WO2015055801A1 - Acylated glucagon analogues - Google Patents
Acylated glucagon analogues Download PDFInfo
- Publication number
- WO2015055801A1 WO2015055801A1 PCT/EP2014/072293 EP2014072293W WO2015055801A1 WO 2015055801 A1 WO2015055801 A1 WO 2015055801A1 EP 2014072293 W EP2014072293 W EP 2014072293W WO 2015055801 A1 WO2015055801 A1 WO 2015055801A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- carboxy
- isoglu
- heptadecanoyl
- ac4c
- peg3
- Prior art date
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Definitions
- the present invention relates to acylated glucagon analogues and their medical use, for example in the treatment of obesity and excess weight, diabetes, and other metabolic disorders.
- Pre-proglucagon is a 158 amino acid precursor polypeptide that is differentially processed in the tissues to form a number of structurally related proglucagon-derived peptides, including glucagon (Glu), glucagon-like peptide-1 (GLP-1 ), glucagon-like peptide-2 (GLP-2), and oxyntomodulin (OXM). These molecules are involved in a wide variety of physiological functions, including glucose homeostasis, insulin secretion, gastric emptying and intestinal growth, as well as regulation of food intake.
- Glu glucagon
- GLP-1 glucagon-like peptide-1
- GLP-2 glucagon-like peptide-2
- OXM oxyntomodulin
- Glucagon is a 29-amino acid peptide that corresponds to amino acids 53 to 81 of pre- proglucagon.
- Oxyntomodulin (OXM) is a 37 amino acid peptide which includes the complete 29 amino acid sequence of glucagon with an octapeptide carboxyterminal extension (amino acids 82 to 89 of pre-proglucagon, and termed "intervening peptide 1" or IP-1.
- IP-1 intervening peptide 1
- the major biologically active fragment of GLP-1 is produced as a 30-amino acid, C-terminally amidated peptide that corresponds to amino acids 98 to 127 of pre-proglucagon.
- Glucagon helps maintain the level of glucose in the blood by binding to glucagon receptors on hepatocytes, causing the liver to release glucose - stored in the form of glycogen - through glycogenolysis. As these stores become depleted, glucagon stimulates the liver to synthesize additional glucose by gluconeogenesis. This glucose is released into the bloodstream, preventing the development of hypoglycemia.
- GLP-1 decreases elevated blood glucose levels by improving glucose-stimulated insulin secretion and promotes weight loss chiefly through decreasing food intake.
- OXM is released into the blood in response to food ingestion and in proportion to meal calorie content. OXM has been shown to suppress appetite and inhibit food intake in humans (Cohen et al, Journal of Endocrinology and Metabolism, 88, 4696-4701 , 2003; WO 2003/022304). In addition to those anorectic effects, which are similar to those of GLP-1 , OXM must also affect body weight by another mechanism, since rats treated with oxyntomodulin show less body weight gain than pair-fed rats (Bloom, Endocrinology 2004, 145, 2687).
- OXM activates both the glucagon and the GLP-1 receptors with a two-fold higher potency for the glucagon receptor over the GLP-1 receptor, but is less potent than native glucagon and GLP-1 on their respective receptors.
- Human glucagon is also capable of activating both receptors, though with a strong preference for the glucagon receptor over the GLP-1 receptor.
- GLP-1 on the other hand is not capable of activating glucagon receptors.
- oxyntomodulin The mechanism of action of oxyntomodulin is not well understood. In particular, it is not known whether some of the extrahepatic effects of the hormone are mediated through the GLP-1 and glucagon receptors, or through one or more unidentified receptors. Other peptides have been shown to bind and activate both the glucagon and the GLP-1 receptor (Hjort et al, Journal of Biological Chemistry, 269, 30121-30124, 1994) and to suppress body weight gain and reduce food intake (see, for example, WO 2006/134340, WO 2007/100535, WO 2008/10101 , WO 2008/152403, WO 2009/155257, WO 2009/155258, WO2010/070252, WO2010/070253, WO2010/070255, WO2010/070251 , WO2011/006497, WO2011/160630, WO2011/160633, WO2013/092703, WO2014/041195.
- Obesity is a globally increasing health problem associated with various diseases, particularly cardiovascular disease (CVD), type 2 diabetes, obstructive sleep apnea, certain types of cancer, and osteoarthritis. As a result, obesity has been found to reduce life expectancy. According to 2005 projections by the World Health Organization there are 400 million adults (age > 15) classified as obese worldwide. In the US, obesity is now believed to be the second-leading cause of preventable death after smoking.
- CVD cardiovascular disease
- type 2 diabetes type 2 diabetes
- obstructive sleep apnea certain types of cancer
- osteoarthritis As a result, obesity has been found to reduce life expectancy.
- WHO projections by the World Health Organization there are 400 million adults (age > 15) classified as obese worldwide. In the US, obesity is now believed to be the second-leading cause of preventable death after smoking.
- the rise in obesity drives an increase in diabetes, and approximately 90% of people with type 2 diabetes may be classified as obese. There are 246 million people worldwide with diabetes, and by 2025 it is estimated that 380 million will have diabetes. Many have additional cardiovascular risk factors, including high/aberrant LDL and triglycerides and low HDL.
- the invention provides a compound having the formula: wherein
- Ci-4 alkyl is H, Ci-4 alkyl, acetyl, formyl, benzoyl or trifluoroacetyl;
- R 2 is OH or NH 2 ;
- P is a peptide having the sequence: H-X2-X3-GTFTSDYSKYLDS4 J AAHDFVEWLLSA wherein:
- X2 is selected from Aib, Ala, D-Ala, Ser, N-Me-Ser, Ac3c, Ac4c and Ac5c;
- X3 is selected from Gin and His;
- P 2 is absent or is a sequence of 1-20 amino acid units independently selected from the group consisting of Ala, Leu, Ser, Thr, Tyr, Cys, Glu, Lys, Arg, Dbu, Dpr and Orn;
- ⁇ is a residue of Lys, Arg, Orn or Cys in which the side chain is conjugated to a substituent having the formula -Z 2 -Z 1 ;
- -Z 1 is a fatty chain having a polar group at one end of the chain and a connection to Z 2 , -X- at the end of the chain distal from the polar group,
- the polar group comprises a carboxylic acid or a carboxylic acid bioisostere, a phos- phonic acid, or a sulfonic acid group;
- each Y is independently -NH, -NR, -S or -O, where R is alkyl, a protecting group or forms a linkage to another part of the spacer Z 2 ;
- each X is independently a bond, CO-, SO-, or SO2-;
- each V is independently a bivalent organic moiety linking Y and X;
- n 1-10; or a pharmaceutically acceptable salt or solvate thereof.
- P 1 may have the sequence:
- H-Aib-QGTFTSDYSKYLDS'+'AAHDFVEWLLSA e.g.
- H-Aib-QGTFTS DYSKYLDS-K([15-carboxy-pentadecanoyl]-isoGlu)-AAHDFVEWLLSA.
- the compound of the invention may be:
- the invention provides a compound having the formula:
- R 1 is H, C alkyl, acetyl, formyl, benzoyl or trifluoroacetyl;
- R 2 is OH or NH 2 ;
- P 1 is a peptide having the sequence:
- X2 is selected from Aib, Ac3c, Ac4c and Ac5c;
- X3 is selected from Gin and His;
- X15 is selected from Asp and Glu
- X16 is selected from Glu and ⁇ ;
- X17 is selected from Arg and ⁇ ;
- X 8 is selected from Ala and Arg
- X20 is selected from Lys and His;
- X24 is selected from Glu and ⁇ ;
- X28 is selected from Ser and ⁇ ; and P 2 is absent or is a sequence of 1-20 amino acid units independently selected from the group consisting of Ala, Leu, Ser, Thr, Tyr, Cys, Glu, Lys, Arg, Dbu, Dpr and Orn; wherein the compound contains one and only one ⁇ and wherein said ⁇ is a residue of Lys, Arg, Orn or Cys in which the side chain is conjugated to a substituent having the formula -Z -Z 1 ;
- -Z 1 is a fatty chain having a polar group at one end of the chain and a connection to Z 2 , -X- at the end of the chain distal from the polar group,
- the polar group comprises a carboxylic acid or a carboxylic acid bioisostere, a phos- phonic acid, or a sulfonic acid group;
- -X- is a bond, -CO-, -SO- or -SO2-;
- each Y is independently -NH, -NR, -S or -O, where R is alkyl, a protecting group or forms a linkage to another part of the spacer Z 2 ;
- each X is independently a bond, CO-, SO- or SO2-;
- each V is independently a bivalent organic moiety linking Y and X;
- n 1-10; or a pharmaceutically acceptable salt or solvate thereof.
- X2 is selected from Aib and Ac4c;
- X3 is Gin
- X15 is selected from Asp and Glu; X17 is Arg;
- X18 is Ala
- X20 is selected from Lys and His;
- X24 is Glu
- X28 is Ser. Useful combinations of residues include the following:
- X2 is Ac4c and X20 is Lys
- X2 is Aib and X20 is His. Additionally or alternatively, it may be desirable that X2 is Aib if X15 is E
- Particularly interesting substituents Z 2 Z 1 include [17-carboxy-heptadecanoyl]-isoGlu-Peg3- Peg3 and [17-carboxy-heptadecanoyl]-isoGlu-GSGSGG.
- P 1 may have a sequence selected from:
- the compound of the invention may be selected from:
- X2 is selected from Aib and Ac4c;
- X3 is selected from Gin and His;
- X15 is Asp
- X16 is Glu
- X17 is selected from Arg and ⁇ ;
- X18 is selected from Ala and Arg
- X20 is Lys
- X24 is selected from Glu and ⁇ ;
- X28 is selected from Ser and ⁇ ;
- X2 is Ac4c.
- X3 is His
- X2 is Ac4c
- X17 is ⁇ .
- Z 2 Z 1 is [17-carboxy-heptadecanoyl]-isoGlu-Peg3- Peg3 or [17-carboxy-heptadecanoyl]-isoGlu.
- Z 2 Z 1 is [17-carboxy-heptadecanoyl]-isoGlu- GSGSGG.
- P may have a sequence selected from:
- H-Ac4c-QGTFTSDYSKYLDERRAKDFIEWLE ⁇ A e.g. from
- H-Ac4c-QGTFTS DYSKYLDE-K([1 7-carboxy-heptadecanoyl]-isoGlu)-AAKDFIEWLESA
- H-Ac4c-QGTFTS DYSKYLDE-K([1 7-carboxy-heptadecanoyI]-isoGlu)-RAKDFIEWLESA
- H-Aib-QGTFTS DYSKYLDERAAKDFI-K([17-carboxy-heptadecanoyl]-isoGlu-GSGSGG)- WLESA
- the compound of the invention may be selected from:
- the compound of the invention comprises a residue ⁇ , i.e. a residue selected from Lys, Arg, Orn and Cys in which the side chain is conjugated to a substituent -Z 2 -Z 1 - as decribed in more detail below.
- the substituent is conjugated to the functional group at the distal end of the side chain from the alpha-carbon.
- the normal ability of the Lys, Arg, Orn or Cys side chain to participate in interactions mediated by that functional group may therefore be reduced or completely eliminated by the presence of the substituent.
- the overall properties of the compound may be relatively insensitive to changes in the actual amino acid present as residue ⁇ . Consequently, it is believed that any of the residues Lys, Arg, Orn and Cys may be present at any position where ⁇ is permitted.
- it may be advantageous that the amino acid component of ⁇ is Lys.
- -Z 1 is an acyl group of formula:
- A is -COOH or a carboxylic acid bioisostere
- B is a bond, Cearylene, or C6arylene-0-;
- Alk is a saturated or unsaturated fatty chain of 6 to 18 carbon atoms in length, optionally substituted with one or more substituents selected from fluoro, Ci-4alkyl, trifluoromethyl, hy- droxymethyl, amino, hydroxyl, Ci-4alkoxy, oxo, and carboxyl;
- -Z 2 - is -SA- -SA-SB- or -SB-SA-;
- -SA- is a single amino acid residue selected from ⁇ -Glu, a-Glu, a-Asp, ⁇ -Asp, Ala, ⁇ -Ala (3- aminopropanoic acid), and Gaba (4-aminobutanoic acid);
- n is 1-10 and each Pu is independently selected from Pu' and Pu each Pu' is independently a natural or unnatural amino acid residue; and each Pu'" is independently a residue of general formula: wherein m is 0-5 and p is 1 , 3, 4, or 5.
- R may be selected from H and 0-4 alkyl (e.g. methyl).
- the compounds of the invention are glucagon analogue peptides.
- References herein to a glucagon analogue peptide should be construed as references to a compound of the invention or to a peptide P 1 or P -P 2 as the context requires.
- Reference to a compound of the invention should be taken to include any pharmaceutically acceptable salt (e.g. an acetate or chloride salt) or solvate thereof, unless otherwise stated or excluded by context.
- the invention provides a composition comprising a compound of the invention as defined herein (including pharmaceutically acceptable salts or solvates thereof, as already described) in admixture with a carrier.
- the composition is a pharmaceutical composition and the carrier is a pharmaceutically acceptable carrier.
- the glucagon analogue peptide may be in the form of a pharmaceutically acceptable salt of the glucagon analogue.
- the compounds described herein find use, inter alia, in preventing weight gain or promoting weight loss.
- preventing is meant inhibiting or reducing when compared to the absence of treatment, and is not necessarily meant to imply complete cessation of weight gain.
- the peptides may cause a decrease in food intake and/or increased energy expenditure, resulting in the observed effect on body weight.
- the compounds of the invention may have a beneficial effect on glucose control and/or on circulating cholesterol levels, being capable of lowering circulating LDL levels and increasing HDL/LDL ratio.
- the compounds of the invention can be used for direct or indirect therapy of any condition caused or characterised by excess body weight, such as the treatment and/or prevention of obesity, morbid obesity, obesity linked inflammation, obesity linked gallbladder disease, obesity induced sleep apnea. They may also be used for the prevention of conditions caused or characterised by inadequate glucose control or dyslipidaemia (e.g. elevated LDL levels or reduced HDL/LDL ratio), diabetes (especially Type 2 diabetes), metabolic syndrome, hypertension, atherogenic dyslipidemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral artery disease, stroke or microvascular disease. Their effects in these conditions may be as a result of or associated with their effect on body weight, or may be independent thereof.
- the invention also provides a compound of the invention for use in a method of medical treatment, particularly for use in a method of treatment of a condition as described above.
- the invention also provides the use of a compound of the invention in the preparation of a medicament for the treatment of a condition as described above.
- the compound of the invention may be administered as part of a combination therapy with an agent for treatment of diabetes, obesity, dyslipidaemia or hypertension.
- the two active agents may be given together or separately, and as part of the same pharmaceutical formulation or as separate formulations.
- an anti-diabetic agent including but not limited to a biguanide (e.g. metformin), a sulfonylurea, a meglitinide or glinide (e.g. nateglinide), a DPP-IV inhibitor, an SGLT2 inhibitor, a glitazone, an insulin, or an insulin analogue.
- biguanide e.g. metformin
- a sulfonylurea e.g. metformin
- meglitinide or glinide e.g. nateglinide
- DPP-IV inhibitor e.g. nateglinide
- an SGLT2 inhibitor e.g. nateglinide
- insulin analogues include but are not limited to LantusTM, NovorapidTM, HumalogTM, NovomixTM, Actraphane HMTM, LevemirTM and ApidraTM.
- the compound can further be used in combination with an anti-obesity agent including but not limited to a glucagon-like peptide receptor 1 agonist, peptide YY or analogue thereof, cannabinoid receptor 1 antagonist, lipase inhibitor, melanocortin receptor 4 agonist, melanin concentrating hormone receptor 1 antagonist, phentermine (alone or in combination with topiramate), a combination of norepinephrine/dopamine reuptake inhibitor and opioid receptor antagonist (e.g. a combination of bupropion and naltrexone), or a serotonergic agent (e.g. lorcaserin).
- an anti-obesity agent including but not limited to a glucagon-like peptide receptor 1 agonist, peptide YY or analogue thereof, cannabinoid receptor 1 antagonist, lipase inhibitor, melanocortin receptor 4 agonist, melanin concentrating hormone receptor 1 antagonist, phentermine (alone or in combination
- the compound can further be used in combination with an anti-hypertension agent including but not limited to an angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker, diuretic, beta-blocker, or calcium channel blocker.
- an anti-hypertension agent including but not limited to an angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker, diuretic, beta-blocker, or calcium channel blocker.
- the compound can be used in combination with an anti-dyslipidaemia agent including but not limited to a statin, a fibrate, a niacin or a cholesterol absorbtion inhibitor.
- an anti-dyslipidaemia agent including but not limited to a statin, a fibrate, a niacin or a cholesterol absorbtion inhibitor.
- the invention further provides a composition or therapeutic kit comprising a compound of the invention and for example an anti-diabetic agent, anti-obesity agent, anti-hypertension agent or anti-dyslipidaemia agent as described above. Also provided is such a composition or therapeutic kit for use in a method of medical treatment, especially for treament of a condition as described above.
- the compound of the invention may be made by synthetic chemistry. Accordingly the invention provides a method of synthesis of a compound of the invention.
- the invention may also be made by a combination of recombinant and synthetic methods.
- the method may comprise expressing a precursor peptide sequence, optionally purifying the compund thus produced, and adding or modifying one or more amino acids to produce a compound of the invention or a compound comprising the amino acid sequence P 1 or P -P 2 .
- the step of modification may comprise introduction of an Orn residue (e.g. by modiication of a precursor residue) and/or introduction of a substituent Z2Z1 at the site of a residue ⁇ .
- the precursor peptide may be expressed from a nucleic acid encoding the precursor peptide in a cell or a cell-free expression system comprising such a nucleic acid.
- amino acids such as Aib (a-aminoisobutyric acid), Orn (ornithine), Dbu (2,4-diaminobutyric acid), Dpr (2,3-diaminopropanoic acid), Ac3c (1-amino-cyclopropanecarboxylic acid), Ac4c (1- amino-cyclobutanecarboxylic acid) and Ac5c (1-amino-cyclopentanecarboxylic acid).
- Ac3c, Ac4c and Ac5c have similar structures and are to some extent interchangeable, although Ac4c may be preferred.
- Glucagon is a 29-amino acid peptide that corresponds to amino acids 53 to 81 of pre- proglucagon and has the sequence His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr- Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr.
- Oxyntomodulin is a 37 amino acid peptide which includes the complete 29 amino acid sequence of glucagon with an octapeptide carboxyterminal extension (amino acids 82 to 89 of pre-proglucagon, having the sequence Lys-Arg-Asn-Arg-Asn-Asn-lle-Ala and termed "intervening peptide 1" or IP-1 ; the full sequence of human oxyntomodulin is thus His-Ser-Gln-Gly-Thr-Phe-Thr-Ser- Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr- Lys-Arg-Asn-Arg-Asn-Arg-Asn-Asn-lle-Ala).
- the major biologically active fragment of GLP-1 is produced as a 30-amino acid, C-terminally amidated peptide that corresponds to amino acids 98 to 127 of pre-proglucagon.
- the term "native glucagon” thus refers to native human glucagon having the sequence H-His- Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe- Val-Gln-Trp-Leu-Met-Asn-Thr-OH.
- Amino acids within the sequence P 1 of the compounds of the invention can be considered to be numbered consecutively from 1 to 29 in the conventional N-terminal to C-terminal direction. Reference to a "position" within P 1 should be construed accordingly, as should reference to positions within native human glucagon and other molecules.
- a compound of the invention may comprise a C-terminal peptide sequence P 2 of 1-20 amino acids, for example to stabilise the conformation and/or secondary structure of the glucagon analogue peptide, and/or to render the glucagon analogue peptide more resistant to enzymatic hydrolysis, e.g. as described in W099/46283.
- P 2 represents a peptide sequence of 1-20 amino acid residues, e.g. in the range of 1-15, more preferably in the range of 1-10, in particular in the range of 1-7 amino acid residues, e.g., 1 , 2, 3, 4, 5, 6 or 7 amino acid residues, such as 6 amino acid residues.
- Each of the amino acid residues in the peptide sequence P 2 may independently be selected from Ala, Leu, Ser, Thr, Tyr, Cys, Glu, Lys, Arg, Dbu (2,4-diaminobutyric acid), Dpr (2,3- diaminopropanoic acid) and Orn (ornithine).
- the amino acid residues are selected from Ser, Thr, Tyr, Glu, Lys, Arg, Dbu, Dpr and Orn, more preferably selected exclusively from Glu, Lys, and Cys.
- the above-mentioned amino acids may have either D- or L- configuration, which in certain embodiments, have an L-configuration.
- Particularly preferred sequences P 2 are sequences of four, five, six or seven consecutive lysine residues (i.e. Lys3, Lys4, Lys5, Lyse or Lys7), and particularly five or six consecutive lysine residues.
- Other exemplary sequences of P 2 are shown in WO 01/04156.
- the C-terminal residue of the sequence P 2 may be a Cys residue.
- the peptide sequence P 2 has no more than 25% sequence identity with the corresponding sequence of the IP- portion of human OXM (which has the sequence Lys-Arg-Asn-Arg-Asn- Asn-lle-Ala).
- Percent (%) amino acid sequence identity of a given peptide or polypeptide sequence with respect to another polypeptide sequence (e.g. IP-1 ) is calculated as the percentage of amino acid residues in the given peptide sequence that are identical with correspondingly positioned amino acid residues in the corresponding sequence of that other polypeptide when the two are aligned with one another, introducing gaps for optimal alignment if necessary. % identity values may be determined using WU-BLAST-2 (Altschul et al., Methods in Enzymology, 266:460-480 (1996)). WU-BLAST-2 uses several search parameters, most of which are set to the default values.
- a % amino acid sequence identity value is determined by the number of matching identical residues as determined by WU- BLAST-2, divided by the total number of residues of the reference sequence (gaps introduced by WU-BLAST-2 into the reference sequence to maximize the alignment score being ignored), multiplied by 100.
- P 2 is aligned optimally with the 8 amino acids of IP-1 , it has no more than two amino acids which are identical with the corresponding amino acids of IP-1 .
- P 2 is absent.
- ⁇ is a residue of Lys, Arg, Orn or Cys whose side chain is conjugated to a substituent Z -Z 1 .
- the substituent binds plasma proteins (e.g. albumin) in the blood stream, thus shielding the compounds of the invention from enzymatic degradation and thereby enhancing the half-life of the compounds. It may also modulate the potency of the compound, e.g. with respect to the glucagon receptor and/or the GLP-1 receptor.
- the group Z 1 is binds plasma proteins (e.g. albumin) in the blood stream, thus shielding the compounds of the invention from enzymatic degradation and thereby enhancing the half-life of the compounds. It may also modulate the potency of the compound, e.g. with respect to the glucagon receptor and/or the GLP-1 receptor.
- Z 1 is a fatty chain having a connection to Z 2 , referred to herein as -X- and, at the end of the chain distal from the connection to Z 2 , a polar group.
- -X- may be, for example, a bond, acyl (-CO-), sulfinyl (-SO-), or sulfonyl (-SO2-), the connection being located at the co-position with respect to the polar group, that is, at the end of the chain distal from the polar group.
- the polar group is an acidic or weakly acid group, for example a carboxylic acid or a carboxylic acid bioisostere, a phosphonate, or a sulfonate.
- the polar group may have a pK a of between -2 and 12 in water, more preferably between 1 and 7, more preferably between 3 and 6.
- Certain preferred polar groups have a pK a of between 4 and 5.
- the polar group preferably comprises a carboxylic acid or carboxylic acid bioisostere.
- Suitable carboxylic acid bioisosteres are known in the art.
- the bioisostere has a proton having a pK a similar to the corresponding carboxylic acid.
- suitable bioisoteres may include, not by way of limitation, tetrazole, acylsulfomides, acylhydroxylamine, and squaric acid derivatives, as shown below (— indicates the point of attachment):
- the polar group may be a group of formula A-B-, wherein A is a carboxylic acid (-COOH) or a carboxylic acid bioisostere, a phosphonic acid (-P(0)(OH)2), or a sulfonic acid (-SO2OH) group, and B is a bond or linker between A and the fatty chain.
- A is a carboxylic acid (-COOH) or a carboxylic acid bioisostere
- -P(0)(OH)2 phosphonic acid
- -SO2OH sulfonic acid
- B when B is a linker, it may be a cycloalkylene, heterocycloalkylene, Cearylene, or
- B When B is phenylene it may, for example, be selected from 1 ,2-phenylene, 1 ,3-phenylene, 1 ,4-phenylene, preferably 1 ,4-phenylene (so that A-B- is a 4-benzoic acid substituent or 4-benzoic acid bioisostere).
- B When B is phenylene-O-, it may, for example, be selected from 1 ,2-phenylene-O- 1 ,3-phenylene-O- 1 ,4-phenylene-O- preferably 1 ,4-phenylene-O.
- Each phenylene of B may be optionally substituted with one or more substituents selected from fluoro, methyl, trifluoromethyl, amino, hydroxyl, and Ci-4alkoxy, preferably methoxy. It will be appreciated that substituent identity and position may be selected to subtly alter the pK a of the polar group. Suitable inductively or mesomerically electron-withdrawing or donating groups and their positional effects are known in the art.
- B may be Cs eheteroarylene, for example, pyridinylene or t iofuranylene, and may be optionally substituted as described.
- A-B- may be selected from:
- A is -COOH.
- A is a carboxylic acid and B is C6arylene-0-.
- Fatty chain refers to a moiety comprising a chain of carbon atoms, the carbon atoms being predominantly substituted with hydrogen or hydrogen-like atoms, for example, a hydrocarbon chain.
- Such fatty chains are often referred to as lipophilic, although it will be ap- preciated that substitution may alter the lipophilic properties of the overall molecule.
- the fatty chain may by aliphatic. It may be entirely saturated or may include one or more double or triple bonds. Each double bond, if present, may be in the E or Z configuration.
- the fatty chain may also have one or more cycloalkylene or heterocycloalkylene moieties in its length, and additionally or alternatively may have one or more arylene or heteroarylene moie- ties in its length.
- the fatty chain may incorporate a phenylene or piperazinylene moiety in its length as, for example, shown below (wherein— represents the points of attachment within the chain).
- the fatty chain may be derived from a fatty acid, for example, it may be derived from a medi- um-chain fatty acid (MCFA) with an aliphatic tail of 6-12 carbon atoms, a long-chain fatty acid (LCFA) with an aliphatic tail of 13-21 carbon atoms, or a very long-chain fatty acid (LCFA) with an aliphatic tail of 22 carbon atoms or more.
- MCFA medi- um-chain fatty acid
- LCFA long-chain fatty acid
- LCFA very long-chain fatty acid
- linear saturated fatty acids from which suitable fatty chains may be derived include tridecylic (tridecanoic) acid, myristic (tetradecanoic) acid, pentadecylic (pentadecanoic) acid, palmitic (hexadecanoic) acid, and margaric (heptadecanoic) acid.
- linear unsaturated fatty acids from which suitable fatty chains may be derived include myristoleic acid, palmitoleic acid, sapienic acid and oleic acid.
- the fatty chain may be connected to Z 2 by an amide linkage, a sulfinamide linkage, a sulfonamide linkage, or by an ester linkage, or by an ether, thioether or amine linkage. Accordingly, the fatty chain may have at the ⁇ position, that is, the position distal to the polar group, a bond to Z 2 or an acyl (-CO-), sulfinyl (-SO-), or sulfonyl (-SO2-) group.
- the fatty chain has an acyl (-CO-) group at the position distal to the polar group and is connected to Z 2 by an amide or ester linkage.
- Z 1 is a group of formula: A-B-Alk-X- where A-B- is the polar group defined above, X is a bond, acyl (-CO-), sulfinyl (-SO-), or sulfonyl (-SO2-), and Alk is a fatty chain that may be optionally substituted with one or more substituents.
- the fatty chain is preferably 6 to 18 carbon atoms in length (e.g. a
- C6-i8alkylene more preferably, 8 to 18 carbons in length (e.g. a Ce-iaalkylene), more prefera- bly, 12 to 16 carbons in length (e.g. C12 -i6alkylene), and may be saturated or unsaturated.
- Alk is saturated, that is, preferably Alk is alkylene.
- Z 1 is an acyl group of formula:
- Optional substituents on the fatty chain may be independently selected from fluoro, preferably methyl; trifluoromethyl, hydroxymethyl, amino, hydroxyl, Ci-4alkoxy, preferably methoxy; oxo, and carboxyl, and may be independently located at any point along the chain.
- each optional substituent is selected from fluoro, methyl, and hydroxyl. Where more than one substituent is present, substituents may be the same or different.
- the number of substituents is 0 to 3; more preferably the fatty chain is unsubstituted.
- Z 1 is an acyl group of formula:
- Z 1 is:
- Z 1 are derived from long-chain saturated ⁇ , ⁇ -dicarboxylic acids of formula HOOC-(CH2)i2-i8-COOH, preferably, long-chain saturated ⁇ , ⁇ -dicarboxylic acids having an even number of carbon atoms in the aliphatic chain.
- Z may be:
- the carboxylic acid group may be replaced by a bioisotere as detailed herein.
- Z 2 is spacer that connects Z to the side chain of the amino acid component of ⁇ .
- Z 2 is a spacer bound at one terminus by Y, which may be a nitrogen, oxygen or sufhur atom, and at the other terminus by X, which may be a bond or an acyl (-CO-), sulfinyl (-SO-), or sulfonyl (-SO2-).
- Z 2 may be a spacer of formula (— indicate points of attachment):
- Y may be -NH, -NR, -S or -O, where R may be alkyl, a protecting group or may form a link- age to another part of the spacer, with the remaining valency forming a linkage to Z 1 ;
- X may be a bond, CO- SO- or SO2-, with the remaining valency forming a linkage to the side chain of the amino acid component of ⁇ ;
- V is a bivalent organic moiety linking Y and X; and n may be 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10. Where n is 2 or more, each Y, V, and X is inde- pendent of every other Y, V, and X.
- Z 2 may be bound at each side by amide, sulfinamide, sulfonamide, or ester linkages or by amino, ether, or thioether linkages depending upon the nature of Y and X and the corresponding linking groups on Z 1 and the side chain.
- Y when Y is -S, X is a bond.
- each V may also be bound to each adjacent V by linkages as de- scribed.
- linkages are amides, esters or sulfonamides, most preferably amides.
- each Y is -NH or -NR and each X is CO- or SO2-.
- Z 2 is a spacer of formula -SA- -SB- -SA-SB- or -SB-SA- wherein SA and SB are as defined below.
- Z 2 is selected from -SA- or -SB-SA-, that is, [side chain]-Z 2 Z 1 is [side chain]-SA-Z 1 or [side chain]-SB-SA-Z 1 .
- SA may be a single amino acid residue or a residue of an amino acid derivative, especially an amino acid derivative residue having a sulfinyl or sulfonyl in place of the carboxy moiety at the C terminus. Additionally or alternatively, the single amino acid residue may have an oxygen or sulfur atom in place of the nitrogen atom at the N terminus.
- SA is a single amino acid residue.
- the amino acid may be selected from ⁇ -Glu, a-Glu, a-Asp, ⁇ -Asp, Ala, ⁇ -Ala (3-aminopropanoic acid), and Gaba (4-aminobutanoic acid). It will be understood that amino acids may be D or L, or a racemic or enantioenriched mixture. In some embodiments, the amino acid is an L-amino acid. In some embodiments, the amino acid is a D-amino acid.
- SA has a carboxylic acid substituent, with ⁇ -Glu, a-Glu, a- Asp, and ⁇ -Asp, and sulfinyl and sulfonyl derivatives thereof, being preferred. Accordingly, in some embodiments, the amino acid residue is:
- -X- is -CO-, -SO-, -SO2-, preferably -CO-, and a is 1 or 2, preferably 2.
- the carboxylic acid is an ester, and the amino acid residue is:
- R is Ci-4alkyl or Cearyl.
- R is Ci-4alkyl, preferably methyl or ethyl, more preferably ethyl.
- SA is y-Glu.
- each polymeric unit Pu may be bound at each side by amide, sulfinamide, sulfonamide, or ester linkages or by amino, ether, or thioether linkages depending upon the nature of Y and X and the corresponding linking groups on Z 1 , SA, and Lys.
- each Pu may be independently a unit of formula:
- Y may be -NH, -NR, -S or -O, wherein R may be alkyl, a protecting group or may form a linkage to another part of the spacer, with the remaining valency forming a linkage to Z ;
- V may be a bond, CO-, SO-, or SO2-, with the remaining valency forming a linkage to Lys; and V is a bivalent organic moiety linking Y and X.
- V is the a-carbon of a natural or unnatural amino acid, that is V is - CHR AA - 1 wherein R AA is an amino acid side chain; or V is an optionally substituted
- Ci-ealkylene, or V is a chain comprising one or more units of ethylene glycol in series, also known as PEG chain, for example, -CH2CH2-(OCH 2 CH2)m-0-(CH 2 )p-, where m is 0, 1 , 2, 3, 4, or 5, and p is 1 , 2, 3, 4, or 5; when X is CO- p is preferably 1 , 3, 4, or 5.
- Optional alkylene substituents include fluoro, methyl, hydroxy, hydroxymethy, and amino.
- Preferred Pu units include:
- Amino-(PEG)m-carboxylic acid residues Pu"', and may be present in any combination or order.
- SB may comprise one or more of each of Pu 1 , Pu", and Pu iH in any order, or may comprise one or more units of Pu', Pu", and Pu iN only, or one of more units selected from Pu' and Pu", Pu' and Pu'", or Pu" and Pu"'.
- Pu' single amino acid residues may be present in any combination or order.
- SB may comprise one or more of each of Pu 1 , Pu", and Pu iH in any order, or may comprise one or more units of Pu', Pu", and Pu iN only, or one of more units selected from Pu' and Pu", Pu' and Pu'", or Pu" and Pu"'.
- Each Pu' may be independently selected from any natural or unnatural amino acid residue and, for example, may be selected from Gly, Pro, Ala, Val, Leu, He, Met, Cys, Phe, Tyr, Trp, His, Lys, Arg, Gin, Asn, a-Glu, ⁇ -Glu, Asp, Ser Thr, Gaba, Aib, ⁇ -Ala, 5-aminopentanoyl, 6- aminohexanoyl, 7-aminoheptanoyl, 8-aminooctanoyl, 9-aminononanoyl, and 10- aminodecanoyl.
- Pu' amino acid residues are selected from Gly, Ser, Ala, Thr, and Cys, more preferably from Gly and Ser.
- SB is -(Pu - wherein n is 1 to 8, more preferably 5 to 7, most preferably 6. In some preferred embodiments, SB is -(Pu')n-, n is 6 and each Pu' is independently selected from Gly or Ser, with a preferred sequence being -Gly-Ser-Gly-Ser-Gly-Gly-.
- Each Pu may be independently selected from any dipeptide residue comprising two natural or unnatural amino acid residues bound by an amide linkage.
- Preferred Pu" dipeptide residues include Gly-Gly, Gly-Ser, Ser-Gly, Gly-Ala, Ala-Gly, and Ala-Ala, more preferably Gly- Ser and Gly-Gly.
- SB is -( ⁇ ") ⁇ -, wherein n is 2 to 4, more preferably 3, and each Pu" is independently selected from Gly-Ser and Gly-Gly. In some preferred embodiments SB is - ( ⁇ ") ⁇ -, n is 3 and each Pu" is independently selected from Gly-Ser and Gly-Gly, with a preferred sequence being -(Gly-Ser)-(Gly-Ser)-(Gly-Gly).
- Amino acids having stereogenic centres within Pu' and Pu" may be racemic, enantioenriched, or enantiopure.
- the or each amino acid is independently an L-amino acid. In some embodiments, the or each amino acid is independently a D-amino acid.
- Each Pu"' may be independently a residue of general formula: wherein m is 0, 1 , 2, 3, 4, or 5, preferably 1 or 2, and p is 1 , 3, 4, or 5, preferably 1 .
- m is 1 and p is 1 , that is, Pu iH is a residue of 8-amino-3,6- dioxaoctanoic acid (also known as ⁇ 2-[2-aminoethoxy]ethoxy ⁇ acetic acid and H2N-PEG3- COOH). This residue is referred to herein as -PEG3-.
- m is 2 and p is 1 , that is, Pu'" is a residue of 11-amino-3,6,9- trioxaundecanoic acid (also known as H2N-PEG4-COOH). This residue is referred to herein
- SB is -( ⁇ " -, wherein n is 1 to 3, more preferably 2. In some preferred embodiments, SB is selected from -PEG3-PEG3- and -PEG4-PEG4-.
- the inventors have found that, especially when longer linkers were included, the polar or charged group at the end of Z 1 may be capable of participating in an undesirable intra-molecular nteraction with the free N- terminus of the molecule which might compromise the beneficial effects of the polar group on pharmacokinetics.
- the peptide backbones of the compounds described herein are belived to adopt relatively well-defined helical secondary structure, so the capacity of the polar group to engage in such interactions may depend on its location within the molecule. When located towards the C-terminus, interaction with the N-terminus may be relatively unlikely. However, the inventors were surprised to find that the substituent could be located at residues 16 and 17 of the molecule without necessarily compromising the pharmacokinetic benefits obtained.
- conjugated is used here to describe the physical attachment of one identifiable chemical moiety to another, and the structural relationship between such moieties. It should not be taken to imply any particular method of synthesis.
- the compounds of the present invention may be manufactured either by standard synthetic methods, recombinant expression systems, or any other state of the art method.
- the glucagon analogues may be synthesized in a number of ways, including, for example, a method which comprises: (a) synthesizing the peptide by means of soiid-phase or liquid-phase methodology, either stepwise or by fragment assembly, and isolation and purifying of the final peptide product; or
- Expression is typically performed from a nucleic acid encoding the precursor peptide, which may be perfomed in a cell or a cell-free expression system comprising such a nucleic acid.
- the nucleic acid fragments encoding the precursor peptide will normally be inserted in suitable vectors to form cloning or expression vectors.
- the vectors can, depending on purpose and type of application, be in the form of plasmids, phages, cosmids, mini-chromosomes, or virus, but also naked DNA which is only expressed transiently in certain cells is an important vector.
- Preferred cloning and expression vectors are capable of autonomous replication, thereby enabling high copy- numbers for the purposes of high-level expression or high-level replication for subsequent cloning.
- an expression vector comprises the following features in the 5' ⁇ 3' direction and in operable linkage: a promoter for driving expression of the nucleic acid fragment, optionally a nucleic acid sequence encoding a leader peptide enabling secretion (to the extracellular phase or, where applicable, into the periplasma), the nucleic acid fragment encoding the precursor peptide, and optionally a nucleic acid sequence encoding a terminator. They may comprise additional features such as selectable markers and origins of replication. When operating with expression vectors in producer strains or cell lines it may be preferred that the vector is capable of integrating into the host cell genome. The skilled person is very familiar with suitable vectors and is able to design one according to their specific requirements.
- the vectors of the invention are used to transform host cells to produce the precursor peptide.
- Such transformed cells can be cultured cells or cell lines used for propagation of the nucleic acid fragments and vectors, and/or used for recombinant production of the precursor peptides.
- Preferred transformed cells are micro-organisms such as bacteria [such as the species Escherichia (e.g. E. coli), Bacillus (e.g. Bacillus subtilis), Salmonella, or Mycobacterium (preferably non-pathogenic, e.g. M. bovis BCG), yeasts (e.g., Saccharomyces cerevisiae and Pichia pastoris), and protozoans.
- the transformed cells may be derived from a multicellular organism, i.e. it may be fungal cell, an insect cell, an algal cell, a plant cell, or an animal cell such as a mammalian cell.
- the transformed cell is capable of replicating the nucleic acid fragment of the invention.
- Cells expressing the nucleic fragment can be used for small-scale or large-scale preparation of the peptides of the invention.
- Binding of the relevant compounds to GLP-1 or glucagon (Glu) receptors may be used as an indication of agonist activity, but in general it is preferred to use a biological assay which measures intracellular signalling caused by binding of the compound to the relevant receptor. For example, activation of the glucagon receptor by a glucagon agonist will stimulate cellular cyclic AMP (cAMP) formation. Similarly, activation of the GLP-1 receptor by a GLP-1 agonist will stimulate cellular cAMP formation. Thus, production of cAMP in suitable cells expressing one of these two receptors can be used to monitor the relevant receptor activity. Use of a suitable pair of cell types, each expressing one receptor but not the other, can hence be used to determine agonist activity towards both types of receptor.
- cAMP cyclic AMP
- the GLP-1 receptor and/or the glucagon receptor may have the sequence of the receptors as described in the examples.
- the assays may employ the human glucagon receptor (Glucagon-R) having primary accession number GL4503947 and/or the human glucagon-like peptide 1 receptor (GLP-1 R) having primary accession number GM66795283. (in that where sequences of precursor proteins are referred to, it should of course be understood that assays may make use of the mature protein, lacking the signal sequence).
- EC50 values may be used as a numerical measure of agonist potency at a given receptor.
- An EC50 value is a measure of the concentration of a compound required to achieve half of that compound's maximal activity in a particular assay.
- EC5o[GLP-1] lower than the ECso[GLP-1] of glucagon in a particular assay may be considered to have higher GLP-1 receptor agonist potency than glucagon.
- the compounds described in this specification are typically GluGLP-1 dual agonists, as determined by the observation that they are capable of stimulating cAMP formation at both the glucagon receptor and the GLP-1 receptor.
- the stimulation of each receptor can be measured in independent assays and afterwards compared to each other.
- the relative GLP-1 R selectivity can be calculated as follows:
- Relative GLP-1 R selectivity [compound] (EC50 [GLP-1 R]) / (EC50 [Glucagon-R])
- EC50 stands for the half maximal Effective Concentration, typically at a particular receptor, or on the level of a particular marker for receptor function, and can refer to an inhibitory or an antagonistic activity, depending on the specific biochemical context.
- a compound's relative selectivity may allow its effect on the GLP-1 or glucagon receptor to be compared directly to its effect on the other receptor.
- the results are compared for glucagon and GLP-1 receptors from the same species, e.g. human glucagon and GLP-1 receptors, or murine glucagon and GLP-1 receptors.
- the compounds of the invention may have a higher relative GLP-1 R selectivity than human glucagon in that for a particular level of glucagon-R agonist activity, the compound may display a higher level of GLP-1 R agonist activity (i.e. greater potency at the GLP-1 receptor) than glucagon.
- the absolute potency of a particular compound at the glucagon and GLP-1 receptors may be higher, lower or approximately equal to that of native human glucagon, as long as the appropriate relative GLP-1 R selectivity is achieved.
- the compounds of this invention may have a lower ECso [GLP-1 R] than human glucagon.
- the compounds may have a lower ECso[GLP-1-R] than glucagon while maintaining an EC50 [Glucagon-R] that is less than 10-fold higher than that of human glucagon, less than 5-fold higher than that of human glucagon, or less than 2-fold higher than that of human glucagon.
- the compounds of the invention may have an EC50 [Glucagon-R] that is less than two-fold that of human glucagon.
- the compounds may have an EC50 [Glucagon-R] that is less than two-fold that of human glucagon and have an EC50 [GLP-1 R] that is less than half that of human glucagon, less than a fifth of that of human glucagon, or less than a tenth of that of human glucagon.
- the relative GLP-1 R selectivity of the compounds may be between 0.05 and 20.
- the compounds may have a relative selectivity of 0.05-0.20, 0.1 -0.30, 0.2-0.5, 0.3-0.7, or 0.5- 1.0; 1 .0-2.0, 1 .5-3.0, 2.0-4.0 or 2.5-5.0; or 0.05-20, 0.075-15, 0.1 -10, 0.15-5, 0.75-2.5 or 0.9- 1 .1 .
- EC50 of any given compound for both the Glucagon-R and GLP-1 R e.g. for the human glucagon and GLP-1 receptors, should be less than 1 nM.
- the compounds of the invention may provide attractive treatment and/or prevention options for, inter alia, obesity and metabolic diseases including diabetes, as discussed below.
- Diabetes comprises a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. Acute signs of diabetes include excessive urine production, resulting compensatory thirst and increased fluid intake, blurred vision, unexplained weight loss, lethargy, and changes in energy metabolism.
- the chronic hyperglycemia of diabetes is associated with long-term damage, dysfunction, and failure of various organs, notably the eyes, kidneys, nerves, heart and blood vessels. Diabetes is classified into type 1 diabetes, type 2 diabetes and gestational diabetes on the basis on pathogenetic characteristics.
- Type 1 diabetes accounts for 5-10% of all diabetes cases and is caused by auto-immune destruction of insulin-secreting pancreatic ⁇ -cells.
- Type 2 diabetes accounts for 90-95% of diabetes cases and is a result of a complex set of metabolic disorders. Type 2 diabetes is the consequence of endogenous insulin production becoming insufficient to maintain plasma glucose levels below the diagnostic thresholds. Gestational diabetes refers to any degree of glucose intolerance identified during pregnancy.
- Pre-diabetes includes impaired fasting glucose and impaired glucose tolerance and refers to those states that occur when blood glucose levels are elevated but below the levels that are established for the clinical diagnosis for diabetes.
- a large proportion of people with type 2 diabetes and pre-diabetes are at increased risk of morbidity and mortality due to the high prevalence of additional metabolic risk factors including abdominal obesity (excessive fat tissue around the abdominal internal organs), atherogenic dyslipidemia (blood fat disorders including high triglycerides, low HDL cholesterol and/or high LDL cholesterol, which foster plaque buildup in artery walls), elevated blood pressure (hypertension) a prothrombotic state (e.g. high fibrinogen or plasminogen activator inhibitor— 1 in the blood), and proinflammatory state (e.g., elevated C-reactive protein in the blood).
- abdominal obesity excessive fat tissue around the abdominal internal organs
- atherogenic dyslipidemia blood fat disorders including high triglycerides, low HDL cholesterol and/or high LDL cholesterol, which foster plaque buildup in artery walls
- elevated blood pressure hypertension
- a prothrombotic state e.g. high fibrinogen or plasminogen activator inhibitor— 1 in the blood
- proinflammatory state
- Dyslipidaemia is associated with increased risk of cardiovascular diasese.
- High Density Lipoprotein (HDL) is of clinical importance since an inverse correlation exists between plasma HDL concentrations and risk of atherosclerotic disease.
- the majority of cholesterol stored in atherosclerotic plaques originates from LDL and hence elevated concentrations
- Low Density Lipoproteins (LDL) is closely associated with atherosclerosis.
- the HDL/LDL ratio is a clinical risk indictor for atherosclerosis and coronary atherosclerosis in particular.
- Metabolic syndrome is characterized by a group of metabolic risk factors in one person.
- abdominal obesity excessive fat tissue around the abdominal internal organs
- atherogenic dyslipidemia blood fat disorders including high triglycerides, low HDL cholesterol and/or high LDL cholesterol, which foster plaque buildup in artery walls
- elevated blood pressure hypertension
- insulin resistance and glucose intolerance
- prothrombotic state e.g. high fibrinogen or plasminogen activator inhibitor— 1 in the blood
- proinflammatory state e.g., elevated C-reactive protein in the blood.
- the compounds of the invention act as dual agonists both on the human glucagon-receptor and the human GLP1- receptor, abbreviated here as dual GluGLP-1 agonists.
- the dual agonist may combine the effect of glucagon, e.g. on fat metabolism, with the effect of GLP-1 , e.g. on blood glucose levels and food intake. They may therefore act to accelerate elimination of excessive adipose tissue, induce sustainable weight loss, and improve glycaemic control.
- Dual GluGLP-1 agonists may also act to reduce cardiovascular risk factors such as high cholesterol, high LDL-cholesterol or low HDL/LDL cholesterol ratios.
- the compounds of the present invention can therefore be used in a subject in need thereof as pharmaceutical agents for preventing weight gain, promoting weight loss, reducing excess body weight or treating obesity (e.g. by control of appetite, feeding, food intake, calorie intake, and/or energy expenditure), including morbid obesity, as well as associated diseases and health conditions including but not limited to obesity linked inflammation, obesity linked gallbladder disease and obesity induced sleep apnea.
- the compounds of the invention may also be used for treatment of conditions caused by or associated with impaired glucose control, including metabolic syndrome, insulin resistance, glucose intolerance, pre-diabetes, increased fasting glucose, type 2 diabetes, hypertension, atherosclerois, arteriosclerosis, coronary heart disease, peripheral artery disease and stroke, in a subject in need thereof. Some of these conditions can be associated with obesity. However, the effects of the compounds of the invention on these conditions may be mediated in whole or in part via an effect on body weight, or may be independent thereof.
- the synergistic effect of dual GluGLP-1 agonists may also result in reduction of
- cardiovascular risk factors such as high cholesterol and LDL, which may be entirely independent of their effect on body weight.
- the invention provides the use of a compound of the invention in the treatment of a condition as described above, in an individual in need thereof.
- the invention also provides a compound of the invention for use in a method of medical treatment, particularly for use in a method of treatment of a condition as described above.
- the compounds described may be used in treating diabetes, esp. type 2 diabetes.
- the present invention comprises use of a compound for treating diabetes, esp. type 2 diabetes in an individual in need thereof.
- the compounds described may be used in preventing weight gain or promoting weight loss.
- the present invention comprises use of a compound for preventing weight gain or promoting weight loss in an individual in need thereof.
- the present invention comprises use of a compound in a method of treatment of a condition caused or characterised by excess body weight, e.g. the treatment and/or prevention of obesity, morbid obesity, morbid obesity prior to surgery, obesity linked inflammation, obesity linked gallbladder disease, obesity induced sleep apnea, prediabetes, diabetes, esp. type 2 diabetes, hypertension, atherogenic dyslipidimia, atherosclerois, arteriosclerosis, coronary heart disease, peripheral artery disease, stroke or microvascular disease in an individual in need thereof.
- the compounds described may be used in a method of lowering circulating LDL levels, and/or increasing HDL/LDL ratio.
- the present invention comprises use of a compound in a method of lowering circulating LDL levels, and/or increasing HDL/LDL ratio in an individual in need thereof.
- the compounds described may be used in a method of lowering circulating triglyceride levels.
- compositions prepared for storage or administration Such a composition typically comprises a
- the therapeutically effective amount of a compound of the present invention will depend on the route of administration, the type of mammal being treated, and the physical characteristics of the specific mammal under consideration. These factors and their relationship to determining this amount are well known to skilled practitioners in the medical arts. This amount and the method of administration can be tailored to achieve optimal efficacy, and may depend on such factors as weight, diet, concurrent medication and other factors, well known to those skilled in the medical arts.
- the dosage sizes and dosing regimen most appropriate for human use may be guided by the results obtained by the present invention, and may be confirmed in properly designed clinical trials.
- the compounds of the present invention may be particularly useful for treatment of humans.
- An effective dosage and treatment protocol may be determined by conventional means, starting with a low dose in laboratory animals and then increasing the dosage while monitoring the effects, and systematically varying the dosage regimen as well. Numerous factors may be taken into consideration by a clinician when determining an optimal dosage for a given subject. Such considerations are known to the skilled person.
- pharmaceutically acceptable carrier includes any of the standard pharmaceutical carriers.
- Pharmaceutically acceptable carriers for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit. 1985).
- sterile saline and phosphate- buffered saline at slightly acidic or physiological pH may be used.
- pH buffering agents may be phosphate, citrate, acetate, tris/hydroxymethyl)aminomethane (TRIS), N- Tris(hydroxymethyl)methyl-3-aminopropanesulphonic acid (TAPS), ammonium bicarbonate, diethanolamine, histidine, which is a preferred buffer, arginine, lysine, or acetate or mixtures thereof.
- TIS tris/hydroxymethyl)aminomethane
- TAPS N- Tris(hydroxymethyl)methyl-3-aminopropanesulphonic acid
- ammonium bicarbonate diethanolamine
- histidine which is a preferred buffer
- arginine arginine
- lysine or acetate or mixtures thereof.
- the term further encompases any agents listed in the US Pharmacopeia for use in animals, including humans.
- salts include pharmaceutically acceptable salts such as acid addition salts and basic salts.
- acid addition salts include hydrochloride salts, citrate salts and acetate salts.
- basic salts include salts where the cation is selected from alkali metals, such as sodium and potassium, alkaline earth metals, such as calcium, and ammonium ions + N(R 3 )3(R 4 ), where R 3 and R 4 independently designates optionally substituted Ci-6-alkyl, optionally substituted C2-6-alkenyl, optionally substituted aryl, or optionally substituted heteroaryl.
- Treatment is an approach for obtaining beneficial or desired clinical results.
- beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable.
- Treatment can also mean prolonging survival as compared to expected survival if not receiving treatment.
- Treatment is an intervention performed with the intention of preventing the development or altering the pathology of a disorder. Accordingly, “treatment” refers to both therapeutic treatment and prophylactic or preventative measures in certain
- Those in need of treatment include those already with the disorder as well as those in which the disorder is to be prevented.
- treatment is meant inhibiting or reducing an increase in pathology or symptoms (e.g. weight gain, hyperglycemia) when compared to the absence of treatment, and is not necessarily meant to imply complete cessation of the relevant condition.
- the pharmaceutical compositions can be in unit dosage form.
- the composition is divided into unit doses containing appropriate quantities of the active component.
- the unit dosage form can be a packaged preparation, the package containing discrete quantities of the preparations, for example, packeted tablets, capsules, and powders in vials or ampoules.
- the unit dosage form can also be a capsule, cachet, or tablet itself, or it can be the appropriate number of any of these packaged forms. It may be provided in single dose injectable form, for example in the form of a pen.
- packaged forms include a label or insert with instructions for use.
- Compositions may be formulated for any suitable route and means of administration.
- Pharmaceutically acceptable carriers or diluents include those used in formulations suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, and transdermal) administration.
- the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.
- compositions of the invention may further be compounded in, or attached to, for example through covalent, hydrophobic and electrostatic interactions, a drug carrier, drug delivery system and advanced drug delivery system in order to further enhance stability of the compound, increase bioavailability, increase solubility, decrease adverse effects, achieve chronotherapy well known to those skilled in the art, and increase patient compliance or any combination thereof.
- carriers, drug delivery systems and advanced drug delivery systems include, but are not limited to, polymers, for example cellulose and derivatives, polysaccharides, for example dextran and derivatives, starch and derivatives, polyvinyl alcohol), acrylate and methacrylate polymers, polylactic and polyglycolic acid and block copolymers thereof, polyethylene glycols, carrier proteins, for example albumin, gels, for example, thermogelling systems, for example block co-polymeric systems well known to those skilled in the art, micelles, liposomes, microspheres, nanoparticulates, liquid crystals and dispersions thereof, L2 phase and dispersions there of, well known to those skilled in the art of phase behaviour in lipid-water systems, polymeric micelles, multiple emulsions, self- emulsifying, self-microemulsifying, cyclodextrins and derivatives thereof, and dendrimers.
- polymers for example cellulose and derivatives, polysaccharides, for example dextran and derivatives
- a compound or composition of the invention may be administered as part of a combination therapy with an agent for treatment of obesity, hypertension, dyslipidemia or diabetes.
- the two active agents may be given together or separately, and as part of the same pharmaceutical formulation or as separate formulations.
- a compound or composition of the invention can further be used in combination with anti-obesity agent, including but not limited to a glucagon-like peptide receptor 1 agonist, peptide YY or analogue thereof, cannabinoid receptor 1 antagonist, lipase inhibitor, melanocortin receptor 4 agonist, melanin concentrating hormone receptor 1 antagonist, phentermine (alone or in combination with topiramate), a combination of
- norepinephrine/dopamine reuptake inhibitor and opioid receptor antagonist e.g. a combination of bupropion and naltrexone
- opioid receptor antagonist e.g. a combination of bupropion and naltrexone
- serotonergic agent e.g. lorcaserin
- a compound or composition of the invention can be used in combination with an anti- hypertension agent, including but not limited to an angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker, diuretics, beta-blocker, or calcium channel blocker.
- a compound or composition of the invention can be used in combination with a dyslipidaemia agent, including but not limited to a statin, a fibrate, a niacin and/or a cholesterol absorbtion inhibitor.
- a dyslipidaemia agent including but not limited to a statin, a fibrate, a niacin and/or a cholesterol absorbtion inhibitor.
- a compound or composition of the invention can be used in combination with an antidiabetic agent, including but not limited to a biguanide (e.g. metformin), a sulfonylurea, a meglitinide or glinide (e.g. nategiinide), a DPP-IV inhibitor, an SGLT2 inhibitor, a giitazone, a different GLP-1 agonist, an insulin or an insulin analogue.
- the compound or salt thereof is used in combination with insulin or an insulin analogue, DPP-IV inhibitor, sulfonylurea or metformin, particularly sulfonylurea or metformin, for achieving adequate glycemic control.
- insulin analogues include but are not limited to Lantus, Novorapid, Humalog, Novomix, and Actraphane HM, Levemir and Apidra.
- SPPS Solid phase peptide synthesis
- ivDde 1-(4,4-dimethyl-2,6-dioxocyclohexylidene)3-methyl-butyl
- DIPEA diisopropylethylamine
- HATU N-[(dimethylamino)-1 HA ,2,3-triazol[4,5-i ]pyridine-1 -ylmethylene]-A/- methylmethanaminium hexafluorophosphate W-oxide
- TFA trifluoroacetic acid
- TIS triisopropylsilane
- the crude peptide was cleaved from the resin by treatment with 95/2.5/2.5 % (v/v) TFA/TIS/ water at room temperature (r.t.) for 2 hours. Most of the TFA was removed at reduced temperature
- H-H-Ac4c-QGTFTS DYSKYLDERAAKDFI-K([17-carboxy-heptadecanoyl]-isoGlu-GSGSGG)-WLESA-NH 2 H-H-Ac4c-QGTFTSDYSKYLDERRAKDFI-K([17-carboxy-heptadecanoyl]-isoGlu-GSGSGG)-WLESA-NH 2 H-H-Ac4c-QGTFTSDYSKYLDERAAKDFIEWLE-K([17-carboxy-heptadecanoyl]-isoGlu-GSGSGG)-A-NH 2 H-H-Ac4c-QGTFTSDYSKYLDERRAKDFIEWLE-K([17-carboxy-heptadecanoyl]-isoGlu-GSGSGG)-A-NH 2
- the acylated GLP-1 analogue semaglutide was also synthesised, and has the structure:
- Glucagon-R human glucagon receptor
- GLP-1 R human glucagon-like peptide 1 receptor
- the mammalian expression vectors encoding the Glucagon-R or the GLP-1 -R were transfected into Chinese hamster ovary (CHO) cells by the Attractene method method. Stably expressing clones were obtained by Zeocin selection (250pg/mL) upon limited dilution of cells resistant to the selection pressure. Glucagon-R and GLP-1 -R cell clones expressing were picked, propagated and tested in the Glucagon-R and GLP-1 -R efficacy assays as described below. One Glucagon-R expressing clone and one GLP-1 -R expressing clone were chosen for compound profiling.
- CHO cells expressing the human Glucagon-R, or human GLP-1 -R were seeded 24 hours prior to the assay at 30,000 cells per well in 96-well microtiter plates in culture in 100 ⁇ growth medium. On the day of analysis, growth medium was removed and the cells were washed once with 200 ⁇ of assay buffer ( rebs-Ringer- buffer - KRBH). The buffer was removed and the cells were incubated for 15 min at room temperature in 10 ⁇ KRBH (KRBH + 10 mM HEPES, 5 mM NaHC03, 0.1 % (V/V) BSA) with 0.1 mM IBMX in deionized water containing increasing concentrations of test peptides..
- assay buffer rebs-Ringer- buffer - KRBH
- the reaction was stopped by the addition of lysis buffer (0.1 % w/v BSA, 5 mM HEPES, 0.3 % v/v Tween-20). After cell lysis for 10min at room temperature, lysates were transferred to 384-well plates and 10 ⁇ of acceptor/donorbead mixture as contained in the AlphaScreenTM cAMP Functional Assay Kit was added. After one hour of incubation at room temperature in the dark, the cAMP content was determined applying the AlphaScreenTM cAMP Functional Assay Kit from Perkin-Elmer according to manufacturer instructions. EC50 and relative efficacies compared to reference compounds (glucagon and GLP-1 ) were calculated applying computer aided curve fitting.. The GLP-1/glucagon ratio is calculated as defined earlier. See Table 1.
- Agonistic activity of the test compounds on endogenous GLP-1 receptors was determined using a murine insulinoma cell line. Intracellular cAMP was used an indicator of receptor activation.
- Cells were cultured for 24h at a density of 10,000 cells/well in a 384-well plate.
- Medium was removed and 10 ⁇ KRBH buffer (NaCI 130 mM, KCI 3.6 mM, NaH 2 P0 4 0.5 mM, MgS0 4 0.5 mM, CaC 1.5 mM) containing test compound or GLP-1 (at increasing concentrations from 0.1 pM to 100 nM) or solvent control (0.1 % (v/v) DMSO) was added to the wells for 15 minutes at a temperature of 26°C.
- KRBH buffer NaCI 130 mM, KCI 3.6 mM, NaH 2 P0 4 0.5 mM, MgS0 4 0.5 mM, CaC 1.5 mM
- test compound or GLP-1 at increasing concentrations from 0.1 pM to 100 nM
- solvent control 0.1 % (v/v) DMSO
- the cellular cAMP content is measured using the AlphaScreen cAMP Functional Assay Kit (Perkin Elmer). Measurement was performed using the Envision (PerkinElmer) according to manufacturer's recommendations. Results were converted into cAMP concentrations using a cAMP standard curve prepared in KRBH buffer containing 0.1 % (v/v) DMSO. The resulting cAMP curves were plotted as absolute cAMP concentrations (nM) over log (test compound concentration) and analyzed using the curve fitting program XLfit.
- pEC50 negative logarithmic value of EC50, a concentration resulting in a half-maximal elevation of cAMP levels, reflecting the potency of the test compound
- %CTL Percent control
- Agonistic activity of the test compounds on endogenous glucagon receptor was deterimed by measuring their effect on rate of glycogen synthesis in primary rat hepatocytes. Upon activation of the glucagon receptor, an inhibition of the glycogen synthesis rate is expected. Rate of glycogen synthesis was determined by counting the amount of radioactively labeled glucose incorporated into the cellular glycogen stores in a defined period of time.
- rat hepatocytes were cultured at a density of 40,000 cells/well in a 24-well plate for 24 hours at 37°C and 5% C0 2 . Medium was discarded and the cells washed with PBS. 180 ⁇ . of KRBH-based buffer containing 0.1 % BSA and glucose at a concentration of 22.5 mM was then added to the wells, followed by test compound and 40 ⁇ / ⁇ D-[U14C] glucose (20 ⁇ _ each). Incubation was continued for 3 hours.
- the incubation buffer was aspirated and cells washed once with ice-cold PBS before lysis by incubation for 30 min at room temperature with 100 ⁇ 1 mol/l NaOH.
- Cell lysates were transferred to 96-well filter plates and glycogen precipitated by incubating the filter-plates for 120 min at 4°C followed by washing the filter plates 4 times with ice-cold ethanol (70%). The resulting precipitates were filtered to dryness and the amount of incorporated 14 C-glucose determined by using a Topcount scintillation counter according to manufacturer's recommendations.
- Endogenous glucagon peptide was used as a positive control.
- %CTL is determined by calculating the percentage of CPM/well in the presence of the test compound compared to the CPM/well of the vehicle control after subtracting the background CPM/well:
- An activator of the glucagon receptor will result in an inhibition of the glycogen synthesis rate and will give %CTL values between 0%CTL (complete inhibition) and 100%CTL (no observable inhibition).
- Rats Male Wistar rats were obtained from Charles River (Germany) weighing approximately 180 to 210 g at time of arrival at the test facility. Rats were caged in European standard rat cages type IV with light cycle of 12-hour dark and 12-hour light. During the study rats were housed in standard rat cages type III. Both diet Altromin 1324 (Altromin, Germany) and water was administered ad libitum during the whole experimental period. The animals were housed in the test facility for at least 4 days in order to assure proper acclimatization.
- the compounds were first dissolved in 0.1 % aqueous ammonia to a nominal concentration of 2 mg/ml, and then diluted to the desired dosing strength (10 ⁇ ) in sterile PBS containing 25 mM phosphate buffer, pH 7.4. Intravenous injections corresponding to 20 nmol/kg were given via a lateral tail vein. Blood samples (200 ⁇ ) were collected from the periorbital plexus at time points 0.08, 0.25, 0.5, 1 , 2, 4, 8, 24, 32 and 48 h post dosing into K3EDTA tubes and centrifuged for 5 minutes at 4°C within 20 minutes of sampling.
- Plasma samples >100 ⁇ were transferred to 96-well PCR plates, immediately frozen and kept at -20°C until analysed for plasma concentration for the respective GLP-1 -glucagon compound using LC-MS/MS.
- Individual plasma concentration- time profiles were analysed by a non-com partmental approach using ToxKinTM version 3.2 (Unilog IT Services), and the resulting pharmacokinetic parameters were determined. See Table 4.
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Citations (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998011125A1 (en) | 1996-09-09 | 1998-03-19 | Zealand Pharmaceuticals A/S | Improved solid-phase peptide synthesis and agent for use in such synthesis |
WO1999046283A1 (en) | 1998-03-09 | 1999-09-16 | Zealand Pharmaceuticals A/S | Pharmacologically active peptide conjugates having a reduced tendency towards enzymatic hydrolysis |
WO2001004156A1 (en) | 1999-07-12 | 2001-01-18 | Zealand Pharmaceuticals A/S | Peptides that lower blood glucose levels |
WO2003022304A1 (en) | 2001-09-07 | 2003-03-20 | Imperial College Innovations Limited | Oxynthomodulin for preventing or treating excess weight |
WO2006134340A2 (en) | 2005-06-13 | 2006-12-21 | Imperial Innovations Limited | Oxyntomodulin analogues and their effects on feeding behaviour |
WO2007100535A2 (en) | 2006-02-22 | 2007-09-07 | Merck & Co., Inc. | Oxyntomodulin derivatives |
WO2008010101A2 (en) | 2006-07-18 | 2008-01-24 | Sanofi-Aventis | Antagonist antibody against epha2 for the treatment of cancer |
WO2008152403A1 (en) | 2007-06-15 | 2008-12-18 | Zealand Pharma A/S | Glucagon analogues |
WO2009155257A1 (en) | 2008-06-17 | 2009-12-23 | Indiana University Research And Technology Corporation | Glucagon analogs exhibiting enhanced solubility and stability physiological ph buffers |
WO2009155258A2 (en) | 2008-06-17 | 2009-12-23 | Indiana University Research And Technology Corporation | Glucagon/glp-1 receptor co-agonists |
WO2010070255A1 (en) | 2008-12-15 | 2010-06-24 | Zealand Pharma A/S | Glucagon analogues |
WO2010070251A1 (en) | 2008-12-15 | 2010-06-24 | Zealand Pharma A/S | Glucagon analogues |
WO2010070252A1 (en) | 2008-12-15 | 2010-06-24 | Zealand Pharma A/S | Glucagon analogues |
WO2010070253A1 (en) | 2008-12-15 | 2010-06-24 | Zealand Pharma A/S | Glucagon analogues |
WO2011006497A1 (en) | 2009-07-13 | 2011-01-20 | Zealand Pharma A/S | Acylated glucagon analogues |
WO2011160630A2 (en) | 2010-06-23 | 2011-12-29 | Zealand Pharma A/S | Glucagon analogues |
WO2011160633A1 (en) | 2010-06-24 | 2011-12-29 | Zealand Pharma A/S | Glucagon analogues |
WO2012098462A1 (en) * | 2011-01-20 | 2012-07-26 | Zealand Pharma A/S | Combination of acylated glucagon analogues with insulin analogues |
WO2013092703A2 (en) | 2011-12-23 | 2013-06-27 | Zealand Pharma A/S | Glucagon analogues |
WO2014041195A1 (en) | 2012-09-17 | 2014-03-20 | Zealand Pharma A/S | Glucagon analogues |
Family Cites Families (140)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4288627A (en) | 1980-02-12 | 1981-09-08 | Phillips Petroleum Company | Oxidation of thiols employing cobalt molybdate/triethylamine catalyst |
NZ202757A (en) | 1981-12-23 | 1985-11-08 | Novo Industri As | Peptides and medicaments |
US5614492A (en) | 1986-05-05 | 1997-03-25 | The General Hospital Corporation | Insulinotropic hormone GLP-1 (7-36) and uses thereof |
US5120712A (en) | 1986-05-05 | 1992-06-09 | The General Hospital Corporation | Insulinotropic hormone |
US5118666A (en) | 1986-05-05 | 1992-06-02 | The General Hospital Corporation | Insulinotropic hormone |
ES2113879T3 (en) | 1990-01-24 | 1998-05-16 | Douglas I Buckley | GLP-1 ANALOGS USEFUL FOR THE TREATMENT OF DIABETES. |
US5545618A (en) | 1990-01-24 | 1996-08-13 | Buckley; Douglas I. | GLP-1 analogs useful for diabetes treatment |
CA2082279C (en) | 1990-05-09 | 2007-09-04 | Grethe Rasmussen | Cellulase preparation comprising an endoglucanase enzyme |
DK36392D0 (en) | 1992-03-19 | 1992-03-19 | Novo Nordisk As | USE OF CHEMICAL COMPOUND |
US5846747A (en) | 1992-03-25 | 1998-12-08 | Novo Nordisk A/S | Method for detecting glucagon-like peptide-1 antagonists and agonists |
DK39892D0 (en) | 1992-03-25 | 1992-03-25 | Bernard Thorens | PEPTIDE |
US5424286A (en) | 1993-05-24 | 1995-06-13 | Eng; John | Exendin-3 and exendin-4 polypeptides, and pharmaceutical compositions comprising same |
AU7531094A (en) | 1993-08-24 | 1995-03-21 | Novo Nordisk A/S | Protracted glp-1 |
ES2154299T3 (en) | 1993-09-07 | 2001-04-01 | Amylin Pharmaceuticals Inc | METHODS FOR THE REGULATION OF GASTROINTESTINAL MOTILITY. |
US5705483A (en) | 1993-12-09 | 1998-01-06 | Eli Lilly And Company | Glucagon-like insulinotropic peptides, compositions and methods |
US5512549A (en) | 1994-10-18 | 1996-04-30 | Eli Lilly And Company | Glucagon-like insulinotropic peptide analogs, compositions, and methods of use |
US5523449A (en) | 1995-05-17 | 1996-06-04 | Bayer Corporation | Process for preparing phosphorodichlorido-dithioates by reacting alkylmercaptans with phosphorus trichloride in the presence of sulfur |
CN1183158C (en) | 1996-06-05 | 2005-01-05 | 罗赫诊断器材股份有限公司 | Exendin analogues, processes for their preparation and medicaments containing them |
US6110703A (en) | 1996-07-05 | 2000-08-29 | Novo Nordisk A/S | Method for the production of polypeptides |
US6956026B2 (en) | 1997-01-07 | 2005-10-18 | Amylin Pharmaceuticals, Inc. | Use of exendins for the reduction of food intake |
PT966297E (en) | 1996-08-08 | 2009-03-18 | Amylin Pharmaceuticals Inc | Regulation of gastrointestinal motility |
US6268343B1 (en) | 1996-08-30 | 2001-07-31 | Novo Nordisk A/S | Derivatives of GLP-1 analogs |
US7235627B2 (en) | 1996-08-30 | 2007-06-26 | Novo Nordisk A/S | Derivatives of GLP-1 analogs |
US6006753A (en) | 1996-08-30 | 1999-12-28 | Eli Lilly And Company | Use of GLP-1 or analogs to abolish catabolic changes after surgery |
US6458924B2 (en) | 1996-08-30 | 2002-10-01 | Novo Nordisk A/S | Derivatives of GLP-1 analogs |
US6277819B1 (en) | 1996-08-30 | 2001-08-21 | Eli Lilly And Company | Use of GLP-1 or analogs in treatment of myocardial infarction |
JP3149958B2 (en) | 1996-08-30 | 2001-03-26 | ノボ ノルディスク アクティーゼルスカブ | GLP-1 derivative |
CA2265454A1 (en) | 1996-09-09 | 1998-03-19 | Zealand Pharmaceuticals A/S | Peptide prodrugs containing an alpha-hydroxyacid linker |
UA65549C2 (en) | 1996-11-05 | 2004-04-15 | Елі Ліллі Енд Компані | Use of glucagon-like peptides such as glp-1, glp-1 analog, or glp-1 derivative in methods and compositions for reducing body weight |
WO1998022577A1 (en) | 1996-11-15 | 1998-05-28 | Maria Grazia Masucci | Fusion proteins having increased half-lives |
US6136784A (en) | 1997-01-08 | 2000-10-24 | Amylin Pharmaceuticals, Inc. | Amylin agonist pharmaceutical compositions containing insulin |
US6410511B2 (en) | 1997-01-08 | 2002-06-25 | Amylin Pharmaceuticals, Inc. | Formulations for amylin agonist peptides |
CA2279836A1 (en) | 1997-02-05 | 1998-08-13 | 1149336 Ontario Inc. | Polynucleotides encoding proexendin, and methods and uses thereof |
US5846937A (en) | 1997-03-03 | 1998-12-08 | 1149336 Ontario Inc. | Method of using exendin and GLP-1 to affect the central nervous system |
CA2289094A1 (en) | 1997-05-07 | 1998-11-12 | Max-Planck-Gesellschaft zur Forderung der Wissenschaften E.V., Berlin | New cysteine derivatives, processes for their production, and pharmaceuticals containing them |
JP2001513512A (en) | 1997-08-08 | 2001-09-04 | アミリン・ファーマシューティカルズ,インコーポレイテッド | New exendin agonist compounds |
US7157555B1 (en) | 1997-08-08 | 2007-01-02 | Amylin Pharmaceuticals, Inc. | Exendin agonist compounds |
ES2294822T3 (en) | 1997-11-14 | 2008-04-01 | Amylin Pharmaceuticals, Inc. | NEW COMPOUNDS OF EXENDINE AGONISTS. |
BR9814189A (en) | 1997-11-14 | 2000-10-03 | Amylin Pharmaceuticals Inc | "exendin agonist compounds" |
US7220721B1 (en) | 1997-11-14 | 2007-05-22 | Amylin Pharmaceuticals, Inc. | Exendin agonist peptides |
US7223725B1 (en) | 1997-11-14 | 2007-05-29 | Amylin Pharmaceuticals, Inc. | Exendin agonist compounds |
EP1049486A4 (en) | 1997-12-05 | 2006-01-04 | Lilly Co Eli | Glp-1 formulations |
US6703359B1 (en) | 1998-02-13 | 2004-03-09 | Amylin Pharmaceuticals, Inc. | Inotropic and diuretic effects of exendin and GLP-1 |
CA2320371C (en) | 1998-02-13 | 2012-01-17 | Amylin Pharmaceuticals, Inc. | Inotropic and diuretic effects of exendin and glp-1 |
WO1999043708A1 (en) | 1998-02-27 | 1999-09-02 | Novo Nordisk A/S | Glp-1 derivatives of glp-1 and exendin with protracted profile of action |
JP2002506792A (en) | 1998-02-27 | 2002-03-05 | ノボ ノルディスク アクティーゼルスカブ | N-terminal modified GLP-1 derivative |
ATE269103T1 (en) | 1998-03-13 | 2004-07-15 | Novo Nordisk As | STABILIZED AQUEOUS GLUCAGON SOLUTIONS CONTAINING DETERGENTS |
WO1999049788A1 (en) | 1998-03-30 | 1999-10-07 | Focus Surgery, Inc. | Ablation system |
SE9802080D0 (en) | 1998-06-11 | 1998-06-11 | Hellstroem | Pharmaceutical composition for the treatment of functional dyspepsia and / or irritable bowel syndrome and new use of substances therein |
DE69941510D1 (en) | 1998-08-10 | 2009-11-19 | Us Gov Nat Inst Health | DIFFERENTIATION OF NON-INSULIN IN INSULIN-PRODUCING CELLS BY GLP-1 AND EXENDIN-4 AND THEIR USE |
WO2000020592A1 (en) | 1998-10-07 | 2000-04-13 | Medical College Of Georgia Research Institute, Inc. | Glucose-dependent insulinotropic peptide for use as an osteotropic hormone |
US6284725B1 (en) | 1998-10-08 | 2001-09-04 | Bionebraska, Inc. | Metabolic intervention with GLP-1 to improve the function of ischemic and reperfused tissue |
CZ295890B6 (en) | 1998-12-07 | 2005-11-16 | Societe De Conseils De Recherches Et D'application | GLP-1 analogues having aminoisobutyric acid in position 8 and D-arginine in position 36, their use and pharmaceutical compositions in which the analogues are comprised |
NZ512657A (en) | 1999-01-14 | 2004-01-30 | Amylin Pharmaceuticals Inc | Glucagon suppression |
DE60021166T3 (en) | 1999-01-14 | 2019-08-22 | Amylin Pharmaceuticals, Llc | NEW EXENDIN AGONIST FORMULATIONS AND THEIR ADMINISTRATION |
US7399489B2 (en) | 1999-01-14 | 2008-07-15 | Amylin Pharmaceuticals, Inc. | Exendin analog formulations |
US6451987B1 (en) | 1999-03-15 | 2002-09-17 | Novo Nordisk A/S | Ion exchange chromatography of proteins and peptides |
US6451974B1 (en) | 1999-03-17 | 2002-09-17 | Novo Nordisk A/S | Method of acylating peptides and novel acylating agents |
ATE409193T1 (en) | 1999-03-17 | 2008-10-15 | Novo Nordisk As | METHOD FOR ACYLATION OF PEPTIDES AND PROTEINS |
US6271241B1 (en) | 1999-04-02 | 2001-08-07 | Neurogen Corporation | Cycloalkyl and aryl fused aminoalkyl-imidazole derivatives: modulators and GLP-1 receptors |
US6924264B1 (en) | 1999-04-30 | 2005-08-02 | Amylin Pharmaceuticals, Inc. | Modified exendins and exendin agonists |
BR0010705A (en) | 1999-04-30 | 2002-02-05 | Amylin Pharmaceuticals Inc | Modified exendins and exendin agonists |
US7601691B2 (en) | 1999-05-17 | 2009-10-13 | Conjuchem Biotechnologies Inc. | Anti-obesity agents |
PT1180121E (en) | 1999-05-17 | 2004-03-31 | Conjuchem Inc | LONG-TERM INSULINOTROPIC PEPTIDES |
US6506724B1 (en) | 1999-06-01 | 2003-01-14 | Amylin Pharmaceuticals, Inc. | Use of exendins and agonists thereof for the treatment of gestational diabetes mellitus |
US6344180B1 (en) | 1999-06-15 | 2002-02-05 | Bionebraska, Inc. | GLP-1 as a diagnostic test to determine β-cell function and the presence of the condition of IGT and type II diabetes |
US6528486B1 (en) | 1999-07-12 | 2003-03-04 | Zealand Pharma A/S | Peptide agonists of GLP-1 activity |
US6586438B2 (en) | 1999-11-03 | 2003-07-01 | Bristol-Myers Squibb Co. | Antidiabetic formulation and method |
AU775663B2 (en) | 2000-10-20 | 2004-08-12 | Amylin Pharmaceuticals, Inc. | Treatment of hibernating myocardium and diabetic cardiomyopathy with a GLP-1 peptide |
WO2003053460A1 (en) | 2001-12-19 | 2003-07-03 | Eli Lilly And Company | Crystalline compositions for controlling blood glucose |
SK2432004A3 (en) | 2001-12-20 | 2005-04-01 | Eli Lilly And Company | Insulin compound having protracted activity |
ES2327328T3 (en) | 2002-07-04 | 2009-10-28 | Zealand Pharma A/S | GLP-1 AND PROCEDURES FOR THE TREATMENT OF DIABETES. |
RU2376314C2 (en) | 2002-10-02 | 2009-12-20 | Зилэнд Фарма А/С | Stabilised compounds of exendin-4 |
US7192922B2 (en) | 2002-11-19 | 2007-03-20 | Allegheny-Singer Research Institute | Method of treating left ventricular dysfunction |
GB0300571D0 (en) | 2003-01-10 | 2003-02-12 | Imp College Innovations Ltd | Modification of feeding behaviour |
KR20050121748A (en) | 2003-04-29 | 2005-12-27 | 일라이 릴리 앤드 캄파니 | Insulin analogs having protracted time action |
US7623530B2 (en) | 2003-11-20 | 2009-11-24 | Nokia Corporation | Indication of service flow termination by network control to policy decision function |
RU2006131046A (en) | 2004-01-30 | 2008-03-10 | Уэрейта Фармасьютикалз, Инк. (Ca) | JOINT USE OF GLP-1 AGONIST AND GASTRIN COMPOUNDS |
US8076288B2 (en) | 2004-02-11 | 2011-12-13 | Amylin Pharmaceuticals, Inc. | Hybrid polypeptides having glucose lowering activity |
RU2413530C9 (en) | 2004-11-12 | 2021-05-18 | Ново Нордиск А/С | Stable preparations of insulin peptides |
TWI372629B (en) | 2005-03-18 | 2012-09-21 | Novo Nordisk As | Acylated glp-1 compounds |
JP2008539735A (en) | 2005-05-06 | 2008-11-20 | バイエル・フアーマシユーチカルズ・コーポレーシヨン | Glucagon-like peptide 1 (GLP-1) receptor antagonists and methods for their pharmacological use |
US20090202497A1 (en) | 2005-08-23 | 2009-08-13 | The General Hospital Corporation | Use of glp-1, glp-1 derivatives or glp-1 fragments for skin regeneration, stimulation of hair growth, or treatment of diabetes |
ES2572952T3 (en) | 2005-11-07 | 2016-06-03 | Indiana University Research And Technology Corporation | Glucagon analogs showing physiological solubility and stability |
US8343914B2 (en) | 2006-01-06 | 2013-01-01 | Case Western Reserve University | Fibrillation resistant proteins |
WO2007095737A1 (en) | 2006-02-21 | 2007-08-30 | Waratah Pharmaceuticals Inc. | Combination therapy for the treatment of diabetes comprising an exendin agonist and a gastrin compound |
ITMI20061607A1 (en) | 2006-08-09 | 2008-02-10 | Maria Vincenza Carriero | PEPTIDES WITH PHARMACOLOGICAL ACTIVITY |
ES2554773T3 (en) | 2006-10-04 | 2015-12-23 | Case Western Reserve University | Insulin and fibrillation resistant insulin analogues |
CA2669806C (en) | 2006-11-08 | 2018-10-02 | Zealand Pharma A/S | Selective glucagon-like-peptide-2 (glp-2) analogues |
WO2008071010A1 (en) | 2006-12-12 | 2008-06-19 | Waratah Pharmaceuticals Inc. | Combination treatments with selected growth/hormone regulatory factors for diabetes and related diseases |
TWI428346B (en) | 2006-12-13 | 2014-03-01 | Imp Innovations Ltd | Novel compounds and their effects on feeding behaviour |
AU2008205229B2 (en) | 2007-01-05 | 2014-03-27 | Indiana University Research And Technology Corporation | Glucagon analogs exhibiting enhanced solubility in physiological pH buffers |
WO2008101017A2 (en) | 2007-02-15 | 2008-08-21 | Indiana Unversity Research And Technology Corporation | Glucagon/glp-1 receptor co-agonists |
FR2917552B1 (en) | 2007-06-15 | 2009-08-28 | Sagem Defense Securite | METHOD FOR REGULATING THE TRANSMISSION GEIGE WITHIN A RECEPTION TERMINAL |
EP2025684A1 (en) | 2007-08-15 | 2009-02-18 | Zealand Pharma A/S | Glucagon analogues |
NZ603812A (en) | 2007-11-20 | 2014-06-27 | Ambrx Inc | Modified insulin polypeptides and their uses |
GB2455553B (en) | 2007-12-14 | 2012-10-24 | Nuaire Ltd | Motor mounting assembly for an axial fan |
DE102008003568A1 (en) | 2008-01-09 | 2009-07-16 | Sanofi-Aventis Deutschland Gmbh | New insulin analogs useful for treating diabetes |
DE102008003566A1 (en) | 2008-01-09 | 2009-07-16 | Sanofi-Aventis Deutschland Gmbh | New insulin analogs useful for treating diabetes |
NZ586590A (en) | 2008-01-09 | 2012-06-29 | Sanofi Aventis Deutschland | Insulin analogues or derivatives having an extremely delayed time-action profile |
KR20100111683A (en) | 2008-01-09 | 2010-10-15 | 사노피-아벤티스 도이칠란트 게엠베하 | Novel insulin derivatives having an extremely delayed time-action profile |
WO2009129250A2 (en) | 2008-04-14 | 2009-10-22 | Case Western Reserve University | Meal-time insulin analogues of enhanced stability |
EP2296692A4 (en) | 2008-04-22 | 2012-06-06 | Univ Case Western Reserve | Isoform-specific insulin analogues |
TWI451876B (en) | 2008-06-13 | 2014-09-11 | Lilly Co Eli | Pegylated insulin lispro compounds |
WO2010011439A2 (en) | 2008-06-17 | 2010-01-28 | Indiana University Research And Technology Corporation | Gip-based mixed agonists for treatment of metabolic disorders and obesity |
PL219335B1 (en) | 2008-07-04 | 2015-04-30 | Inst Biotechnologii I Antybiotyków | New slow-release insulin analogues |
CN102171245B (en) | 2008-07-31 | 2015-03-25 | 卡斯西部储备大学 | Halogen-stabilized insulin |
US9074014B2 (en) | 2008-08-07 | 2015-07-07 | Ipsen Pharma S.A.S. | Analogues of glucose-dependent insulinotropic polypeptide |
EP2340049B1 (en) | 2008-09-12 | 2015-11-11 | Novo Nordisk A/S | Method of acylating a peptide or protein |
AU2009335715B2 (en) | 2008-12-19 | 2016-09-15 | Indiana University Research And Technology Corporation | Amide-based insulin prodrugs |
EP2376520B1 (en) | 2008-12-19 | 2014-02-12 | Indiana University Research&Technology Corporation | Insulin analogs |
WO2010096052A1 (en) | 2009-02-19 | 2010-08-26 | Merck Sharp & Dohme Corp. | Oxyntomodulin analogs |
WO2010107487A2 (en) | 2009-03-18 | 2010-09-23 | Wu Nian | Lipid-drug conjugates for drug delivery |
CN101519446A (en) | 2009-03-31 | 2009-09-02 | 上海一就生物医药有限公司 | Method for preparing recombinant human insulin and analogs of recombinant human insulin |
CA2838400A1 (en) | 2009-05-08 | 2010-11-11 | Genentech, Inc. | Humanized anti-egfl7 antibodies and methods using same |
PE20120914A1 (en) | 2009-06-16 | 2012-08-22 | Univ Indiana Res & Tech Corp | GIP RECEIVER ACTIVE GLUCAGON COMPOUNDS |
MX2012006634A (en) | 2009-12-16 | 2012-06-21 | Novo Nordisk As | Double-acylated glp-1 derivatives. |
WO2011084808A2 (en) | 2009-12-21 | 2011-07-14 | Amunix Operating Inc. | Bifunctional polypeptide compositions and methods for treatment of metabolic and cardiovascular diseases |
EA026384B1 (en) | 2010-01-20 | 2017-04-28 | Зилэнд Фарма А/С | Treatment of cardiac conditions |
IN2012DN06437A (en) | 2010-01-27 | 2015-10-09 | Univ Indiana Res & Tech Corp | |
US20130143798A1 (en) | 2010-03-26 | 2013-06-06 | Novo Nordisk A/S | Novel glucagon analogues |
AR080592A1 (en) | 2010-03-26 | 2012-04-18 | Lilly Co Eli | PEPTIDE WITH ACTIVITY FOR GIP-R AND GLP-1-R, FAMILY FORMULATION THAT UNDERSTANDS IT, ITS USE TO PREPARE A USEFUL MEDICINAL PRODUCT FOR THE TREATMENT OF MELLITUS DIABETES AND TO INDICATE WEIGHT LOSS |
WO2011117417A1 (en) | 2010-03-26 | 2011-09-29 | Novo Nordisk A/S | Novel glucagon analogues |
CA2797431C (en) | 2010-04-27 | 2016-06-21 | Zhejiang Beta Pharma Inc. | Glucagon-like peptide-1 analogue and use thereof |
CN103003300B (en) | 2010-04-27 | 2017-06-09 | 西兰制药公司 | Peptide conjugate of the receptor stimulating agents of GLP 1 and gastrin and application thereof |
US9708383B2 (en) | 2010-11-09 | 2017-07-18 | Novo Nordisk A/S | Double-acylated GLP-1 derivatives |
AU2012234276A1 (en) | 2011-03-28 | 2013-08-29 | Novo Nordisk A/S | Novel glucagon analogues |
AU2012241894B2 (en) | 2011-04-12 | 2015-12-03 | Novo Nordisk A/S | Double-acylated GLP-1 derivatives |
WO2012150503A2 (en) * | 2011-05-03 | 2012-11-08 | Zealand Pharma A/S | Glu-glp-1 dual agonist signaling-selective compounds |
EP2707713A2 (en) | 2011-05-10 | 2014-03-19 | Zealand Pharma A/S | Glu-glp-1 dual agonist signaling-selective compounds |
KR102002783B1 (en) | 2011-06-10 | 2019-07-24 | 베이징 한미 파마슈티컬 컴퍼니 리미티드 | Glucose dependent insulinotropic polypeptide analogs, pharmaceutical compositions and use thereof |
BR112014006684A2 (en) | 2011-09-23 | 2017-03-28 | Novo Nordisk As | glucagon analogs |
BR112014027348B1 (en) | 2012-05-03 | 2022-12-20 | Zealand Pharma A/S | GIP-GLP-1 DOUBLE AGONIST COMPOUNDS AND METHODS |
EA028929B1 (en) | 2012-05-03 | 2018-01-31 | Зилэнд Фарма А/С | Glucagon-like-peptide-2 (glp-2) analogues |
CN109456400A (en) | 2012-07-23 | 2019-03-12 | 西兰制药公司 | Glucagon analogue |
PT3057984T (en) | 2013-10-17 | 2018-10-24 | Boehringer Ingelheim Int | Acylated glucagon analogues |
US9988429B2 (en) | 2013-10-17 | 2018-06-05 | Zealand Pharma A/S | Glucagon analogues |
JP6682432B2 (en) | 2013-11-06 | 2020-04-15 | ジーランド ファーマ アクティーゼルスカブ | GIP-GLP-1 dual agonist compounds and methods |
KR20160114082A (en) | 2014-02-18 | 2016-10-04 | 노보 노르디스크 에이/에스 | Stable glucagon analogues and use for treatment of hypoglycaemia |
CN107636010B (en) | 2015-04-16 | 2021-10-01 | 西兰制药公司 | Acylated glucagon analogues |
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Patent Citations (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998011125A1 (en) | 1996-09-09 | 1998-03-19 | Zealand Pharmaceuticals A/S | Improved solid-phase peptide synthesis and agent for use in such synthesis |
WO1999046283A1 (en) | 1998-03-09 | 1999-09-16 | Zealand Pharmaceuticals A/S | Pharmacologically active peptide conjugates having a reduced tendency towards enzymatic hydrolysis |
WO2001004156A1 (en) | 1999-07-12 | 2001-01-18 | Zealand Pharmaceuticals A/S | Peptides that lower blood glucose levels |
WO2003022304A1 (en) | 2001-09-07 | 2003-03-20 | Imperial College Innovations Limited | Oxynthomodulin for preventing or treating excess weight |
WO2006134340A2 (en) | 2005-06-13 | 2006-12-21 | Imperial Innovations Limited | Oxyntomodulin analogues and their effects on feeding behaviour |
WO2007100535A2 (en) | 2006-02-22 | 2007-09-07 | Merck & Co., Inc. | Oxyntomodulin derivatives |
WO2008010101A2 (en) | 2006-07-18 | 2008-01-24 | Sanofi-Aventis | Antagonist antibody against epha2 for the treatment of cancer |
WO2008152403A1 (en) | 2007-06-15 | 2008-12-18 | Zealand Pharma A/S | Glucagon analogues |
WO2009155257A1 (en) | 2008-06-17 | 2009-12-23 | Indiana University Research And Technology Corporation | Glucagon analogs exhibiting enhanced solubility and stability physiological ph buffers |
WO2009155258A2 (en) | 2008-06-17 | 2009-12-23 | Indiana University Research And Technology Corporation | Glucagon/glp-1 receptor co-agonists |
WO2010070255A1 (en) | 2008-12-15 | 2010-06-24 | Zealand Pharma A/S | Glucagon analogues |
WO2010070251A1 (en) | 2008-12-15 | 2010-06-24 | Zealand Pharma A/S | Glucagon analogues |
WO2010070252A1 (en) | 2008-12-15 | 2010-06-24 | Zealand Pharma A/S | Glucagon analogues |
WO2010070253A1 (en) | 2008-12-15 | 2010-06-24 | Zealand Pharma A/S | Glucagon analogues |
WO2011006497A1 (en) | 2009-07-13 | 2011-01-20 | Zealand Pharma A/S | Acylated glucagon analogues |
WO2011160630A2 (en) | 2010-06-23 | 2011-12-29 | Zealand Pharma A/S | Glucagon analogues |
WO2011160633A1 (en) | 2010-06-24 | 2011-12-29 | Zealand Pharma A/S | Glucagon analogues |
WO2012098462A1 (en) * | 2011-01-20 | 2012-07-26 | Zealand Pharma A/S | Combination of acylated glucagon analogues with insulin analogues |
WO2013092703A2 (en) | 2011-12-23 | 2013-06-27 | Zealand Pharma A/S | Glucagon analogues |
WO2014041195A1 (en) | 2012-09-17 | 2014-03-20 | Zealand Pharma A/S | Glucagon analogues |
Non-Patent Citations (9)
Title |
---|
"Remington's Pharmaceutical Sciences", 1985, MACK PUBLISHING CO. |
"Remington's Pharmaceutical Sciences", 1985, MARK PUBLISHING COMPANY |
ALTSCHUL ET AL., METHODS IN ENZYMOLOGY, vol. 266, 1996, pages 460 - 480 |
BLOOM, ENDOCRINOLOGY, vol. 145, 2004, pages 2687 |
COHEN ET AL., JOURNAL OF ENDOCRINOLOGY AND METABOLISM, vol. 88, 2003, pages 4696 - 4701 |
FIELDS, GB ET AL.: "Synthetic Peptides", 2002, article "Principles and practice of solid-phase peptide synthesis" |
HJORT ET AL., JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 269, 1994, pages 30121 - 30124 |
LAROCK, R. C.: "Comprehensive Organic Transformations, A Guide to Functional Group Preparations", 1999, WILEY-VCH |
PARLEVLIET ET AL., AM J PHYSIOL ENDOCRINOL METAB, vol. 294, 2008, pages E142 - 7 |
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WO2019066609A1 (en) | 2017-09-29 | 2019-04-04 | 한미약품 주식회사 | Protein conjugate comprising non-peptidyl polymer-coupled fatty acid derivative compound as linker and preparation method therefor |
WO2021094259A1 (en) | 2019-11-11 | 2021-05-20 | Boehringer Ingelheim International Gmbh | Npy2 receptor agonists |
US20210330749A1 (en) * | 2020-04-24 | 2021-10-28 | Boehringer Ingelheim International Gmbh | Glucagon analogues as long-acting glp-1/glucagon receptor agonists in the treatment of fatty liver disease and steatohepatitis |
WO2021214220A1 (en) | 2020-04-24 | 2021-10-28 | Boehringer Ingelheim International Gmbh | Glucagon analogues as long-acting glp-1/glucagon receptor agonists in the treatment of fatty liver disease and steatohepatitis |
US11813312B2 (en) | 2020-04-24 | 2023-11-14 | Boehringer Ingelheim International Gmbh | Glucagon analogues as long-acting GLP-1/glucagon receptor agonists in the treatment of fatty liver disease and steatohepatitis |
WO2022029231A1 (en) | 2020-08-07 | 2022-02-10 | Boehringer Ingelheim International Gmbh | Soluble npy2 receptor agonists |
WO2023006923A1 (en) | 2021-07-30 | 2023-02-02 | Boehringer Ingelheim International Gmbh | Dose regimen for long-acting glp1/glucagon receptor agonists |
WO2024038067A1 (en) | 2022-08-18 | 2024-02-22 | Boehringer Ingelheim International Gmbh | Combination therapy comprising long acting glp-1/glucagon and npy2 receptor agonists |
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