in monkeys, for example, is expected to be less than 1 h. The PEGylated OXM peptide analogs of the present invention can have an elimination half-life of at least 24 h in the monkey and more preferably at least 48 h. The half-life reported here is the elimination half-life, which corresponds to the terminal lineal elimination rate. The person skilled in the art assesses that half-life is a derived parameter that varies as a function of clearance and volume of distribution. The long-acting GLP-1R agonist expression as used here, refers to a GLP-1 peptide analog covalently coupled to one or more polyethylene glycol (PEG) molecules. PEGylated GLP-1 compounds are described in U.S. Patent 7,557,183. Clearance is a measure of the body's ability to eliminate a drug from circulation. As clearance decreases, for example, due to changes in a drug, the half-life can be expected to increase. However, this reciprocal relationship is accurate only where there is no change in the volume of distribution. A useful approximate relationship between terminal log-linear half-life (ty 2 ), clearance (C) and volume of distribution (V) is given by the equation: ty 2 »0.693 (V / C). The clearance does not indicate how much of the drug is being removed, but preferably the volume of biological fluid, such as blood or plasma that is being completely released from the drug due to elimination. The clearance is expressed as volume per unit of time. The PEGylated OXM peptide analogs of the present invention preferably have a clearance value of 200 ml / h / kg or less in monkeys, more preferably 180, 150, 120, 100, 80, 60 ml / h / kg or less and the more preferably 50, 40 or 20 ml / h / kg or less. The OXM peptide analogs of the present invention will typically be administered parenterally. Parenteral administration includes, for example, systemic administration, such as by intramuscular, intravenous, subcutaneous, intradermal or intraperitoneal injection. The OXM peptide analog is administered to an individual in conjunction with an acceptable pharmaceutical carrier, diluent or excipient as part of a pharmaceutical composition to treat non-insulin dependent (type 2) diabetes mellitus, NIDDM or the disorders discussed below. The pharmaceutical composition can be a solution or a suspension such as that in which the OXM peptide analog is complexed with a divalent metal cation such as zinc. The peptide analog can also be formulated in a solid formulation such as by lyophilization or spray drying, which is then reconstituted in a suitable diluent solution before administration. Suitable pharmaceutical carriers can contain inert ingredients that do not interact with the peptide or peptide derivative. Pharmaceutical vehicles suitable for parenteral administration include, for example, sterile water, physiological saline, bacteriostatic saline (saline containing about 0.9% mg / ml benzyl alcohol), phosphate buffered saline, Hank's solution, Ringer-lactate and similars. Some examples of suitable excipients include lactose, dextrose, sucrose, trehalose, sorbitol and mannitol and 20 preservatives such as phenol and m-cresoL Standardized pharmaceutical formulation techniques, such as those described in Remington’s Pharmaceutical Sciences (Mack Publishing Company, Easton, PA) can be employed. The OXM peptide analogs of the present invention can alternatively be formulated for administration via the buccal, oral, transdermal, nasal or pulmonary routes. The OXM peptide analogs of the invention can be formulated for prolonged release such that plasma levels are maintained in the efficacy range for extended periods of time after administration. The OXM peptide analogs of the present invention can be used to treat diabetes, specifically type 2 diabetes (non-insulin dependent diabetes mellitus, NIDDM). Additional individuals who may benefit from treatment with the OXM peptide analogs of the present invention include those with impaired glucose tolerance or impaired fasting glucose, individuals whose body weight is about 25% or more above body weight normal for the individual's height and body constitution, individuals who have one or more relatives with NIDDM, individuals who have gestational diabetes and individuals with metabolic disorders such as those resulting from decreased endogenous insulin secretion. The OXM peptide analog can be used to prevent individuals with impaired glucose tolerance from progressing to developing type 2 diabetes, preventing pancreatic β cell deterioration, inducing β cell proliferation, activating inactive β cells, promoting differentiation cells in β cells, stimulate β cell replication and inhibit β cell apoptosis. Other diseases and conditions that can be treated or prevented using the compounds of the invention in the methods of the invention 15 include: Maturity-Onset Diabetes of the Young (MODY) (Herman, et al., Diabetes 43:40, 1994); Adult Latent Autoimmune Diabetes (LADA) (Zimmet, et al., Diabetes Med. 11: 299, 1994); impaired glucose tolerance (IGT) (Expert Committee on Classification of Diabetes Mellitus, Diabetes Care 22 (Supp. 1): S5, 1999); impaired fasting glucose (IFG) (Charles, et al., Dia20 betes 40: 796, 1991); gestational diabetes (Metzger, Diabetes, 40: 197, 1991); metabolic syndrome X, dyslipidemia, hyperglycemia, hyperinsulinemia, hypertriglyceridemia, and insulin resistance. The OXM peptide analogs of the invention can also be used in methods of the invention to treat secondary causes of diabetes (Expert Committee on Classification of Diabetes Mellitus, Diabetes Care 22 (Supp.1): S5, 1999). Such secondary causes include excess glucorticoids, excess growth hormone, pheochromocytoma and drug-induced diabetes. The drugs that can induce diabetes include, but are not limited to, pyriminil, nicotinic acid, glucocorticoids, fe30 nitoin, thyroid hormone, β-adrenergic agents, α interferon and drugs used to treat HIV infection. The OXM peptide analogs of the present invention can 14/34 be effective in suppressing food intake and treating obesity. An effective amount of an OXM peptide analog is the amount that results in a desired therapeutic and / or prophylactic effect 5 without causing undesirable side effects when administered to an individual. A desired therapeutic effect includes one or more of the following: 1) improvement in the symptom (s) associated with the disease or condition; 2) delay in the appearance of symptoms associated with the disease or condition; 3) increased longevity compared to no treatment; and 4) 0 10 better quality of life compared to no treatment. For example, an effective amount of an OXM peptide analogue for the treatment of NIDDM is the amount that will result in greater control of blood glucose concentration than in the absence of treatment, thereby resulting in delayed onset of 15 diabetes such as retinopathy, neuropathy or kidney disease. An effective amount of an OXM peptide analog for the prevention of NIDDM, for example, in individuals with impaired glucose tolerance or impaired fasting glucose, is the amount that can delay, compared to the lack of treatment, the appearance of levels elevated san20 guinea glucose levels that require treatment with hyperglycemic anti-O drugs such as sulfonylureas, thiazolidinediones, insulin and / or bisguanidines. An effective amount of an OXM peptide analogue administered to an individual will also depend on the type and severity of the disease and the characteristics of the individual, such as overall health, age, sex, body weight and drug tolerance. The dose of an OXM peptide analog effective to normalize an individual's blood glucose will depend on several factors, including, without limitation, the individual's sex, weight and age, the severity of the inability to regulate blood glucose , the route of administration and bioavailability, the pharmacokinetic profile of the peptide, the potency and formulation. A typical once-a-week dose of peptide analogs PEGylated OXM deo of the present invention will preferably range from about 0.1 mg to about 1000 mg (total weight of the conjugate). More preferably, the once-weekly dose will vary between about 1 mg to about 100 mg or about 1 mg to about 30 mg. Most preferably, the dose once a week will vary between about 5 mg to about 30 mg or about 1 mg to about 5 mg. An individual is a mammal, preferably a human, but can also be an animal, including domestic animals (for example, dogs, cats and the like), farm animals (for example, cows, sheep, pigs, horses and the like, and laboratory animals (for example, rats, mice, guinea pigs and the like). Various preferred aspects and embodiments of the present invention will now be described by way of example only. Example 1: Peptide Synthesis The peptide analog according to SEQ ID NO: 1 and SEQ ID No. 2 of the present invention is generated by the solid phase peptide synthesis in an automated peptide synthesizer Protein Technologies Inc. Symphony or Applied Biosystems 433A. The synthesis is performed on a polystyrene resin Fmoc-Rínk amide (Rapp Polymere Tubingen, Germany) 20 with replacement of approximately 0.7 mmol / g. The synthesis is performed using the Fmoc main chain protecting group strategy. The amino acid side chain derivatives used are: Arg (Pbf), Asn (Trt), Asp (OtBu), Cys (Trt), Gln (Trt), Glu (OtBu), His (Trt), Lys (Boc), Ser (OtBu), Thr (OtBu), Trp (Boc), and Tyr (OtBu). Coupling is performed with approximately 10 equivalents of amino acids activated with diisopropylcarbodiimide (DIC) and hydroxybenzotriazole (HOBt) (1: 1: 1 molar ratio) in dimethylformamide (DMF) or N-methyl pyrrolidinone (NMP). The coupling is performed for 45 to 90 minutes at room temperature. Concomitant dividing of the resin and removal of the protecting group from the side chain are carried out in a solution containing trifluoroacetic acid (TFA): triisopropylsilane: 3,6-dioxa-1,8-octane-dithiol: methaneLanisol 90: 4: 2: 2: 2 (v / v) for 1.5 h to 2 h at room temperature. The solution is to filter 16/34 da and concentrated to <2 mL and the peptides are precipitated with ice cold diethyl ether, redissolved in 30 to 40 mL of 10% acetonitrile and purified by reverse performance liquid chromatography on a C 18 column (HPLC) ( typically a Waters SymmetryPrep 7 um, 19 x 5 x 300 mm) column at a flow rate of 12 to 15 mL / min. The samples are eluted with a two-stage linear AB gradient of 0 to 25% B over minutes, followed by 25 to 75% B over 100 minutes where A = 0.05% TFA / water and B = 0.05 TFA % / acetonitrile. The product generally elutes in 30 to 35% acetonitrile. Peptide purity and molecular weight are confirmed in an Agilent 1100 Series liquid mass chromatography (LC / MS) spectrometry system with a single MS quadripolar detector. Analytical HPLC separation is done on a Zorbax Eclipse XDB-C8 column, 5 microns, 4.6 mm id x 15 cm with a linear gradient of AB from 6 to 60% B over 15 minutes in which A = TFA 0, 05% / H2O and B = 0.05% TFA / acetonitrile and the flow rate is 1 ml / min. The peptide analog is purified to> 95% purity and it is confirmed to have the molecular weight that corresponds to the calculated value within 1 unit of atomic mass (amu). Example 2: PEGylation of peptide containing two Cys residues with mPEG-MAL-20 kPa The lyophilized peptide analog (SEQ ID NO: 2) generated according to Example 1 is weighed (typically 30 to 50 mg). A 2.1-fold molar equivalent of mPEG-20kDa maleimide (CH3O (CH 2 CH2O) n (CH 2 ) 3NHCO (CH 2 ) 2-maleimide) (NOF Sunbright ME-200MA) is weighed and combined with the peptide. The reagents are dissolved in a 50/50 (v / v) mixture of water / acetonitrile to a peptide concentration of approximately 20 mg / ml. The peptide analog solution is diluted twice with 100 mM ammonium acetate, 10 mM ethylene diaminetetraacetic acid (EDTA), pH 7. The resulting mixture is stirred at room temperature. The reaction mixture is monitored by reverse phase analytical HPLC (the analytical comparison by HPLC is done on a Waters SymmetryShield column C18, 3.5 microns, 4.6 mm i.d. x 10 cm at 50 ° C with a two-stage linear AB gradient of 0 to 30% B over 5 minutes, followed by 30 to 90% I 17/34 B during the subsequent 30 minutes where A = 0.05% TFA / Η2θ and B = 0.05% TFA / acetonitrile and the flow rate is 1ml / min) and typically after 1 to 2 hours of reaction time, shows the almost complete disappearance of the peptide peak. Two peaks due to the mono- and di-PEGylated peptide appear with the PEGylated peptide, typically constituting 90 to 95% of the total peak area. The sample is diluted to about 20 ml with water and purified as in Example 1 with a two stage linear AB gradient of 0 to 30% B over 20 minutes, followed by 30 to 80% B over 100 i min. The product generally elutes at 35-40% acetonitrile. The purified peptide 10 is quantified by the ultraviolet (UV) absorbance at 280 nm using a molar extinction coefficient calculated based on the peptide sequence. The yield after purification is in the range of 70 to 80% based on the amount of the starting peptide. Example 3: Glucagon Receptor Binding Assay (hGcgR) The glucagon receptor binding assay uses the cloned human glucagon receptor (hGcgR) (Lok S, Kuijper JL, Jelinek LJ, Kramer JM, Whitmore TE, Sprecher CA, Mathewes S, Grant FJ, Biggs SH, Rosenberg GB, et a / .Gene 140 (2), 203-209 (1994)) isolated from HEK293 membranes. The hGcgR cDNA is subcloned into the phD expression plasmid (transactivated expression of fully recombinant human protein C gamma-carboxylated, an antithrombotic factor. Grinnell, B.W., Berg, D.T., Walls, J. and Yan, S.B. Bio / Technology 5: 1189-1192 (1987)). This plasmid DNA is transfected into 293HEK cells and selected with 200 | pg / ml of hygromycin. 25 i The crude plasma membranes are prepared using Ias 1 Cellular a suspension culture. The cells are lysed on ice in hypotonic buffer containing 25 mM Tris HCI, pH 7.5, 1 mM MgCh, DNAsel ug / ml and Roche Complete Inhibitors without EDTA. The cell suspension is homogenized with a Dounce glass homogenizer using a Teflon pestle for 25 strokes. The homogenate is centrifuged at 4 ° C at 1800 xg per min. The supernatant is collected and the pellet is resuspended in hypotonic buffer and homogenized again. The mixture is centrifuged at 1800 xg 18/34 for 15 min. The second supernatant is combined with the first supernatant. The combined supernatants are centrifuged at 1800 x g for 15 min to clarify. The clarified supernatant is transferred to high speed tubes and centrifuged at 25000 x g for 30 min at 4 ° C. The membrane pellet is resuspended in the homogenization buffer and stored as frozen aliquots at -80 ° C until use. The glucagon is radioiodinated by the 125 lactoperoxidase procedure and purified by reverse phase HPLC in a PerkinElmer / NEN (NEX207). The specific activity is about 2200 Ci / mmoL The determination of K D is performed by homologous competition instead of saturation bonding due to the high propanol content in the glucagon material marked with 125 1. The Kd is assessed to be 2.62 nM and is used to calculate Ki values for all tested compounds. The receptor binding assay is performed using the Proximity Scintillation Assay (SPA) with wheat germ agglutinin (WGA) beads previously blocked with 1% bovine serum albumin (BSA) without fatty acid. The binding buffer contains 4- (2-hydroxyethyl) -1 piperazinoethanesulfonic acid (HEPES) 25 mM, pH 7.4, CaCh, 2.5 mM, 1 mM MgCE, 1% BSA without fatty acid, 0.003% Tween20, and Roche Complete Inhibitors without EDTA. Glucagon is dissolved in HCI 0.01 to 1 mg / ml and immediately frozen at -80 ° C in 30 μΙ aliquots. The Glucagon aliquot is diluted and used in the binding assay within 1 h. The OXM peptide analog is dissolved in phosphate buffered saline (PBS) and diluted seriously in binding buffer. Then, 10 μι of diluted compounds or PBS are transferred to Corning 3632 light-bottomed assay plates containing 40 μ binding assay buffer! or frozen glucagon (non-specific binding (NSB) at 1 μΜ at the end). Then, 90 μΙ of membranes (3 pg / well), 50 μΙ of Glucagon labeled with 125 l (final concentration of 0.15 nM in the reaction), and 50 μΙ of WGA beads (150 pg / well) are added. The plates are sealed, mixed, end to end and read with a MicroBeta scintillation counter after 1 h of time of stabilization at room temperature. 19/34 The results are calculated as a percentage of the specific binding of 125 l labeled glucagon in the presence of the compound. The absolute IC 50 concentration of the compound is derived from the non-linear regression of the percentage of specific binding of 125 l-labeled glucagon. concentration of the added compound. The IC50 dose is converted to Ki using the Cheng-Prusoff equation (Cheng Y., Prusoff WH, Biochem. Pharmacol. 22, 3099-3108, 1973). The Ki of the OXM peptide analog of SEQ ID NO: 3, where Cys (PEG20k) at position 39 is amidated was 2050 + 70 nM for hGcgR binding. 10 Example 4: Glucagon Similar Peptide 1 Receptor Binding Assay (hGLP-1-R) The GLP-1 receptor binding assay uses glucagon-like receptor 1 (hGLP-1R) (Graziano MP, Hey PJ, Borkowski D, Chicchi GG, Strader CD, Biochem Biophys Res Commun. 1993 Oct 15; 196 (1 ): 141 -6) 15 isolated from 293HEK membranes. The hGLP-1 R cDNA is subcloned into the phD expression plasmid (transactivated expression of fully gamma-carboxylated recombinant human protein C, an antithrombotic factor. Grinnell, BW, Berg, DT, Walls, J. and Yan, SB Bio / Technology 5: 11891192 (1987)). This DNA plasmid is transfected into 293HEK and 20 cells selected with 200 pg / ml of hygromycin. O Crude plasma membranes are prepared using cells from a suspension culture. The cells are lysed on ice in hypotonic buffer containing 25 mM Tris HCI, pH 7.5, 1 mM MgCE, DNAsel 20 µg / ml and Roche Complete Inhibitors without EDTA. The cell suspension is homogenized with a Dounce glass homogenizer using a Teflon pestle for 25 strokes. The homogenate is centrifuged at 4 ° C at 1800 x g for 15 min. The supernatant is collected and the pellet is resuspended in hypotonic buffer and homogenized again. The mixture is centrifuged at 1800 x g for 15 min. The second supernatant is combined with the first supernatant. The combined supernatants are centrifuged at 1800 x g for 15 min to clarify. The clarified supernatant is transferred to high speed tubes and centrifuged at 25000 x g for 30 min at 4 ° C. The pellet of 20/34 membrane is resuspended in the homogenization buffer and stored as aliquots frozen at -80 ° C until use. Glucagon-like peptide 1 (GLP-1) is radioiodinated by the 125 -lactoperoxidase procedure and purified by reverse phase HPLC on a Perkin-Elmer / NEN (NEX308). The specific activity is about 2200 Ci / mmol. The determination of Kd is performed by homologous competition instead of saturation bonding due to the high propanol content in the 125 L labeled LPG-1 material. AK D is assessed to be 0.96 nM and is used to calculate Ki values for all compounds tested. The receptor binding assay is performed using the Proximity Scintillation Assay (SPA) with wheat germ agglutinin (WGA) beads previously blocked with 1% BSA without fatty acid (ICN). The binding buffer contains 4- (2-hydroxyethyl) -1piperazinoethanesulfonic acid (HEPES) 25 mM, pH 7.4, CaCI 2 , 2.5 mM, MgCI 2 1 mM, BSA 1% without fatty acid, Tween20 0.003%, and Roche Complete Inhibitors without EDTA. GLP-1 is dissolved in PBS at 1 mg / ml and immediately frozen at -80 ° C in 30 μΙ aliquots. The aliquots of GLP-1 are thawed, diluted and used in the binding assay within 1 h. The OXM peptide analog is dissolved in PBS and diluted seriously in binding buffer. Then, 10 μΙ of diluted compounds or PBS are transferred to Corning 3632 light-bottom assay plates containing 40 μΙ binding assay buffer or ice-cold GLP-1 (NSB at 1 μΜ at the end). Then, 90 μΙ of membranes (1pg / well), 50 μΙ of LPG-1 labeled with 125 l (final concentration of 0.15 nM in the reaction), and 50 μΙ of WGA beads (150 pg / well) are added. The plates are sealed, mixed, end to end and read with a MicroBeta scintillation counter after 12 hours of room temperature stabilization. The results are calculated as a percentage of the specific binding of 125 1-labeled GLP-1 in the presence of the compound. The absolute concentration of the compound is derived from the non-linear regression of the percentage of specific binding of GLP-1 labeled with 125 l vs. the concentration of the compound added. IC5o concentration is converted to Ki using 21/34 of the Cheng-Prusoff equation (Cheng Y., Prusoff W. H., Biochem. Pharmacol. 22, 3099-3108, 1973). The Ki of the OXM peptide analog of SEQ ID NO: 3, where Cys (PEG20k) at position 39 is amidated was 73 + 23 nM for hGLP-1R binding. Example 5: Functional assay of cAMP stimulated by the glucagon receptor (hGcgR) The glucagon-stimulated cAMP functional assay uses the same cloned cell line that expresses hGcgR as used in the hGlucR binding assay described above in Example 3. The cells are streaked with the OXM peptide analog and the cAMP generated within the cell is quantified using Perkin Elmer's Amplified Luminescent Proximity Homogeneous Assay (Alpha Screen) (6760625R). Briefly, the cAMP induced inside the cell competes for binding the kit's biotinylated cAMP to an Acceptor bead coated with an anti-cAMP antibody and a Donor bead coated with streptavidin. As the level of cAMP inside the cell increases, a rupture of the biotinylated AceptoracAMP-Donor sphere complex occurs and the signal that is observed decreases. HGcgR-HEK293 cells are collected from sub-confluent tissue culture disks with Cell 20 Dissociation Solution without Enzyme (Specialty Media 5-004-B). The cells are pelleted at low speed and washed 3 times with assay buffer [25 mM HEPES in Hank's buffered saline (HBSS) with Mg and Ca (GIBCO, 14025092) with 0.1% BSA without fatty acid] then diluted to a final concentration of 125,000 cells / ml. The biotinylated cAMP in the Alpha Screen kit is added to the diluted cells in a final concentration of 1 unit / 0.04 ml. A phosphodiesterase inhibitor, IBMX (250 mM in dimethyl sulfoxide (DMSO)), is also added to the diluted cells to a final concentration of 500 µM. The glucagon is initially dissolved in 0.01 N HCI at 1 mg / ml and immediately frozen at -80 ° C. After thawing, glucagon 30 should be used within 1 h. The glucagon, model cAMP and the OXM peptide analog are diluted in assay buffer to a final concentration of 6X. The functional test is carried out on Costar Plates (3688) of 96 I 22/34 wells, low volume, white, polystyrene. The reaction begins by adding 0.01 ml of the peptides, glucagon or cAMP diluted in 0.04 ml of the cell mixture. After one hour at room temperature, the reaction is stopped by adding 0.03 ml of Lysis Buffer [10 mM HEPES, pH 7.4, 1% NP40 and 0.01% BSA without fatty acid containing 1 unit of each / 0.03 ml of Alpha Screen Kit Acceptor and Donor spheres]. The lysis buffer is added in the dark to avoid bleaching the detection spheres. The plates are wrapped in aluminum foil, carefully stirred for 1 min, then left to equilibrate overnight at θ 10 at room temperature. The plates are read on a Perkin-Elmer instrument Envision. Alpha Screen units are converted to pmoles of cAMP generated per well based on the standardized cAMP curve. The pmoles of cAMP generated in each well are converted into a percentage of maximum response observed with the glucagon control. An EC50 value is derived15 by nonlinear regression analysis using the percentage of maximum response vs. the concentration of the added peptide. The OXM peptide analog of SEQ ID NO: 3, where Cys (PEG20k) at position 39 is amidated, as wild-type OXM, was fully effective and potent in hGcgR with an EC50 of 59.9 ± 4.14 nM . Example 6: Functional assay of cAMP stimulated by the glucagon-like peptide receptor (hGLP-1R) The GLP-1-stimulated cAMP functional assay uses the same cloned cell line that expresses hGLP-1R as used in the binding assay described above in Example 4. The cells are stimulated with the OXM peptide analogue and the cAMP generated within of the cell is quantified using Perkin Elmer's Amplified Luminescent Proximity Homogeneous Assay (Alpha Screen) (6760625R). Briefly, the cAMP induced within the cell competes for binding the kit's biotinylated cAMP to an Acceptor sphere coated with an anti-cAMP antibody and a Donor sphere coated with streptavidin. As the level of cAMP inside the cell increases, a rupture of the Receptor-cAMP biotinylated donor sphere complex breaks down and the signal that is observed decreases. 23/34 HGLP-1 R-HEK293 cells are collected from sub-confusing tissue culture discs with Cell Dissociation Solution without Enzyme (Specialty Media 5-004-B). The cells are pelleted at low speed and washed 3 times with assay buffer [25 mM HEPES in 5 HBSS with Mg and Ca (GIBCO, 14025-092) with 0.1% BSA without fatty acid] then diluted to a final concentration of 125,000 cells / ml The biotinylated cAMP in the Alpha Screen kit is added to the diluted cells in a final concentration of 1 unit / 0.04 ml. A phosphodiesterase inhibitor, IBMX (250 mM in DMSO), is also added to the diluted cells to a final concentration of 500 µM. GLP-1 is stored at 1 mg / ml in PBS as aliquots frozen at -80 ° C. GLP-1, model cAMP and the OXM peptide analog are diluted in assay buffer to a final concentration of 6X. The functional test is carried out on Costar Plates (3688), 96 wells, low volume, white, made of polystyrene. The reaction begins by adding 15 0.01 ml of the OXM peptide analog, GLP-1 or cAMP diluted in 0.04 ml of the cell mixture. After one hour at room temperature, the reaction is stopped by the addition of 0.03 ml of Lysis Buffer [10 mM HEPES, pH 7.4, 1% NP40 and 0.01% BSA without fatty acid containing 1 unit of each / 0 , 03 ml of Alpha Screen Kit Acceptor and Donor spheres]. Addition of the lysis buffer is performed in the dark to prevent bleaching of the detection beads. The plates are wrapped in aluminum foil, carefully stirred for 1 min, then left to equilibrate overnight at room temperature. The plates are read on a Perkin-Elmer Envision instrument. Alpha Screen units are converted to pmoles of cAMP 25 generated per well based on the standardized cAMP curve. The pmoles of cAMP generated in each well are converted into a percentage of maximum response observed with the GLP-1 control. An EC 50 value is derived by nonlinear regression analysis using the percentage of maximum response vs. the concentration of the added peptide. The 30 OXM peptide analog of SEQ ID NO: 3, where Cys (PEG20k) at position 39 is amidated, as wild-type OXM, was fully effective and potent in hGLP-1 R with EC 50 of 2.75 ± 0.55 nM. 24/34 Example 7: Effects on food intake, body weight and body composition in mice with diet-induced obesity (IOP) Three-to-four-month-old male C57BL / 6 mice with diet-induced obesity (DIO) are used. The animals are housed individually in a temperature-controlled facility (24 ° C) with a 12-hour light / dark cycle (lights on 2200 hours) and with free access to food and water. After two weeks of acclimatization at the facility, the mice are randomized into treatment groups (n = 8 - 10 / group), each group having similar average body weight and fat mass. Before the experiment, the mice are injected subcutaneously (sc) with a vehicle solution and weighed for 2 days to acclimate them to the procedures. Vehicle or OXM peptide analog (dose range 6.7 to 20 nmoles / kg) dissolved in vehicle are administered by sc injection to DIO mice fed ad libitum 30 to 90 minutes before the start of the dark cycle every 3 days for 2 to 4 weeks. The body weight and the weight of the food plus the feed tank are measured at the same time. The food consumed in the previous 24 hours is calculated by subtracting the current weight plus the weight of the feeder from that of the previous day. Absolute changes in body weight are calculated by subtracting the animal's body weight before the first injection. On days 1, 14 and 28, total fat mass is measured by nuclear magnetic resonance (NMR) using an Echo Medical System instrument (Houston, TX). The fat-free mass is calculated by subtracting the fat mass from the total body weight. Study 1: Two-week treatment The OXM peptide analogue of SEQ ID NO: 3 where Cys (PEG20k) at position 39 is amidated in vivo, is administered by subcutaneous injection to C57BL / 6 4 month old male with diet-induced obesity (DIO) . The OXM peptide analog is injected once every 3 days for 2 weeks at doses of 7.5 and 15 nmoles / kg and compared to vehicle-treated mice and animals treated as positive controls (7.5 nmoles / kg of a long-acting GLP-1R agonist 25/34 injected every 3 days). Treatment with the OXM peptide analog of SEQ ID NO: 3 in which Cys (PEG20k) at position 39 is amidated produced a dose-dependent reduction in food intake and body weight. At the end of the 2-week study period, cumulative food intake in the 15 nmoles / kg group was reduced by 27% when compared to the vehicle group. The accumulated weight loss in the group treated with 7.5 moles / kg was similar to that observed with the positive control, which was a reduction of about 9% when compared with the group with vehicle. The accumulated weight loss of the vehicle control of the group treated with 15 nmoles / kg was 18%. The analysis of body composition showed that the weight loss was due primarily to the loss of fat mass (Table 1). Table 1 Weight loss in DIO mice over a 14-day treatment period (mean ± SEM; n = 8) Dose of OXM peptide analog of SEQ ID NO: 3 whereCys (PEG20k) in position 3d is amidated (nmole / kg) Overall weight loss (g of weight change for 14 days) Total food intake (total in g for 14 days) Loss of fat mass (g of fat weight change for 14 days) 0 (Vehicle) 1.0 ± 0.5 40.7 ± 1.3 0.3 ± 0.3 7.5 -3.1 ± 0.4 * 35.0 ± 0.8 * -2.2 ± 0.3 * 15 -6.1 ± 0.9 * 29.8 ± 1.5 * -3.9 ± 0.7 * These data show that the OXM peptide analogue of SEQ ID NO: 3 in which Cys (PEG20k) at position 39 is amidated decreased the accumulated food intake and body weight in studies with DIO mice for 14 days, compared with the vehicle-treated mice. The reduced body weight was due primarily to the reduction in fat mass. * p <0.05 versus vehicle (Dunnett test). Study 2: Treatment for four weeks The OXM peptide analog of SEQ ID NO: 3 where i 26/34 Cys (PEG20k) at position 39 is amidated (6.7 or 20 nmoles / kg) and the positive control (7.5 or 22.5 nmoles / kg of a long-acting GLP-1R agonist) is administered every 3 days by subcutaneous injection to C57BL / 6 male mice at 4 months of age with diet-induced obesity (DIO) for 4 weeks. High-dose treatment of the OXM peptide analog of SEQ ID NO: 3 in which Cys (PEG20k) at position 39 is amidated significantly decreased the accumulated food intake. At lower doses, the OXM peptide analog of SEQ ID NO: 3 in which Cys (PEG20k) in position 39 is amidated decreased body weight to a degree similar to that seen in the positive control group. At the dose of 20 nmoles / kg, the OXM peptide analog of SEQ ID NO: 3 in which Cys (PEG20k) at position 39 is amidated caused a significantly greater weight loss when compared to the dose 22.5 nmoles / kg positive control. The maximum weight reduction (about 25% of the initial body weight) was obtained after 15 days of treatment. The analysis of body composition confirmed that the weight loss associated with the OXM peptide analog and the positive control was due primarily to the loss of fat mass (Table 2). The effect of the OXM peptide analog of SEQ ID NO: 3 out of 20 that Cys (PEG20k) at position 39 is amidated is further evaluated with indirect calorimetry on days 21 to 23. Animals treated with the OXM peptide analog SEQ ID NO: 3 where Cys (PEG20k) at position 39 is amidated (20 nmoles / kg) had significantly higher energy expenditure than vehicle-treated controls (average energy expenditure 25 in 24 hours a day 21 was increased by 18%). The OXM peptide analog of SEQ ID NO: 3 in which Cys (PEG20k) at position 39 is amidated did not result in a significant change in the level of motor activity compared to vehicle control. At the end of the study, plasma insulin and cholesterol levels were significantly lower in all treated groups than in vehicle-treated controls whereas only the group treated with a high dose of OXM peptide analog of SEQ ID N °: 3 27/34 in which Cys (PEG20k) at position 39 is amidated had leptin levels significantly reduced. All treated groups had higher plasma levels of adíponectin than vehicle-treated controls, but only the group treated with a high dose of OXM peptide analogue of SEQ ID NO: 3 where Cys (PEG20k) at position 39 is starch had a statistically significant difference. Table 2 Weight change in DIO mice over a 28-day treatment period (mean ± SEM; n = 9). Dose of OXM peptide analog of SEQ ID NO: 3 whereCys (PEG20k) at position 39 is amidated (nmole / kg) Overall weight loss (g of weight change for 28 days) Total food intake (total in g for the first 14 days) Loss of fat mass (g of change in fat weight for 28 days) 0 (Vehicle) 0.8 ± 0.2 39.2 ± 0.8 0.5 ± 0.1 6.7 -2.0 ± 0.4 * 36.0 ± 1.1 -0.7 ± 0.2 * 20.0 -11.1 ± 0.9 * 26.1 ± 1.4 * -7.5 ± 0.7 * These data show that the OXM peptide analog of SEQ ID NO: 3 in which Cys (PEG20k) at position 39 is amidated decreased the accumulated food intake and body weight in studies with DIO mice for 28 days, compared with vehicle-treated mice. The reduced body weight was due primarily to the reduction of fat mass. * p <0.05 versus vehicle (Dunnett test). Example 8: Effect on rapid elevation of blood glucose during an oral glucose tolerance test or an intraperitoneal glucose tolerance test after two weeks or 4 weeks of treatment in DIO mice, respectively Fifty-six hours after the last injection as described in Example 7 (Study 1) in DIO mice, the mice are fasted for 16 hours before the glucose tolerance test begins. At time 0, animals are given 2g / kg dextrose by gavage 28/34 oral or intraperitoneal (IP) injection. Blood is collected by bleeding from the tail vein at 0, 15, 30, 60 and 120 minutes after glucose administration. The glucose concentration is measured by the glucometer. All doses of the OXM peptide analogue of SEQ ID NO: 3 where Cys (PEG20k) at position 39 is amidated, as well as the positive control, significantly reduced blood glucose at all time points measured before and after oral glucose administration when compared to vehicle-treated controls (Table 3). An intraperitoneal glucose tolerance test is performed on days 29, 3 days after the last injection as described in Example 7 (Study 2) in DIO mice. The low dose of OXM peptide analog of SEQ ID NO: 3 in which Cys (PEG20k) at position 39 is amidated decreases fasting blood glucose compared to vehicle-treated controls, but had little effect on levels of glucose after IP glucose injection. The high dose of OXM peptide analogue of SEQ ID NO: 3 where Cys (PEG20k) at position 39 is amidated and both doses of the positive control significantly decreased blood glucose at all time points, measured before and after glucose injection IP when compared to vehicle-treated controls (Table 4). Table 3 Effects of the OXM peptide analog of SEQ ID NO: 3 where Cys (PEG20k) at position 39 is amidated on the rapid rise in blood glucose after administration of an oral glucose load Data provided as area under the glucose curve (= integrated values of t + 0 to 120 min) (n = 8) OXM peptide analogue dose of SEQ ID NO: 3 where Cys (PEG20k) in position39 is amidated (nmoles / kg) Glucose AUC (mg * min / dL) AVERAGE WITHOUT 0 (Vehicle) 27771 1434 7.5 17722 * 1009 15 17518 * 1686 29/34 These data show that after a 2-week treatment in DIO mice with the OXM peptide analog of SEQ ID NO: 3 in which Cys (PEG20k) at position 39 is amidated there was a significant reduction in the rapid rise in blood glucose after of an oral load of glucose. Statistical significance assessed by the Dunnett test (8p <0.05 vs. vehicle). Table 4 Effects of the OXM peptide analog of SEQ ID NO: 3 where Cys (PEG20k) at position 39 is amidated on the rapid rise in blood glucose after administration of an intraperitoneal (ip) glucose load Data provided as area under the glucose curve (- integrated values from t + 0 to 120 min) (n = 6) OXM peptide analog dose of SEQ ID NO: 3 where Cys (PEG20k) at position 39 is amidated (nmoles / kg) Glucose AUC (mg * min / dl) AVERAGE WITHOUT 0 (Vehicle) 35518 1969 6.7 30073 3389 20.0 19264 * 1894 These data show that after a 4-week treatment in DIO mice with the OXM peptide analog of SEQ ID NO: 3 in which Cys (PEG20k) at position 39 is amidated there was a significant reduction in the rapid rise in blood glucose after of an intraperitoneal (ip) load of glucose. Statistical significance assessed by the Dunnett test (* p <0.05 vs. vehicle). Example 9: Effects on rapid elevation of blood glucose during an intraperitoneal glucose tolerance test in lean mice Nine-week-old male C57BL / 6 mice are used in the study. Animals are randomized into groups based on body weight, animals are injected with a vehicle or peptide analog. 30/34 OXM deo (dose from 5.1 to 15.0 nmoles / kg) 16 h before the start of the test. The food is removed at the time of injection of the peptide or vehicle. At time 0, the animals are injected with 2 g / kg dextrose by IP injection. Blood is collected by puncturing the tail vein at 0, 3, 6, 12 and 30 minutes after glucose inoculation. The glucose concentration is measured by the glucometer. Insulin is measured by Mesoscale. The high dose of OXM peptide analogue of SEQ ID NO: 3 in which Cys (PEG20k) at position 39 is amidated significantly decreased the rapid rise in blood glucose when compared to vehicle-treated controls 10 (Table 5). Both doses of the OXM peptide analog of SEQ ID NO: 3 where Cys (PEG20k) at position 39 is amidated significantly increased plasma insulin when compared to vehicle-treated controls (Table 6). Table 5 Effects of the OXM peptide analog of SEQ ID NO: 3 where Cys (PEG20k) at position 39 is amidated on the rapid rise in blood glucose after an intraperitoneal (ip) glucose tolerance test in lean mice Data provided as area under the glucose curve (= integrated values of t + 0 to 30 min) (n = 6) ________________ OXM peptide analog dose of SEQ ID NO: 3 where Cys (PEG20k) at position 39 is amidated (nmoles / kg) Glucose AUC (mg * min / dL) AVERAGE WITHOUT Vehicle 8718 496 5 7059 476 15 6103 * 530 These data show that the OXM peptide analog of SEQ ID NO: 3 where Cys (PEG20k) at position 39 is amidated significantly reduced the rapid elevation of blood glucose after an intraperitoneal (ip) glucose tolerance test in lean mice. Statistical significance assessed by the Dunnett test (* p <0.05 vs. vehicle). 31/34 Table 6 Effects of the OXM peptide analogue of SEQ ID NO: 3 where Cys (PEG20k) at position 39 is amidated on the plasma insulin level after an intraperitoneal (ip) glucose tolerance test in lean mice Data provided as area under the insulin curve (= integrated plasma insulin values at t + 0 to 30 min) (n = 6) OXM peptide analog dose of SEQ ID NO: 3 where Cys (PEG20k) at position 39 is amidated (nmoles / kg) AUC insulin (ng * min / ml) AVERAGE WITHOUT 0 (Vehicle) 8.14 1.13 5 30.67 * 4.76 15 45.26 * 6.78 These data show that the OXM peptide analog of SEQ ID NO: 3 in which Cys (PEG20k) at position 39 is amidated significantly increased the plasma insulin AUC after an intraperitoneal (ip) glucose tolerance test in mice thin. Statistical significance assessed by the Dunnett test (* p <0.05 vs. vehicle). Example 10: Effects on rapid glucose elevation during an oral glucose tolerance test (OGTT) or an intraperitoneal (ip) glucose tolerance test (IPGTT) in ob / ob mice Male ob / ob mice aged two to three months are housed individually in a temperature-controlled facility (24 ° C) with a 12-hour light / dark cycle (lights on 2200 hours) and with free access to standardized food and water . After 2 weeks of acclimatization at the facility, the 3-hour fasting blood glucose is measured by bleeding from the tail vein at 9 AM. Mice with blood glucose below 180 mg / dL are not used. The remaining animals are randomized into treatment groups (N = 6-7 / group), each group has 32/34 going a similar average blood glucose level. Mice have free access to food until the moment of injection. The animals are injected with vehicle or with 7.5 nmoles / kg of OXM peptide analog at 4 PM of the same day. Food is removed at the time of injection. An OGTT (Table 7) or IPGTT (Table 8) is performed 16 hours after the injection of the peptide. At time 0, the animals are administered 2 g / kg dextrose by oral gavage (Table 7) or intraperitoneal injection (Table 8). Blood is collected by bleeding from the tail vein at 0, 15, 30, 60 or 120 minutes after the glucose injection. Glucose concentration is measured by a glucometer. A single injection of the OXM peptide analog of SEQ ID NO: 3 in which Cys (PEG20k) at position 39 is amidated normalized blood glucose in ob / ob mice. Blood glucose levels at all time points measured after glucose injection were significantly lower than in the vehicle control group. Table 7 Effects of the OXM peptide analog of SEQ ID NO: 3 where Cys (PEG20k) at position 39 is amidated on the rapid rise in blood glucose after an oral glucose tolerance test in ob / ob mice Data provided as area under the glucose curve (= integrated values of t + 3 to 120 min) (n = 7) OXM peptide analog dose of SEQ ID NO: 3 where Cys (PEG20k) at position 39 is amidated (nmoles / kg) Glucose A UC (mg * min / dl) AVERAGE WITHOUT 0 (Vehicle) 23938 1629 7.5 12266 * 1215 These data show that the OXM peptide analog of SEQ ID NO: 3 where Cys (PEG20k) at position 39 is amidated significantly reduced rapid rise in blood glucose after a 33/34 oral glucose tolerance in ob / ob mice. Statistical significance assessed by the Dunnett test (* p <0.05 vs. vehicle). Table 8 Effects of the OXM peptide analog of SEQ ID NO: 3 in which Cys (PEG20k) at position 39 is amidated on the rapid rise in blood glucose after an intraperitoneal glucose tolerance test (ip / ip) in ob / mice ob Data provided as area under the glucose curve (= integrated values of t + 3 to 120 min) (n = 6) OXM peptide analog dose of SEQ ID NO: 3 where Cys (PEG20k) at position 39 is amidated (nmoles / kg) Glucose AUG (mg * min / dL) AVERAGE WITHOUT 0 (Vehicle) 37894 1482 7.5 18878 * 3224 These data show that the OXM peptide analog of SEQ ID NO: 3 in which Cys (PEG20k) at position 39 is amidated significantly reduced rapid rise in blood glucose after an intraperitoneal glucose tolerance test (yp) in ob / mice ob. Statistical significance assessed by the Dunnett test (* p <0.05 vs. vehicle). Example 11: Acute effects on plasma FGF21, triglyceride levels and liver gene expression in male C57BL / 6 mice with diet-induced obesity In order to investigate the metabolic pathways that are modulated by treatment with the OXM peptide analog of SEQ ID NO: 3 where Cys (PEG20k) at position 39 is amidated regardless of weight loss, the OXM peptide analog and a positive control (a long-acting GLP1R agonist) is administered by subcutaneous injection to three-month-old male mice with diet-induced obesity (DIO). The day before the study, mice are randomized into treatment groups (N = 7 / group), each group having body weight 34/34 similar average. That same night (approximately 10 PM), the animals are placed in clean cages and treated with vehicle or OXM peptide analog by subcutaneous injection. The OXM peptide analog and controls are treated at 22.5 nmoles / kg. The food is removed at the time of vehicle or peptide injection. The following morning (approximately 10 AM), the animals are sacrificed to collect plasma and liver tissue. Glucose and triglyceride concentrations are measured using a Hitachi blood chemistry analyzer. The gene expression is determined by RT-PCR. The levels of malonyl-CoA and acetyl-CoA are measured by 10 HPLC. After a single injection, plasma glucose was significantly decreased compared to vehicle control in all treatment groups. The plasma triglyceride level was decreased in relation to vehicle control only in mice treated with the OXM peptide analog of SEQ ID NO: 3 in which Cys (PEG20k) at position 39 is amidated, but not in those treated with long-acting GLP1R agonist. Liver concentrations of malonyl-CoA and acetyl-coA were significantly decreased by 63% and 39%, respectively versus vehicle control, after treatment with the OXM peptide analog 20 of SEQ ID NO: 3 where Cys ( PEG20k) at position 39 is amidated. Treatment with the OXM peptide analogue of SEQ ID NO: 3 in which Cys (PEG20k) at position 39 is amidated altered the expression of several liver genes including a 7-fold increase in the expression of the pgc-1o gene and a decrease in the expression of the ChREBP and PCSK9 25 gene in 52% and 61%, respectively. In addition, FGF21 gene expression was induced 17 times, corresponding to a 6-fold increase in circulating FGF21 after acute treatment with the OXM peptide analog of SEQ ID NO: 3 where Cys (PEG20k) in position 39 is amidada. All of these changes were specific to mice treated with the OXM peptide analog of SEQ ID NO: 3 where Cys (PEG20k) at position 39 is amidated.
权利要求:
Claims (16) [1] 1. Oxintomodulin peptide analog, characterized by the fact that it comprises the amino acid sequence: His- (Aib) -Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-LeuAsp-Ser-Lys-Lys-Ala-Gln-Glu-Phe-Val-Gln-Trp- Leu-Leu-Asn- (Aib) -Gly-ArgAsn-Arg-Asn-Asn-Ile-Ala- Xaa38-Xaa39 (SEQ ID NO: 5), where Xaa38 is Cys, Cys-PEG, or is absent; Xaa39 is Cys, Cys-PEG, or is absent; and the C-terminal amino acid is optionally amidated. [2] 2. Oxintomodulin peptide analog, according to claim 1, characterized by the fact that it comprises the amino acid sequence: His- (Aib) -Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-LeuAsp-Ser-Lys-Lys-Ala-Gln-Glu-Phe-Val-Gln-Trp- Leu-Leu-Asn- (Aib) -Gly-ArgAsn-Arg-Asn-Asn-Ile-Ala-Cys-Cys (SEQ ID NO: 2), with the Cys residue at position 38 being optionally PEGylated; and the Cys residue at position 39 is optionally PEGylated; and the Cys carboxyl group at position 39 is optionally amidated. [3] Oxintomodulin peptide analog according to claim 2, characterized in that the analog is PEGylated with a PEG molecule with approximately 40 kDa coupled to the thiol group of the Cys residue at position 38 or at position 39. [4] 4. Oxintomodulin peptide analog, according to claim 1 or 2, characterized by the fact that the analog is PEGylated on the thiol of both Cys residues at positions 38 and 39 with a PEG molecule with approximately 20 kDa in each case and comprises the amino acid sequence: His- (Aib) -Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-LeuAsp-Ser-Lys-Lys-Ala-Gln-Glu-Phe-Val-Gln-Trp- Leu-Leu-Asn- (Aib) -Gly-ArgAsn-Arg-Asn-Asn-Ile-Ala-Cys (PEG20K) -Cys (PEG20K) (SEQ ID NO: 3), Petition 870190076187, of 07/08/2019, p. 8/21 2/3 with the Cys PEGylated carboxyl group at position 39 being optionally amidated. [5] Oxintomodulin peptide analogue according to any one of claims 1 to 4, characterized in that the PEG molecule is linear. [6] An oxintomodulin peptide analog according to any one of claims 1 to 5, characterized in that the carboxyl group of the Cys residue at position 39 is optionally amidated. [7] 7. Oxintomodulin peptide analog, according to claim 1, characterized by the fact that the Cys residue at position 39 is absent and the Cys residue at position 38 is PEGylated with a PEG molecule of approximately 40 kDa and is optionally amidated. [8] 8. Pharmaceutical composition, characterized in that it comprises an oxintomodulin peptide analog, as defined in any one of claims 1 to 7, and a pharmaceutically acceptable carrier, diluent or excipient. [9] Pharmaceutical composition, characterized in that it comprises an oxintomodulin peptide analog, as defined in any of claims 1 to 7, together with a pharmaceutically acceptable carrier, diluent or excipient, and, optionally, other therapeutic ingredients. [10] 10. Use of an effective amount of an oxintomodulin peptide analog, as defined in any of claims 1 to 7, characterized in that it is for the manufacture of a medicament useful for the treatment of non-insulin-dependent diabetes in a needy individual. [11] 11. Use of an effective amount of an oxintomodulin peptide analog, as defined in any one of claims 1 to 7, characterized in that it is for the manufacture of a medicament useful in the treatment of obesity in a needy individual. [12] 12. Use of an effective amount of an oxintomodulin peptide analog, as defined in any one of claims 1 to Petition 870190076187, of 07/08/2019, p. 9/21 3/3 7, characterized by the fact that it is for the manufacture of a drug usable in the treatment of non-insulin-dependent diabetes or obesity in a needy individual. [13] An oxintomodulin peptide analog according to any one of claims 1 to 7, characterized in that it is for use as a medicament. [14] 14. Oxintomodulin peptide analog according to any one of claims 1 to 7, characterized in that it is for use in the treatment of non-insulin-dependent diabetes. 10 [15] An oxintomodulin peptide analog according to any one of claims 1 to 7, characterized in that it is for use in the treatment of obesity. [16] 16. Oxintomodulin peptide analog according to any one of claims 1 to 7, characterized in that it is for use in the treatment of non-insulin-dependent diabetes or obesity.
类似技术:
公开号 | 公开日 | 专利标题 BR112012017348B1|2019-11-05|oxintomodulin peptide analog, its use as well as pharmaceutical composition JP5717758B2|2015-05-13|Oxint modulin peptide analog JP6412183B2|2018-10-24|Modified polypeptides with increased duration of action ES2809548T3|2021-03-04|Glucagon receptor agonists JP5820349B2|2015-11-24|Pancreatic polypeptide family motifs, polypeptides and methods comprising these ES2833458T3|2021-06-15|Glucagon and GLP-1 coagonist compounds JP5743371B2|2015-07-01|Pancreatic polypeptide family motifs, polypeptides and methods comprising these JP5252435B2|2013-07-31|Amylin derivatives WO2017047788A1|2017-03-23|Long-acting adrenomedullin derivative US11236142B2|2022-02-01|Acylated oxyntomodulin peptide analog US20080125360A1|2008-05-29|Composition Comprising Pyy for the Treatment of Gastrointestinal Disorders
同族专利:
公开号 | 公开日 DK2515928T3|2014-08-25| KR101399671B1|2014-05-27| EA022820B1|2016-03-31| AU2010341651B2|2014-01-16| CL2012001686A1|2012-11-23| EP2515928A1|2012-10-31| CR20120338A|2012-07-23| MX2012007438A|2012-07-17| PT2515928E|2014-09-03| EP2515928B1|2014-06-18| US20110152182A1|2011-06-23| TW201143793A|2011-12-16| US8367607B2|2013-02-05| RS53505B1|2015-02-27| CN102740873A|2012-10-17| IL220161A|2018-12-31| SG181430A1|2012-07-30| HN2012001321A|2015-08-31| JP2013515057A|2013-05-02| BR112012017348A2|2017-01-10| MY160773A|2017-03-15| MA33825B1|2012-12-03| HK1170941A1|2013-03-15| SI2515928T1|2014-08-29| TWI423812B|2014-01-21| CO6551738A2|2012-10-31| AU2010341651A1|2012-06-07| PE20121393A1|2012-10-26| TN2012000302A1|2013-12-12| DOP2012000176A|2012-08-31| PL2515928T3|2014-11-28| IL220161D0|2012-07-31| ES2486675T3|2014-08-19| NZ600731A|2014-06-27| KR20120096022A|2012-08-29| JO2976B1|2016-03-15| CN102740873B|2014-11-05| CA2784671C|2015-06-16| HRP20140616T1|2014-08-15| JP5717759B2|2015-05-13| CA2784671A1|2011-07-21| EA201290549A1|2013-01-30| AR079345A1|2012-01-18| WO2011087672A1|2011-07-21|
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法律状态:
2018-01-23| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]| 2018-04-10| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]| 2019-02-12| B07E| Notice of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI | 2019-06-11| B06T| Formal requirements before examination [chapter 6.20 patent gazette]| 2019-09-03| B09A| Decision: intention to grant [chapter 9.1 patent gazette]| 2019-11-05| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 15/12/2010, OBSERVADAS AS CONDICOES LEGAIS. |
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