WO2015067715A2 - Gip-glp-1 dual agonist compounds and methods - Google Patents
Gip-glp-1 dual agonist compounds and methods Download PDFInfo
- Publication number
- WO2015067715A2 WO2015067715A2 PCT/EP2014/073970 EP2014073970W WO2015067715A2 WO 2015067715 A2 WO2015067715 A2 WO 2015067715A2 EP 2014073970 W EP2014073970 W EP 2014073970W WO 2015067715 A2 WO2015067715 A2 WO 2015067715A2
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- WIPO (PCT)
- Prior art keywords
- peg3
- aib
- carboxy
- isoglu
- nonadecanoyl
- Prior art date
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- the invention relates to compounds having agonist activity at both the GIP and GLP- receptors, and to their use in the treatment of metabolic disorders.
- CVD cardiovascular diseases
- obstructive sleep apnea obstructive sleep apnea
- stroke peripheral artery disease
- microvascular complications CAD
- osteoarthritis CAD
- CVD cardiovascular diseases
- Many have additional cardiovascular risk factors including high/aberrant LDL and triglycerides and low HDL.
- Cardiovascular diseases account for about 50% of the mortality in people with diabetes, and the morbidity and mortality rates relating to obesity and diabetes underscore the medical need for efficacious treatment options.
- Incretins are gastrointestinal hormones that regulate blood glucose by enhancing glucose- stimulated insulin secretion (Drucker, DJ and Nauck, MA, Lancet 368: 1696-705 (2006)). To date there are two known incretins: glucagon-like peptide-1 (GLP-1 ), and glucose-dependent insulinotropic polypeptide (GIP).
- GLP-1 glucagon-like peptide-1
- GIP glucose-dependent insulinotropic polypeptide
- the incretin GLP-1 is derived from the pre-proglucagon gene.
- Pre-proglucagon is a 158-amino acid precursor polypeptide that is processed in different tissues to form a number of different proglucagon-derived peptides, including glucagon, GLP-1 , glucagon-like peptide-2 (GLP-2) and oxyntomodulin (OXM).
- Glucagon is a 29-amino acid peptide that corresponds to amino acids 33 through 61 of pre-proglucagon, while GLP-1 is produced as a 37-amino acid peptide that corresponds to amino acids 72 through 108 of pre-proglucagon.
- GIP is a 42-amino acid peptide derived by proteolytic processing from a 133-amino acid precursor, pre-pro-GIP. All the peptides are involved in a wide variety of physiological functions, including glucose homeostasis, insulin secretion, gastric emptying, and intestinal growth, as well as the regulation of food intake.
- GLP-1 receptor agonists protect pancreatic ⁇ -cells by inhibiting apoptosis and enhancing proliferation.
- Farilla ei a/ showed that GLP-1 has anti-apoptotic effects in human islets (Farilla, L, Endocrinology 144: 5 49-58 (2003)). Such effects have not been reported for GIP until recently.
- Weidenmaier et al. reported that a DPP-4 resistant GIP analogue had anti- apoptotic effects (Weidenmaier, SD, PLOS One 5(3): e9590 (2010)).
- GIP GLP-1 receptor agonist
- the present invention concerns acylated and truncated GIP analogues which comprise one or more substitutions as compared to wild-type GIP and which may have the property of an altered, preferably increased GLP-1 activity, e.g., as assessed in in vitro efficacy assays and an altered, preferably increased terminal elimination half-life (T1 ⁇ 2), as assessed in in vivo studies in mice.
- GLP-1 activity e.g., as assessed in in vitro efficacy assays
- T1 ⁇ 2 terminal elimination half-life
- GIP-GLP1 dual acting receptor agonists are superior to existing and marketed GLP-1 analogues because the dual agonists offer improved glycemic control, and enhanced body weight loss.
- the GIP-GLP1 dual agonists disclosed herein may thus be used as therapeutics for metabolic disorders including, but not limited to, type 2 diabetes mellitus, obesity and related disorders.
- the invention provides a GIP analogue having the general Formula I:
- R 1 is H, Ci-4 alkyl, acetyl, formyl, benzoyl, trifluoroacetyl or pGlu;
- X2 is selected from Aib and D-Ala;
- X10 is selected from Tyr and Leu;
- X13 is selected from Ala, Tyr and Aib;
- X15 is selected from Asp and Glu
- X16 is selected from Glu and Lys
- X19 is selected from Gin and Ala
- X20 is selected from Lys and Arg;
- X21 is selected from Ala and Glu
- X23 is selected from Val and lie
- X24 is selected from Asn and Glu
- X27 is selected from Leu, Glu and Val
- X28 is selected from Ala, Ser and Arg;
- X29 is selected from Aib, Ala, and Gin;
- X30 is selected from Lys, Gly and Y1 , or is absent;
- Y1 (when present) is selected from Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser, Lys-Pro-Ser- Ser-Gly-Ala-Pro-Pro-Pro-Ser, Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser, Pro-Ser-Ser-Gly-Ala-Pro- Pro-Pro-Ser and Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser;
- ⁇ is a residue of Lys, Arg, Orn or Cys in which the side chain is conjugated to a substituent having the formula -Z 1 or -Z 2 -Z 1 ;
- -Z 1 is a fatty chain having a polar group at one end of the chain and a connection to ⁇ or Z 2 , -X- at the end of the chain distal from the polar group, wherein the polar group comprises a carboxylic acid or a carboxylic acid bioisostere, a phosphonic acid, or a sulfonic acid group; and -X- is a bond, -CO-, -SO-, or -S0 2 -;
- -Z 2 - (if present) is a spacer of formula: -Y-V-X- n connecting Z 1 to ⁇ ; wherein: 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-; with the proviso that when Y is -S, the X to which it is bound is a bond; each V is independently a bivalent organic moiety linking Y and X; and n is 1-10; and
- R 2 is -NH2 or -OH
- the invention also provides a GIP analogue having the general Formula lb:
- R 1 is H, C1-4 alkyl, acetyl, formyl, benzoyl, trifluoroacetyl or pGlu;
- X2 is selected from Aib and D-Ala;
- X10 is selected from Tyr and Leu;
- X13 is selected from Ala, Tyr and Aib;
- X15 is selected from Asp and Glu
- X16 is selected from Glu and Lys
- X19 is selected from Gin and Ala
- X20 is selected from Lys and Arg;
- X21 is selected from Ala and Glu
- X23 is selected from Val and lie
- X24 is selected from Asn and Glu
- X27 is selected from Leu, Glu and Val
- X28 is selected from Ala, Ser and Arg;
- X29 is selected from Aib, Ala, Glu and Gin;
- X30 is selected from Lys, Gly and Y1 , or is absent;
- Y1 (when present) is selected from Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser, Lys-Pro-Ser- Ser-Gly-Ala-Pro-Pro-Pro-Ser, Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser, Pro-Ser-Ser-Gly-Ala-Pro- Pro-Pro-Ser and Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser;
- ⁇ is a residue of Lys, Arg, Orn or Cys in which the side chain is conjugated to a substituent having the formula -Z 1 or -Z 2 -Z 1 ;
- -Z 1 is a fatty chain having a polar group at one end of the chain and a connection to ⁇ or Z 2 , -X- at the end of the chain distal from the polar group, wherein the polar group comprises a carboxylic acid or a carboxylic acid bioisostere, a phosphonic acid, or a sulfonic acid group; and -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 S0 2 -; with the proviso that when Y is -S, the X to which it is bound is a bond;
- each V is independently a bivalent organic moiety linking Y and X; and n is 1-10;
- R 2 is -NHzor -OH
- the invention further provides a GIP analogue having the general Formula II: R 1 -Tyr-X2-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-lle-X13-Leu-X1 S-Glu-M ⁇ -Ala-Ala-Arg ⁇ I -
- R 1 is H, Ci-4 alkyl, acetyl, formyl, benzoyl, trifluoroacetyl or pGlu;
- X2 is selected from Aib and D-Ala;
- X13 s selected from Ala, Tyr;
- X15 s selected from Asp and Glu
- X21 s selected from Ala and Glu
- X24 s selected from Asn and Glu
- X28 s selected from Ala, Ser;
- X29 s selected from Ala, Glu and Gin.
- X30 s selected from Lys, Gly and Y1 , or is absent;
- Y1 (when present) is selected from Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser, Lys-Pro-Ser- Ser-Gly-Ala-Pro-Pro-Pro-Ser, Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser, Pro-Ser-Ser-Gly-Ala-Pro- Pro-Pro-Ser and Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser;
- ⁇ is a residue of Lys, Arg, Orn or Cys in which the side chain is conjugated to a substituent having the formula -Z or -Z 2 -Z 1 ;
- -Z is a fatty chain having a polar group at one end of the chain and a connection to ⁇ or Z 2 , -X- at the end of the chain distal from the polar group, wherein the polar group comprises a carboxylic acid or a carboxylic acid bioisostere, a phosphonic acid, or a sulfonic acid group; and -X- is a bond, -CO-, -SO-, or -S0 2 -;
- 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-; with the proviso that when Y is -S, the X to which it is bound is a bond;
- each V is independently a bivalent organic moiety linking Y and X; and n is 1-10;
- R 2 is -NH 2 or -OH
- positions 1 to 29 of the GIP analogue have a maximum of 8 changes (within the constraints of Formula I) compared to the sequence:
- positions 1 to 29 of the GIP analogue may possess all of Ala19, Lys20 and Glu21. They may also possess one or both of Ser28 and Ala29.
- positions 1 to 29 typically have 4 or fewer changes compared to that sequence.
- positions 1 to 29 of the GIP analogue have a maximum of 6 changes (within the constraints of Formula I) compared to the sequence
- Aib2 Tyr10, Ala13, Glu15, Lys16, Gln19, Arg20, Ala21 , Val23, Glu24, Leu27, Ala28, Gln29; Aib2, Leu10, Aia13, Glu15, Lys16, Gln19, Arg20, Ala21 , Val23, Glu24, Leu27, Ala28, Gln29; Aib2, Tyr10, Tyr13, Glu15, Lys16, Gln19, Arg20, Ala21 , Val23, Glu24, Leu27, Arg28, Ala29; Aib2, Leu10, Ala13, Asp15, Lys16, Gln19, Arg20, Ala21 , Val23, Asn24, Val27, Ala28 Aib29; Aib2, Tyr10, Ala13, Asp15, Lys16, Gln19, Arg20, Ala21 , Val23, Asn24, Val27,
- Aib2 Leu10, Ala13, Glu15, Lys16, Gln19, Arg 20, Ala21 , Val23, Glu24, Glu27, Ala28, Gln29; Aib2, Tyr10, Ala13, Asp15, Lys16, Gln19, Arg20, Ala21 , Val23, Glu24, Leu27, Ala28, Gln29; D-Ala2, Tyr10, Ala13, Asp15, Lys16, Gln19, Arg20, Ala21 , Val23, Glu24, Leu27, Ala28, Gln29;
- Aib2 Tyr10, Ala13, Asp15, Lys16, Gln19, Arg20, Ala21 , Val23, Asn24, Leu27, Ala28, Aib29; Aib2, Tyr10, Ala13, Asp15, Glu16, Ala19, Lys20, Glu21 , Ile23, Glu24, Glu27, Ser28, Ala29;
- Aib2 Tyr10, Ala13, Glu15, Lys16, Gln19, Arg20, Ala21 , Ile23, Glu24, Glu27, Ala28, Gln29; Aib2, Leu10, Ala13, Glu15, Lys16, Gln19, Arg 20, Ala21 , Ile23, Glu24, Glu27, Ala28, Gln29.
- Residues 1-29 of Formula I may have the sequence: Y-Aib-EGTFTSDYSIYLDKTAQRAFVEWLLAQ;
- Residues 1 -29 of Formula I may have the sequence:
- the peptide backbone of Formula ! may have the sequence:
- the peptide backbone of Formula I may have the sequence:
- the peptide backbone of Formula I may have the sequence:
- Certain of the Y1 groups when present, may provide increased stability in vivo, e.g. in serum, and so may contribute to the half life of the GIP analogue. Without wishing to be bound by theory, it is believed that these groups may help to stabilize the three dimensional
- the Y1 sequences Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser, Gly-Pro-Ser-Ser- Gly-Ala-Pro-Pro-Ser, Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser and Pro-Ser-Ser-Gly-Ala-Pro-Pro- Ser have homology with a C-terminal portion of the Exendin-4 molecule and appear to contribute to the stability of the molecule without concomitantly providing significant levels of GLP-1 agonist activity.
- the invention further provides a pharmaceutical composition
- a pharmaceutical composition comprising a GIP analogue as described herein, or a pharmaceutically acceptable salt or solvate thereof, in admixture with a carrier, preferably a pharmaceutically acceptable carrier.
- a carrier preferably a pharmaceutically acceptable carrier.
- the GIP analogue may.for example, be a pharmaceutically acceptable acid addition salt.
- the pharmaceutical composition may be formulated as a liquid suitable for administration by injection or infusion, or which is formulated to cause slow release of said GIP analogue.
- the invention further provides a therapeutic kit comprising a GIP analogue as descibed herein, and a device comprising a GIP analogue as described herein.
- the invention further provides a GIP analogue as described herein, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of medical treatment, e.g. for use in the treatment and/or prevention of a metabolic disorder.
- the invention further provides the use of a GIP analogue as described herein, or a pharmaceutically acceptable salt or solvate thereof, in the preparation of a medicament for the treatment and/or prevention of a metabolic disorder.
- the invention further provides a method of prevention and or/treatment of a metabolic disorder in a subject, comprising administering a GIP analogue as described herein, or a pharmaceutically acceptable salt or solvate thereof, to the subject.
- the metabolic disorder may be diabetes or a diabetes related disorder, or obesity or an obesity related disorder.
- diabetes or a diabetes related disorder, or obesity or an obesity related disorder.
- the link between obesity and diabetes is well known, so these conditions are not necessarily separate or mutually exclusive.
- Diabetes related disorders include insulin resistance, glucose intolerance, increased fasting glucose, pre-diabetes, type 1 diabetes, type 2 diabetes, gestational diabetes hypertension, dyslipidemia, and combinations thereof.
- Diabetes related disorders also include atherosclerosis, arteriosclerosis, coronary heart disease, peripheral artery disease and stroke; or conditions associated with atherogenic dyslipidemia, blood fat disorders, elevated blood pressure, hypertension, a prothrombotic state, bone related disorders and a proinflammatory state.
- Bone related disorders include, but are not limited to, osteoporosis and increased risk of bone fracture.
- the blood fat disorder may be selected from high triglycerides, low HDL cholesterol, high LDL cholesterol, and plaque buildup in artery walls, or a combination thereof.
- the prothrombotic state may be selected from high fibrinogen levels in the blood and high plasminogen activator inhibitor-1 levels in the blood.
- the proinflammatory state may be an elevated C-reactive protein level in the blood.
- Obesity related disorders include obesity linked inflammation, obesity linked gallbladder disease and obesity induced sleep apnea, or may be associated with a condition selected from atherogenic dyslipidemia, blood fat disorders, elevated blood pressure, hypertension, a prothrombotic state, and a proinflammatory state, or a combination thereof.
- FIG. 1 Blood glucose levels (A, B) and area under the blood glucose curves (AUC) (C) in an IPGTT in 5-hour fasted diabetic db/db mice. The mice were injected s.c. with vehicle or GIP-GLP-1 dual acting receptor agonists (0.5 and 5 nmol/kg) 22 hours prior to the i.p.
- patient may be used interchangeably and refer to either a human or a non-human animal. These terms include mammals such as humans, primates, livestock animals (e.g., bovines, porcines), companion animals (e.g., canines, felines) and rodents (e.g., mice and rats).
- livestock animals e.g., bovines, porcines
- companion animals e.g., canines, felines
- rodents e.g., mice and rats.
- solvate in the context of the present invention refers to a complex of defined stoichiometry formed between a solute (in casu, a peptide conjugate or pharmaceutically acceptable salt thereof according to the invention) and a solvent.
- the solvent in this connection may, for example, be water, ethanol or another pharmaceutically acceptable, typically small-molecular organic species, such as, but not limited to, acetic acid or lactic acid.
- a solvate is normally referred to as a hydrate.
- agonist as employed in the context of the invention refers to a substance (ligand) that activates the receptor type in question.
- GIP-GLP 1 dual receptor agonist as employed in the context of the invention refers to a substance (ligand) that activates both the GIP receptor and the GLP-1 receptor.
- R groups are possible at the N-terminus, including pyroglutamic acid (pGlu; (S)-(-)-2- pyrrolidone-5-carboxylic acid), Ci- 4 alkyl, acetyl, formyl, benzoyl and trifluoroacetyl.
- pGlu pyroglutamic acid
- S S-(-)-2- pyrrolidone-5-carboxylic acid
- Ci- 4 alkyl acetyl, formyl, benzoyl and trifluoroacetyl.
- the compounds described herein are GIP-GLP 1 dual receptor agonists. That is to say, they have agonist activity at both the GIP receptor and the GLP-1 receptor.
- agonist refers to a substance (ligand) that is capable of binding to a particular receptor and activating signaling by that
- GIP receptor agonist is capable of binding to the GIP receptor (designated GIP-R) and activating signaling by that receptor, e.g. by generation of cAMP or inducing Ca 2+ release.
- Agonist activity at the GIP receptor may therefore be measured by assessing GIP receptor signalling, which may, for example, be measured via cAMP production or Ca 2+ release.
- the cDNA sequence encoding the human GIP receptor has GenBank accession no.
- the compounds have agonist activity at the GLP-1 receptor (GLP-1 -R), i.e. they are capable of binding to the GLP-1 receptor and activating signaling by that receptor, e.g. by generation of cAMP or inducing Ca 2+ release.
- Agonist activity at the GLP-1 receptor may therefore be measured by assessing GLP-1 receptor signalling, which may, for example, be measured via cAMP production or Ca 2+ release.
- the GLP-1 receptor may have the sequence of the human glucagon-like peptide 1 receptor (GLP-1 R) having primary accession number P43220.
- the precursor protein (including signal peptide) has primary accession number NP_002053.3; Gl:166795283 and has sequence:
- This may be employed in any assays to determine GIP signalling.
- the compounds of the present invention have at least one GIP and one GLP-1 biological activity, in particular in treatment of metabolic diseases such as diabetes and obesity. This can be assessed, e.g., in in vivo assays, for example as described in the examples, in which the blood glucose level or another biological activity is determined after a test animal has been treated or exposed to a GIP analogue.
- compounds of the invention may be capable of improving glycaemic control when adminstered to a diabetic subject. Additionally or alternatively, they may be capable of reducing body weight when administered to an overweight or obese subject.
- the effect may be superior to that obtained with an equivalent quantity (by mass, or molar ratio) of wild type human GIP or GLP-1 in comparable subjects when given according to a comparable dosing regime.
- Activity in in vitro assays may also be used as a measure of the compounds' activity.
- EC 5 o 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.
- a compound having EC50 [GLP-1 R] lower than the EC50 [GLP-1 R] of native GIP in a particular assay may be considered to have higher potency at the GLP-1 R than GIP.
- the EC50 GLP-1 -R and/or EC50 GIP-R is below 1.0 nM, below 0.9 nM, below 0.8 nM, below 0.7 nM, below 0.6 nM, below 0.5 nM, below 0.4 nM, below 0.3 nM, below 0.2 nM, below 0.1 nM, below 0.09 nM, below 0.08 nM, below 0.07 nM, below 0.06 nM, below 0.05 nM, below 0.04 nM, below 0.03 nM, below 0.02 nM, below 0.01 nM, below 0.009 nM, below 0.008 nM, below 0.007 nM, below 0.006 nM, below 0.005 nM, or below 0.004 nM, e.g.
- the EC50 value of a compound in a given assay may be assessed relative to the EC50 of human GIP.
- the ratio of the EC50 value of the test compound to the EC50 value of wild type human GIP (ECso[test compound] / EC5o[GIP]) at the human GIP receptor may be less than 10, less than 5, less than 1 , less than 0.1 , less than 0.05 or less than 0.01.
- the ratio of the EC50 value of the test compound to the EC50 value of wild type human GIP (ECso[test compound] / EC 5 o[GIP]) at the GLP-1 receptor may be less than 10, less than 5, less than 1 , less than 0.1 , less than 0.05 or less than 0.01. It may also be desirable to compare the ratio of EC50 values at the two receptors for the test compound and for human GIP.
- the test compound has an EC 5 o[GIP] / EC 5 o[GLP-1] which is greater than the equivalent ratio for GIP in the same assays. Lipophilic group
- 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 binds plasma proteins (e.g. albumin) in the blood stream, thus shielding the compounds of the invention from enzymatic degradation and renal clearance and thereby enhancing the half-life of the compounds. It may also modulate the potency of the compound, e.g. with respect to the GIP receptor and/or the GLP-1 receptor.
- 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.
- ⁇ is a residue of Lys, Arg, Orn or Cys in which the side chain is conjugated to a substituent having the formula -Z 1 or -Z 2 -Z 1 ;
- -Z 1 is a fatty chain having a polar group at one end of the chain and a connection to ⁇ or Z 2 , -X-, at the end of the chain distal from the polar group, wherein the polar group comprises a carboxylic acid or a carboxylic acid bioisostere, a phosphonic acid, or a sulfonic acid group; and -X- is a bond, -CO-, -SO-, or -S02-;
- 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-; with the proviso that when Y is -S, the X to which it is bound is a bond;
- each V is independently a bivalent organic moiety linking Y and X; and n is 1-10;
- Z 1 is a fatty chain having a connection to ⁇ or 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.
- -X- is acyl (-CO-), sulfinyl (-SO-), or sulfonyl (-SO2-).
- -X- is acyl (-CO-).
- 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 Ka 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 pKa 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 pKa similar to the corresponding carboxylic acid.
- suitable bioisoteres may include, not by way of limitation, tetrazole, acylsulfomides,
- 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.
- the polar group is -COOH, that is, A is -COOH and B is a bond.
- 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 pKa 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 thiofuranylene, 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 appreciated 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 moieties 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 medium-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 medium-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, margaric (heptadecanoic) acid, and arachidic (eicosanoic) 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 ⁇ or 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 16 to 28 carbon atoms in length (e.g. a
- Ci6-28alkylene more preferably, 16 to 26 carbons in length (e.g. a Ci6-26alkylene), more preferably, 16 to 22 carbons in length (e.g. Ci6-alkylene), and may be saturated or
- 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, Ci-4alkyl, preferably methyl; trifluoromethyl, hydroxymethyl, amino, hydroxyl, 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: A-B-alkylene-(CO)- where A and B are as defined above.
- Z 1 is:
- Z 1 are derived from long-chain saturated ⁇ , ⁇ -dicarboxylic acids of formula HOOC-(CH 2 )i2-22-COOH, preferably, long-chain saturated ⁇ , ⁇ -dicarboxylic acids having an even number of carbon atoms in the aliphatic chain .
- Z 1 may be:
- the carboxylic acid group may be replaced by a bioisotere as detailed herein.
- Z 2 is an optional spacer that connects Z 1 to the side chain of the amino acid component of ⁇ .
- Z 2 if present, is a spacer bound at one terminus by Y, which may be a nitrogen, oxygen or sulfur atom, and at the other terminus by X, which may be a bond or an acyl (-CO-), sulfinyl (-SO-), sulfonyl (-S0 2 -)or absent.
- 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 linkage to another part of the spacer, with the remaining valency forming a linkage to Z 1 ;
- X may be a bond, CO- SO- or S0 2 - 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 independent 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 and the side chain.
- each V may also be bound to each adjacent V by linkages as described.
- linkages are amides, esters or sulfonamides, most preferably amides.
- each Y is -NH or -NR and each X is CO- or S0 2 -.
- Z 2 is a spacer of formula or -SB-SA-, wherein SA and SB are as defined below.
- Z 2 is selected from -SA-, -SB-, or -SB-SA-, that is, [side chain]-Z 2 Z 1 is [side chain]-SA-Z 1 , [side chain]-SB-Z 1 or [side chain]-S B -SA-Z 1 .
- the group SA is the group SA
- 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 may comprise a nitrogen-containing heterocycle, said nitrogen-containing heterocycle being bound within the lipophilic group at one end via a bond, a carboxy, a sulfinyl, or a sulfonyl group, and at the other via a ring nitrogen atom.
- SA may comprise a piperazine ring.
- SA is a 5-8-membered heterocycle having 1 or 2 nitrogen atoms and substituted with an -X or an -L-X group, where X is a bond, CO-, SO-, or SO2-, and where L, if present, is Ci-4alkylene (- denotes a point of attachment within the lipophilic group).
- SA is a 6-membered heterocycle having 1 or 2 nitrogen atoms, preferably 2, and substituted with a -CH 2 CO- -CH 2 SO- or -CH2SO2- group.
- SA may be:
- SA may be:
- SA is a single amino acid residue or piperazine-1 -yl-acetyl. More preferably SA is a single amino acid residue
- the amino acid may be selected from ⁇ - Glu, a-Glu, a-Asp, ⁇ -Asp, Ala, Dapa (2,3-diaminopropionic acid), or Dab (2,4- diaminobutanoic). It will be understood that where more than one carboxylic acid or amino moiety is present, connection may be at any moiety as appropriate. Any carboxylic acid or amino resides not bound within the residue may be free, that is, present as a free carboxylic acid or primary amine, or may be derivatised.
- Suitable derivatisation is known in the art.
- carboxylic acid moieties may be present in SA amino acid residues as esters, for example, as methyl esters.
- Amino moieties may be present as alkylated amines, for example, methylated, or may be protected as amide or carbamate moieties.
- Other suitable amino acids include ⁇ -Ala (3-aminopropanoic acid) and Gaba (4-aminobutanoic acid) and similar ⁇ amino acids.
- amino acids may be D or L, or a racemic or enantioenriched mixture.
- the amino acid is an L-amino acid.
- 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- 4 alkyl or Cearyl.
- R is Ci- 4 alkyl, preferably methyl or ethyl, more preferably ethyl.
- a preferred SA group bearing a carboxylic acid is ⁇ -Glu.
- SA is selected from Dapa or ⁇ -Glu.
- SA is ⁇ -Glu.
- SB may be a linker of general formula:
- 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 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 ;
- X 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 - wherein R AA is an amino acid side chain; or V is an optionally substituted
- Ci- 6 alkylene, 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-(CH2) 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: (i) . Single amino acid residues: Pu' ;
- 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', Pu", and Pu'" in any order, or may comprise one or more units of Pu', Pu", and Pu"' 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, lie, Met, Cys, Phe, Tyr, Trp, His, Lys, Arg, Gin, Asn, a-Glu, ⁇ -Glu, Asp, Ser Thr, Dapa, 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')n-, wherein n is 1 to 8, more preferably 5 to 7, most preferably 6.
- S B is -(Pu%- 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 -(Pu'%-, wherein n is 2 to 4, more preferably 3, and each Pu" is independently selected from Gly-Ser and Gly-Gly.
- S B 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.
- 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 , 2, 3, or 4, more preferably 1 or 2, and p is 1 , 2, 3, 4 or 5, e.g. 1 , 3, 4, or 5, preferably 1 .
- m is 1 and p is 1 , that is, Pu"' is a residue of 8-amino-3,6- dioxaoctanoic acid (also known as ⁇ 2-[2-aminoethoxy]ethoxy ⁇ acetic acid and H2N-PEG 3 - COOH). This residue is referred to herein as -PEG 3 -.
- m is 5 and p is 2, that is, Pu'" is a residue of 2-[2-[2-[2-[2- [2- (2- aminoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]propanoic acid (also known as H2N-PEG6- COOH). This residue is referred to herein as -PEG 6 -.
- m is 2 and p is 1 , that is, Pu in 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.
- S B is selected from -PEG3-PEG3- and -PEG3-PEG3- PEG3-. Most preferably, S B is -PEG3-PEG3-.
- the GIP analogue compounds employed in the context of the invention may provide an attractive treatment option for metabolic diseases including obesity, diabetes mellitus
- Diabetes comprises a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. Diabetes is classified into type 1 diabetes, type 2 diabetes and gestational diabetes on the basis on pathogenic characteristics. Type 1 diabetes accounts for 5-10% of all diabetes cases and is caused by auto-immune destruction of insulin-secreting pancreatic ⁇ -cells. 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. However, in type 2 diabetes symptoms are often not severe or may be absent.
- Type 2 diabetes accounts for 90-95% of diabetes cases and is a result of a complex set of metabolic disorders. However, symptoms are often not severe or may be absent. Type 2 diabetes is the consequence of endogenous insulin production becoming insufficient to maintain plasma glucose levels below 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/or a 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
- Dyslipidemia is associated with increased risk of cardiovascular disease.
- 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 an elevated concentration of Low
- LDL Density Lipoproteins
- GIP-GLP1 dual agonists act as GIP-GLP1 dual agonists.
- the dual agonist may combine the effect of GIP, e.g., on fat metabolism and weight loss, and blood glucose, 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 glycemic control.
- Dual GIP-GLP1 agonists may also act to reduce cardiovascular risk factors such as high cholesterol, such as high LDL-cholesterol.
- the GIP-GLP1 dual agonist compounds of the present invention may therefore be used (alone or in combination) 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 and lipolysis), 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 GIP-GLP1 dual agonist compounds employed in the context of the invention may also be used for treatment of insulin resistance, glucose intolerance, pre-diabetes, increased fasting glucose, type 2 diabetes, hypertension, dyslipidemia (or a combination of these metabolic risk factors), atherosclerosis, arteriosclerosis, coronary heart disease, peripheral artery disease and stroke. These are all conditions which may be associated with obesity. However, the effects of the compounds employed in the context 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 GIP-GLP1 dual agonist compounds may thus be used (alone or in combination) for the treatment and/or prevention of any of the diseases, disorders, or conditions described herein, including insulin resistance, glucose intolerance, increased fasting glucose, pre-diabetes, type 1 diabetes, type 2 diabetes, gestational diabetes hypertension, dyslipidemia, or a combination thereof.
- the diabetes related disorder is selected from
- the blood fat disorder is selected from high triglycerides, low HDL cholesterol, high LDL cholesterol, plaque buildup in artery walls, or a combination thereof.
- the prothrombotic state is selected from high fibrinogen levels in the blood and high plasminogen activator inhibitor-1 levels in the blood.
- the proinflammatory state is an elevated C-reactive protein level in the blood.
- the obesity related disorder is selected from obesity linked inflammation, obesity linked gallbladder disease and obesity induced sleep apnea.
- the GIP-GLP1 dual agonist compounds may also be used for the treatment and/or prevention of any of the diseases, disorders, or conditions associated with diabetes related osteoporosis including increased risk of bone fractures.
- the observed increase in fracture risk is likely to be related to impaired bone quality rather than to bone mineral density.
- the related mechanisms due at least in part to hyperglycemia, neuropathy, and higher incidence of hypovitaminosis D, are not yet fully understood.
- the invention provides the use of a GIP-GLP1 dual agonist compound as described, in the manufacture of a medicament for any of the clinical applications described in this
- the invention also provides a therapeutic kit comprising a GIP analogue of the invention, optionally in combination with a pharmaceutically acceptable carrier.
- the invention provides a device comprising a GIP analogue of the invention for delivery of the GIP analogue to a subject.
- the GIP-GLP1 dual agonist compounds of the present invention, or salts or solvates thereof, may be formulated as pharmaceutical compositions prepared for storage or administration, which typically comprise a therapeutically effective amount of a compound employed in the context of the invention, or a salt or solvate thereof, in a pharmaceutically acceptable carrier.
- the pharmaceutical composition is formulated as a liquid suitable for administration by injection or infusion, or which is formulated to cause slow release of the GIP-GLP1 dual agonist compound.
- the therapeutically effective amount of a compound of the present invention will depend, e.g., on the route of administration, the type of mammal being treated, and the physical characteristics of the specific mammal under consideration.
- 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.
- 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
- Suitable pH buffering agents may be, e.g., phosphate, citrate, acetate, lactate, maleate,
- TIS tris/hydroxymethyl)aminomethane
- TAPS /V-Tris(hydroxymethyl)methyl-3- aminopropanesulphonic acid
- ammonium bicarbonate diethanolamine
- histidine which in certain embodiments is a preferred buffer, arginine, lysine, or acetate or mixtures thereof.
- pharmaceutically acceptable salt refers to a salt of the compound. Salts include pharmaceutically acceptable salts, such as, e.g., acid addition salts and basic salts.
- Examples of acid addition salts include hydrochloride salts, citrate salts and acetate salts.
- Examples of 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
- R 3 and R 4 independently designate optionally substituted Ci-6-alkyl, optionally substituted C2- 6 -alkenyl, optionally substituted aryl, or optionally substituted heteroaryl.
- R 3 and R 4 independently designate optionally substituted Ci-6-alkyl, optionally substituted C2- 6 -alkenyl, optionally substituted aryl, or optionally substituted heteroaryl.
- Other examples of pharmaceutically acceptable salts are described in
- 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 may 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 embodiments. Those in need of treatment include those already with the disorder as well as those in which the disorder is to be prevented. By 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.
- pathology or symptoms e.g. weight gain, hyperglycemia
- compositions of the invention may 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 an injection pen.
- 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 or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, and
- transdermal administration may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.
- Subcutaneous or transdermal modes of administration may be particularly suitable for certain of the compounds described herein.
- a GIP-GLP-1 dual agonist compound employed in the context of the invention may be administered as part of a combination therapy with at least one other agent for treatment of diabetes, obesity, dyslipidemia, or hypertension.
- the at least two active agents may be given together or separately, and as part of the same pharmaceutical formulation or as separate formulations.
- the GIP-GLP-1 dual agonist compound employed in the context of the invention (or the salt or solvate thereof) may be used in combination with an antidiabetic agent including but not limited to metformin, a sulfonylurea, a glinide, a DPP-IV inhibitor, a glitazone, or insulin.
- the compound or salt or solvate thereof is used in combination with insulin, DPP-IV inhibitor, sulfonylurea or metformin, particularly sulfonylurea or metformin, for achieving adequate glycemic control.
- the compound or salt or solvate thereof is used in combination with insulin or an insulin analogue for achieving adequate glycemic control.
- insulin analogues include but are not limited to Lantus®, NovoRapid®, Humalog®, NovoMix®, Actraphane HM®, Levemir® and Apidra®.
- the GIP-GLP-1 dual agonist compound or salt or solvate thereof may further be used in combination with one or more of 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, or melanin concentrating hormone receptor 1 antagonist.
- 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.
- the GIP-GLP-1 dual agonist compound or salt thereof may be used in combination with an anti-dyslipidemia agent, including but not limited to a statin, a fibrate, a niacin and/or a cholesterol absorption inhibitor.
- an anti-dyslipidemia agent including but not limited to a statin, a fibrate, a niacin and/or a cholesterol absorption inhibitor.
- a nucleic acid molecule may encode the amino acid sequence of Formula I or a precursor thereof.
- the amino acid sequence encoded can be regarded as a precursor of a compound of the invention.
- nucleic acid sequences will be provided as expression constructs wherein the encoding nucleic acid is in functional linkage with appropriate control sequences to direct its expression.
- the expression construct may be provided in the context of a host cell capable of expressing (and optionally also secreting) the amio acid precursor, or ina cell-free expression system.
- the invention provides a method of producing a GIP analogue of the invention, the method comprising expressing an amino acid precursor of the GIP analogue and modifying the precursor to provide the GIP analogue.
- the modification may conmprise chemical modification of a Lys, Arg or Cys residue present at position 17 to introduce the lipophilic moiety, modification of the N- or C- terminus, and/or modification of any other amino acid side chains in the molecule (e.g. to introduce a non-naturally occurring amino acid residue).
- the compounds of the invention may also be manufactured by standard peptide synthetic methods, e.g. by standard solid-phase or liquid-phase methodology, either stepwise or by fragment assembly, and isolating and purifying the final peptide compound product, or by any combinations of recombinant and synthetic methods. It may be preferable to synthesize the peptide compounds of the invention by means of solid- phase or liquid-phase peptide synthesis.
- synthesize the peptide compounds of the invention by means of solid- phase or liquid-phase peptide synthesis.
- GIP-GLP1 dual agonist compounds that exhibit signaling selectivity, and methods for screening these compounds.
- Signaling selectivity may be, for example, preferential pathway activation or preferential pathway inhibition, or both.
- the GIP-GLP1 dual agonist compounds may be useful for the treatment and/or prevention of diseases or conditions caused or characterized by excess body weight, including, but not limited to, obesity, morbid obesity, obesity linked inflammation, obesity linked gallbladder disease, obesity induced sleep apnea, metabolic syndrome, pre-diabetes, insulin resistance, glucose intolerance, type 2 diabetes, type I diabetes, hypertension, atherogenic dyslipidaemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral artery disease, and stroke or microvascular disease.
- Piperidine/DMF (20%; 10 ml) was added to the resin for initial deprotection and the mixture was heated by microwaves (30 sec; 40°C).
- the reaction vessel was drained and a second portion of piperidine/NMP (20%; 10 ml) was added and heated (75°C; 3 min.) again.
- the resin was then washed with DMF (6 x 10 ml).
- Fmoc-Lys(ivDde)-OH or alternatively another amino acid with an orthogonal side chain protective group was introduced at the position of the acylation.
- the N-terminal of the peptide backbone was then Boc-protected using Boc20 or alternatively by using a Boc-protected amino acid in the last coupling. While the peptide was still attached to the resin, the orthogonal side chain protective group was selectively cleaved using freshly prepared hydrazine hydrate (2-4%) in NMP for 2 x 15 min.
- the unprotected lysine side chain was first coupled with Fmoc-Glu-OtBu or another spacer amino acid, which was deprotected with piperidine and acylated with a lipophilic moiety using the peptide coupling methodology as described above.
- Abbreviations employed are as follows:
- COMU l-[(l-(cyano-2-ethoxy-2-oxoethylideneaminooxy)-dimethylamino- morpholinomethylene)]methanaminium hexaflourophosphate
- ivDde 1 -(4,4-dimethyl-2,6-dioxocyclohexylidene)3-methyl-butyl
- DIPEA diisopropylethylamine
- HATU /V-[(dimethylamino)-1 H-1 ,2,3-triazol[4,5-b]pyridine-1 -ylmethylene]-/V- methylmethanaminium hexafluorophosphate
- MeCN acetonitrile
- TIS triisopropylsilane
- the resin was washed with EtOH (3 x 10 ml) and Et20 (3 x 10 ml) and dried to constant weight at room temperature (r.t.).
- the crude peptide was cleaved from the resin by treatment with TFA/TIS/water (95/2.5/2.5; 40 ml, 2 h; r.t.). Most of the TFA was removed at reduced pressure and the crude peptide was precipitated and washed three times with diethylether and dried to constant weight at room temperature.
- the crude peptide was purified to greater than 90% by preparative reverse phase HPLC using a PerSeptive Biosystems VISION Workstation equipped with a C-18 column (5 cm; 10 ⁇ ) and a fraction collector and run at 35 ml/min with a gradient of buffer A (0.1 % TFA, aq.) and buffer B (0.1% TFA, 90% MeCN, aq.). Fractions were analyzed by analytical HPLC and MS and relevant fractions were pooled and lyophilized. The final product was characterized by HPLC and MS.
- Solid phase peptide synthesis was performed on a CEM Liberty Peptide Synthesizer using standard Fmoc chemistry.
- TentaGel S Ram S resin (1 ,05 g; 0.25 mmol/g) was swelled in DMF (10 ml) prior to use and transferred between tube and reaction vessel using DCM and DMF.
- Lys17 was incorporated as Fmoc-Lys(Dde)-OH for orthogonal coupling.
- the first 9 amino acids and amino acid number 24 (counting from the C-terminal) was double couple meaning the building block was coupled twice before deprotection.
- Boc- Tyr(tBu)-OH was incorporated as the final building block in the N-terminal. Deprotection
- Piperidine/DMF (20%; 10 ml) was added to the resin for initial deprotection and the mixture was heated by microwaves (30 sec; 40°C).
- the reaction vessel was drained and a second portion of piperidine/DMF (20%; 10 ml) was added and heated (75°C; 3 min.) again.
- the resin was then washed with DMF (6 x 10 ml). Side chain acylation
- the orthogonal side chain protective group was selectively cleaved using freshly prepared hydrazine hydrate (2-4%) in NMP for 2 x 15 min.
- the unprotected lysine side chain was first coupled with Fmoc-Glu-OtBu and the two Peg3 buildingblocks using standard coupling and deprotection conditions as explained aboved.
- the lipophilic moiety was incporated as a 17-carboxy-heptadecanoic acid mono tert butyl ester again using standard coupling conditions.
- the resin was washed with EtOH (3 x 0 ml) and Et20 (3 x 10 ml) and dried to constant weight at room temperature (r.t.).
- the crude peptide was cleaved from the resin by treatment with TFA/TIS/H2O (95/2.5/2.5; 60 ml, 2 h; r.t.). Most of the TFA was removed at reduced pressure and the crude peptide was precipitated and washed three times with diethylether and dried to constant weight at room temperature.
- the crude peptide was first purified from 45% by preparative reverse phase HPLC using a PerSeptive Biosystems VISION Workstation equipped with a Gemini NX 5 ⁇ C-18 110A,
- GIP R Human GIP receptor
- GLP-1 R GLP-1 receptor
- HEK293 cells expressing the human GIP R or GLP-1 R were seeded at 30,000 cells/well in 96-well microtiter plates coated with 0.01 % poly-L-lysine, and grown for 1 day in culture in 200 ⁇ growth medium (DMEM, 10% FCS, Penicillin (100 lU/ml), Streptomycin (100 pg/ml)). On the day of analysis, growth medium was removed and the cells were washed once with 150 ml Tyrode's buffer (Tyrode's Salts (9.6 g/l), 10 mM HEPES, pH 7.4). Cells were then incubated in 100 ml Assay buffer
- Table 3 EC50 average values of all the compounds on the GIP-R and GLP1-R.
- mice Males with a body weight of approximately 25 g were given either a single subcutaneous (s.c.) bolus or a single intravenous (i.v.) bolus of each peptide to be tested.
- s.c. subcutaneous
- i.v. intravenous
- the dosing vehicle was a phosphate buffer containing mannitol (pH 7.5).
- mice were included for each compound and each administration route.
- the mice were euthanized immediately after blood sampling by cervical dislocation.
- Plasma samples were analyzed after solid phase extraction (SPE) or protein precipitation followed by liquid chromatography mass
- IPGTT Intraperitoneal Glucose Tolerance Test
- the GLP-1 analogue liraglutide (10 nmol/kg) was administered subcutaneously 4 hours before the i.p. injection of glucose.
- mice Male C57BL/6J mice (Taconic A/S, Denmark) fed high-fat diet (60% of total energy from fat, D12492, Research Diet Inc.) for approximately 6 months were used.
- Mice from cages of 4 were split into two cages (2 mice per cage) two weeks prior to start of the mock phase. All mice were mock-treated (once daily s.c. injection of vehicle) for a week to acclimatize the animals to handling and injections.
- OGTT oral glucose tolerance test
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Abstract
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Priority Applications (11)
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CA2929459A CA2929459C (en) | 2013-11-06 | 2014-11-06 | Gip-glp-1 dual agonist compounds and methods |
JP2016527453A JP6682432B2 (en) | 2013-11-06 | 2014-11-06 | GIP-GLP-1 dual agonist compounds and methods |
AU2014345569A AU2014345569B2 (en) | 2013-11-06 | 2014-11-06 | GIP-GLP-1 dual agonist compounds and methods |
EA201690660A EA035466B9 (en) | 2013-11-06 | 2014-11-06 | Gip-glp-1 dual agonist compounds and methods |
KR1020167014987A KR102310389B1 (en) | 2013-11-06 | 2014-11-06 | Gip-glp-1 dual agonist compounds and methods |
BR112016009889-7A BR112016009889B1 (en) | 2013-11-06 | 2014-11-06 | gip analogue, pharmaceutical composition comprising a gip analogue, or a pharmaceutically acceptable salt thereof, and its use |
CN201480060723.9A CN105849122B (en) | 2013-11-06 | 2014-11-06 | GIP-GLP-1 dual agonist compounds and methods |
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US16/112,926 US11008375B2 (en) | 2013-11-06 | 2018-08-27 | GIP-GLP-1 dual agonist compounds and methods |
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CN (1) | CN105849122B (en) |
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BR (1) | BR112016009889B1 (en) |
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US9896495B2 (en) | 2013-10-17 | 2018-02-20 | Zealand Pharma A/S | Acylated glucagon analogues |
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Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
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Family Cites Families (171)
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 |
US5118666A (en) | 1986-05-05 | 1992-06-02 | The General Hospital Corporation | Insulinotropic hormone |
US5120712A (en) | 1986-05-05 | 1992-06-09 | The General Hospital Corporation | Insulinotropic hormone |
US5614492A (en) | 1986-05-05 | 1997-03-25 | The General Hospital Corporation | Insulinotropic hormone GLP-1 (7-36) and uses thereof |
US5545618A (en) | 1990-01-24 | 1996-08-13 | Buckley; Douglas I. | GLP-1 analogs useful for diabetes treatment |
ES2113879T3 (en) | 1990-01-24 | 1998-05-16 | Douglas I Buckley | GLP-1 ANALOGS USEFUL FOR THE TREATMENT OF DIABETES. |
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 |
PT966297E (en) | 1996-08-08 | 2009-03-18 | Amylin Pharmaceuticals Inc | Regulation of gastrointestinal motility |
US6956026B2 (en) | 1997-01-07 | 2005-10-18 | Amylin Pharmaceuticals, Inc. | Use of exendins for the reduction of food intake |
US6006753A (en) | 1996-08-30 | 1999-12-28 | Eli Lilly And Company | Use of GLP-1 or analogs to abolish catabolic changes after surgery |
US7235627B2 (en) | 1996-08-30 | 2007-06-26 | Novo Nordisk A/S | Derivatives of GLP-1 analogs |
US6268343B1 (en) | 1996-08-30 | 2001-07-31 | Novo Nordisk A/S | Derivatives of GLP-1 analogs |
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 |
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 |
CA2265454A1 (en) | 1996-09-09 | 1998-03-19 | Zealand Pharmaceuticals A/S | Peptide prodrugs containing an alpha-hydroxyacid linker |
AU723268B2 (en) | 1996-09-09 | 2000-08-24 | Zealand Pharma A/S | Improved solid-phase peptide synthesis and agent for use in such synthesis |
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 |
US6410511B2 (en) | 1997-01-08 | 2002-06-25 | Amylin Pharmaceuticals, Inc. | Formulations for amylin agonist peptides |
US6136784A (en) | 1997-01-08 | 2000-10-24 | Amylin Pharmaceuticals, Inc. | Amylin agonist pharmaceutical compositions containing insulin |
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 |
US7157555B1 (en) | 1997-08-08 | 2007-01-02 | Amylin Pharmaceuticals, Inc. | Exendin agonist compounds |
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 |
US7220721B1 (en) | 1997-11-14 | 2007-05-22 | Amylin Pharmaceuticals, Inc. | Exendin agonist peptides |
BR9814189A (en) | 1997-11-14 | 2000-10-03 | Amylin Pharmaceuticals Inc | "exendin agonist compounds" |
US7223725B1 (en) | 1997-11-14 | 2007-05-29 | Amylin Pharmaceuticals, Inc. | Exendin agonist compounds |
ES2294822T3 (en) | 1997-11-14 | 2008-04-01 | Amylin Pharmaceuticals, Inc. | NEW COMPOUNDS OF EXENDINE AGONISTS. |
EP1049486A4 (en) | 1997-12-05 | 2006-01-04 | Lilly Co Eli | Glp-1 formulations |
CA2320371C (en) | 1998-02-13 | 2012-01-17 | Amylin Pharmaceuticals, Inc. | Inotropic and diuretic effects of exendin and glp-1 |
US6703359B1 (en) | 1998-02-13 | 2004-03-09 | Amylin Pharmaceuticals, Inc. | Inotropic and diuretic effects of exendin and GLP-1 |
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 |
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 |
IL138214A0 (en) | 1998-03-09 | 2001-10-31 | Zealand Pharmaceuticals As | Pharmacolgically active peptide conjugates having a reduced tendency towards enzymatic hydrolysis |
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 |
US7399489B2 (en) | 1999-01-14 | 2008-07-15 | Amylin Pharmaceuticals, Inc. | Exendin analog formulations |
DE60021166T3 (en) | 1999-01-14 | 2019-08-22 | Amylin Pharmaceuticals, Llc | NEW EXENDIN AGONIST FORMULATIONS AND THEIR ADMINISTRATION |
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 |
PT1180121E (en) | 1999-05-17 | 2004-03-31 | Conjuchem Inc | LONG-TERM INSULINOTROPIC PEPTIDES |
US7601691B2 (en) | 1999-05-17 | 2009-10-13 | Conjuchem Biotechnologies Inc. | Anti-obesity agents |
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 |
EP1076066A1 (en) | 1999-07-12 | 2001-02-14 | Zealand Pharmaceuticals A/S | Peptides for lowering blood glucose levels |
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 |
GB0121709D0 (en) | 2001-09-07 | 2001-10-31 | Imp College Innovations Ltd | Food inhibition agent |
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 |
US20030232761A1 (en) | 2002-03-28 | 2003-12-18 | Hinke Simon A. | Novel analogues of glucose-dependent insulinotropic polypeptide |
EP1837031B1 (en) | 2002-06-07 | 2009-10-14 | Waratah Pharmaceuticals, Inc. | Compositions and methods for treating diabetes |
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 |
CA2523408A1 (en) * | 2003-05-09 | 2004-11-18 | Novo Nordisk A\S | Peptides for use in treating obesity |
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 |
CA2849552A1 (en) | 2004-02-11 | 2005-08-25 | Amylin Pharmaceuticals, Llc | Hybrid polypeptides with selectable properties |
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 |
EP2351776A1 (en) | 2005-06-13 | 2011-08-03 | Imperial Innovations Limited | Oxyntomodulin analogues and their effects on feeding behaviour |
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 |
US7928058B2 (en) | 2006-02-22 | 2011-04-19 | Merck Sharp & Dohme Corp. | Pharmaceutical composition comprising oxyntomodulin derivatives and a method for reducing body weight using the composition |
ZA200900545B (en) | 2006-07-18 | 2010-03-31 | Sanofi Aventis | Antagonist antibody against EPHA2 for the treatment of cancer |
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 |
WO2008101017A2 (en) | 2007-02-15 | 2008-08-21 | Indiana Unversity Research And Technology Corporation | Glucagon/glp-1 receptor co-agonists |
EP2025684A1 (en) | 2007-08-15 | 2009-02-18 | Zealand Pharma A/S | Glucagon analogues |
FR2917552B1 (en) | 2007-06-15 | 2009-08-28 | Sagem Defense Securite | METHOD FOR REGULATING THE TRANSMISSION GEIGE WITHIN A RECEPTION TERMINAL |
ATE520714T1 (en) | 2007-06-15 | 2011-09-15 | Zealand Pharma As | GLUCAGON ANALOGUE |
WO2009030738A1 (en) | 2007-09-05 | 2009-03-12 | Novo Nordisk A/S | Glucagon-like peptide-1 derivatives and their pharmaceutical use |
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 |
NZ586590A (en) | 2008-01-09 | 2012-06-29 | Sanofi Aventis Deutschland | Insulin analogues or derivatives having an extremely delayed time-action profile |
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 |
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 |
JP5753779B2 (en) | 2008-06-17 | 2015-07-22 | インディアナ ユニバーシティー リサーチ アンド テクノロジー コーポレーションIndiana University Research And Technology Corporation | Glucagon analogs with improved solubility and stability in buffers at physiological pH |
EP2676673B1 (en) | 2008-06-17 | 2016-11-16 | Indiana University Research and Technology Corporation | Glucagon/glp-1 receptor co-agonists |
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 |
BRPI0823376A2 (en) | 2008-12-15 | 2015-06-16 | Zealand Pharma As | Glucagon analogs |
BRPI0823378A2 (en) * | 2008-12-15 | 2019-09-24 | Zealand Pharma As | glucagon analogs |
ES2439499T3 (en) | 2008-12-15 | 2014-01-23 | Zealand Pharma A/S | Glucagon analogues |
BRPI0823377A2 (en) | 2008-12-15 | 2016-09-27 | Zealand Pharma As | glucagon analogs |
EP2376520B1 (en) | 2008-12-19 | 2014-02-12 | Indiana University Research&Technology Corporation | Insulin analogs |
AU2009335715B2 (en) | 2008-12-19 | 2016-09-15 | Indiana University Research And Technology Corporation | Amide-based insulin prodrugs |
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 |
PE20120914A1 (en) | 2009-06-16 | 2012-08-22 | Univ Indiana Res & Tech Corp | GIP RECEIVER ACTIVE GLUCAGON COMPOUNDS |
KR101809024B1 (en) | 2009-07-13 | 2017-12-14 | 질랜드 파마 에이/에스 | Acylated glucagon analogues |
US20110144006A1 (en) | 2009-12-15 | 2011-06-16 | Igelosa Life Science Ab | Protein composition |
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 | |
WO2011117417A1 (en) | 2010-03-26 | 2011-09-29 | 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 |
US20130143798A1 (en) | 2010-03-26 | 2013-06-06 | 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 |
AR081975A1 (en) | 2010-06-23 | 2012-10-31 | Zealand Pharma As | GLUCAGON ANALOGS |
MX2012014961A (en) | 2010-06-24 | 2013-02-26 | Zealand Pharma As | Glucagon analogues. |
US9708383B2 (en) | 2010-11-09 | 2017-07-18 | Novo Nordisk A/S | Double-acylated GLP-1 derivatives |
EA201390796A1 (en) | 2011-01-20 | 2014-07-30 | Зилэнд Фарма А/С | APPLICATION OF ACYLATED GLUCAGON ANALOG |
AU2012234276A1 (en) | 2011-03-28 | 2013-08-29 | Novo Nordisk A/S | Novel glucagon analogues |
EP2694095B1 (en) * | 2011-04-05 | 2018-03-07 | Longevity Biotech, Inc. | Compositions comprising glucagon analogs and methods of making and using the same |
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 |
US9259477B2 (en) | 2011-11-03 | 2016-02-16 | Zealand Pharma A/S | GLP-1 receptor agonist peptide gastrin conjugates |
JP2015502380A (en) | 2011-12-23 | 2015-01-22 | ジーランド ファーマ アクティーゼルスカブ | Glucagon analog |
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 |
EP2863954A1 (en) | 2012-06-21 | 2015-04-29 | Indiana University Research and Technology Corporation | Incretin receptor ligand polypeptide fc-region fusion polypeptides and conjugates with altered fc-effector function |
CN109456400A (en) | 2012-07-23 | 2019-03-12 | 西兰制药公司 | Glucagon analogue |
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KR20150096684A (en) | 2012-12-21 | 2015-08-25 | 사노피 | Exendin-4 derivatives |
US9988429B2 (en) | 2013-10-17 | 2018-06-05 | Zealand Pharma A/S | Glucagon analogues |
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WO2015086730A1 (en) * | 2013-12-13 | 2015-06-18 | Sanofi | Non-acylated exendin-4 peptide analogues |
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JP6682432B2 (en) | 2020-04-15 |
EP3065767B1 (en) | 2020-12-30 |
CA2929459A1 (en) | 2015-05-14 |
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US11008375B2 (en) | 2021-05-18 |
MX2016005556A (en) | 2016-07-15 |
BR112016009889A2 (en) | 2017-12-05 |
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WO2015067715A3 (en) | 2015-10-15 |
EA035466B9 (en) | 2020-08-17 |
EA201690660A1 (en) | 2017-03-31 |
BR112016009889B1 (en) | 2023-11-28 |
JP2020040979A (en) | 2020-03-19 |
JP2016540741A (en) | 2016-12-28 |
CN105849122A (en) | 2016-08-10 |
EP3065767A2 (en) | 2016-09-14 |
CN105849122B (en) | 2021-04-30 |
KR20160079875A (en) | 2016-07-06 |
TW201605888A (en) | 2016-02-16 |
CA2929459C (en) | 2022-05-03 |
KR102310389B1 (en) | 2021-10-13 |
AU2014345569B2 (en) | 2020-08-13 |
US20190218270A1 (en) | 2019-07-18 |
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US20160280754A1 (en) | 2016-09-29 |
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