WO2013164483A1 - Gip-glp-1 dual agonist compounds and methods - Google Patents
Gip-glp-1 dual agonist compounds and methods Download PDFInfo
- Publication number
- WO2013164483A1 WO2013164483A1 PCT/EP2013/059319 EP2013059319W WO2013164483A1 WO 2013164483 A1 WO2013164483 A1 WO 2013164483A1 EP 2013059319 W EP2013059319 W EP 2013059319W WO 2013164483 A1 WO2013164483 A1 WO 2013164483A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- ser
- aib
- pro
- ala
- glu
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/16—Central respiratory analeptics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
- A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
- C07K14/605—Glucagons
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- 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- (GLP-1 ), and glucose-dependent insulinotropic polypeptide (GIP). The in cretin 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 et al. showed that GLP-1 has anti- apoptotic effects in human islets (Farilla, L, Endocrinology 144: 5149-58 (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
- the present invention concerns 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.
- 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 also known as GIP analogues
- preferred GIP analogues of the present invention comprise non-conservative substitutions at one or more of amino acid positions 1 , 2, 3, 7, 9, 13, 14, 15, 17, 19, 20, 21 , 22, 23, 24, 27, 28, 29, and 30 of the wild-type GIP sequence in combination with lie, Gin, Lys, Arg or Glu in position 17, optionally in combination with further conservative or non-conservative substitutions at one or more of amino acid positions 10,11 , and 16; and acylation of one or more of amino acid positions 15, 16, 17, 19, 20, 24, 27, 28 and 30 and/or a substitution or deletion of one or more of amino acids corresponding to positions 30 to 42 of the wild-type GIP sequence.
- a GIP analogue of the invention is represented by the general Formula I:
- R 1 is Hy-, Ac or pGlu
- X1 is: His or Tyr
- X2 is Ala, Aib or Gly
- X3 is Glu or Asp
- X7 is Thr, Ser or lie
- X9 is Asp, Glu
- X10 is Tyr, Leu or Ser
- X11 is Ser or Leu
- X13 is Ala, Tyr or Aib
- X14 is Met, Leu or Ser
- X15 is Asp or Glu
- X16 is Lys, Gly, Ser or Glu
- X17 is lie, Lys, Gin, Arg or Glu;
- X19 is Gin, Ala, Glu or Lys
- X20 is Gin, Lys or Arg
- X21 is Asp, Ala or Glu
- X22 is Phe or 1 Nal
- X23 is Val, lie or Leu
- X24 is Asn, Glu, Arg or Lys
- X27 is Leu, Val, lie, Lys, Glu or Ser;
- X28 is Ala, Ser, Arg or Aib;
- X29 is Gin, Aib, Glu, Lys, Gly or Tyr;
- X30 is Lys, Gly, Pro or absent;
- X31 is Gly, Pro, Ser, Glu or absent
- X32 is Lys, Ser or absent
- X33 is Lys, Ser, Glu or absent
- X34 is Asn, Gly, Ala, Lys or absent;
- X35 is Asp, Ala, Pro, Glu or absent
- X36 is Trp, Pro, Lys or absent
- X37 is Lys, Pro, Glu or absent
- X38 is His, Pro, Ser, Lys or absent
- X39 is Asn, Ser or absent
- X40 is lie or absent
- X41 is Thr or absent
- X42 is Gin or absent
- R 2 is -NH 2 or -OH.
- a GIP analogue of the invention is represented by the general Formula ⁇ :
- R 1 is Hy-, Ac or pGlu
- X2 is Ala, Aib or Gly
- X3 is Glu or Asp
- X7 is Thr, Ser or lie
- X9 is Asp or Glu
- X10 is Tyr, Leu or Ser
- X11 is Ser or Leu
- X12 is lie or Lys
- X13 is Ala, Tyr or Aib
- X14 is Met, Leu or Ser
- X15 is Asp or Glu
- X16 is Lys, Gly, Ser or Glu
- X19 is Gin, Ala, Glu or Lys
- X20 is Gin, Lys, Arg or His;
- X21 is Asp, Ala or Glu;
- X22 is Phe or 1 Nal
- X23 is Val, lie or Leu
- X24 is Asn, Glu, Arg or Lys
- X27 is Leu, Val, lie, Lys, Glu or Ser;
- X28 is Ala, Ser, Arg or Aib;
- X29 is Gin, Aib, Lys, Gly or Ala;
- X30 is Lys, Gly, Pro or absent
- X31 is Gly, Pro, Ser, Glu or absent
- X32 is Lys, Ser or absent
- X33 is Lys, Ser, Glu or absent
- X34 is Asn, Gly, Ala, Lys or absent;
- X35 is Asp, Ala, Pro, Glu or absent
- X36 is Trp, Pro, Lys or absent
- X37 is Lys, Pro, Glu or absent
- X38 is His, Pro, Ser, Lys or absent
- X39 is Asn, Ser or absent
- X40 is lie or absent
- X41 is Thr or absent
- X42 is Gin or absent
- R 2 is -NH 2 or -OH.
- a GIP analogue of the invention is represented by the general Formula l(a):
- R 1 is Hy-, Ac or pGlu
- X1 is His or Tyr
- X2 is Ala, Aib or Gly
- X3 is Glu or Asp
- X7 is Thr, Ser or lie
- X9 is Asp or Glu
- X10 is Tyr, Leu or Ser; X11 is Ser or Leu;
- X13 is Ala, Tyr or Aib
- X14 is Met, Leu or Ser
- X15 is Asp or Glu
- X16 is Lys, Gly, Ser or Glu
- X17 is lie, Lys, Gin, Arg or Glu;
- X19 is Gin, Ala, Glu or Lys
- X20 is Gin, Lys or Arg
- X21 is Asp, Ala or Glu
- X22 is Phe or l Nal
- X23 is Val, lie or Leu ;
- X24 is Asn, Glu, Arg or Lys
- X27 is Leu, Val. lie, Lys, Glu or Ser;
- X28 is Ala, Ser, Arg or Aib;
- X29 is Gin, Aib, Glu, Lys or Tyr;
- X30 is Lys, Gly, Pro or absent
- X31 is Gly, Pro, Ser, Glu or absent
- X32 is Lys, Ser or absent
- X33 is Lys, Ser, Glu or absent
- X34 is Asn, Gly, Ala, Lys or absent;
- X35 is Asp, Ala, Pro, Glu or absent
- X36 is Trp, Pro, Lys or absent
- X37 is Lys, Pro, Glu or absent
- X38 is His, Pro, Ser, Lys or absent
- X39 is Asn, Ser or absent
- X40 is lie or absent
- X41 is Thr or absent
- X42 is Gin or absent
- R 2 is -NH 2 or -OH.
- a GIP analogue of the invention is represented by the general Formula l(a)':
- R 1 is Hy-, Ac or pGiu
- X2 is Ala, Aib or Gly
- X3 is Glu or Asp
- X7 is Thr, Ser or lie
- X9 is Asp or Glu
- X10 is Tyr, Leu or Ser
- X11 is Ser or Leu
- X12 is lie or Lys
- X13 is Ala, Tyr or Aib
- X14 is Leu or Ser
- X15 is Asp or Glu
- X16 is Lys, Gly, Ser or Glu
- X17 is He, Gin, Arg or Glu
- X19 is Gin, Ala, Glu or Lys
- X20 is Gin, Lys, Arg or His
- X21 is Asp, Ala or Glu
- X22 is Phe or 1 Nal
- X23 is Val, lie or Leu ;
- X24 is Asn, Glu, Arg or Lys
- X27 is Leu, Val, He, Lys, Glu or Ser
- X28 is Ala, Ser, Arg or Aib;
- X29 is Gin, Aib, Lys, Gly or Ala;
- X30 is Lys, Gly, Pro or absent;
- X31 is Gly, Pro, Ser, Glu or absent;
- X32 is Lys, Ser or absent
- X33 is Lys, Ser, Glu or absent
- X34 is Asn, Gly, Ala, Lys or absent;
- X35 is Asp, Ala, Pro, Glu or absent;
- X36 is Trp, Pro, Lys or absent;
- X37 is Lys, Pro, Glu or absent
- X38 is His, Pro, Ser, Lys or absent
- X39 is Asn, Ser or absent
- X40 is He or absent
- X41 is Thr or absent
- X42 is Gin or absent
- R 2 is -NH 2 or -OH.
- a GIP analogue of the invention is represented by the general Formula l(b):
- R 1 is Hy-, Ac or pGlu
- XI is His or Tyr
- X2 is Ala, Aib or Gly
- X3 is Glu or Asp
- X7 is Thr or Ser
- X9 is Asp or Glu
- X10 is Tyr, Leu or Ser
- XI I is Ser or Leu
- X13 is Ala, Tyr or Aib
- X14 is Met, Leu or Ser
- X15 is Asp or Glu
- X16 is Lys, Gly, Ser or Glu
- X17 is lie, Lys, Gin, Arg or Glu;
- X19 is Gin, Ala, Glu or Lys
- X20 is Gin, Lys or Arg
- X21 is Asp, Ala or Glu
- X22 is Phe or 1 Nal
- X23 is Val, He or Leu ;
- X24 is Asn, Glu, Arg or Lys
- X27 is Leu, Val, lie, Lys or Ser
- X28 is Ala or Aib
- X29 is Gin, Gly, Aib or Tyr
- X30 is Lys, Gly, Pro or absent
- X31 is Gly, Pro, Ser, Glu or absent
- X32 is Lys, Ser or absent;
- X33 is Lys, Ser, Glu or absent;
- X34 is Asn, Gly, Ala, Lys or absent;
- X35 is Asp, Ala, Pro, Glu or absent
- X36 is Trp, Pro, Lys or absent
- X37 is Lys, Pro, Glu or absent
- X38 is His, Pro, Ser, Lys or absent
- X39 is Asn, Ser or absent
- X40 is lie or absent
- X41 is Thr or absent
- X42 is Gin or absent
- R 2 is -NH 2 or -OH.
- a GIP analogue of the invention is represented by the general Formula l(b)':
- R 1 is Hy-, Ac or pGlu
- X2 is Ala, Aib or Gly
- X3 is Glu or Asp
- X7 is Thr or Ser
- X9 is Asp or Glu
- X10 is Tyr or Leu
- X1 1 is Ser or Leu
- X12 is He or Lys
- X13 is Ala, Tyr or Aib
- X14 is Leu or Ser
- X15 is Asp or Glu
- X16 is Lys, Ser or Glu
- X19 is Gin, Ala, Glu or Lys
- X20 is Gin, Lys, Arg or His
- X21 is Asp, Ala or Glu
- X23 is Val, lie or Leu
- X24 is Asn, Glu, Arg or Lys;
- X27 is Leu, Glu, Va! or He;
- X28 is Ala, Ser, Arg or Aib;
- X29 is Gin, Gly, Aib or Ala
- X30 is Lys, Gly, Pro or absent
- X31 is Gly, Pro, Ser, Glu or absent
- X32 is Lys, Ser or absent
- X33 is Lys, Ser, Glu or absent
- X34 is Asn, Gly, Ala, Lys or absent;
- X35 is Asp, Ala, Pro, Glu or absent
- X36 is Trp, Pro, Lys or absent
- X37 is Lys, Pro, Glu or absent
- X38 is His, Pro, Ser, Lys or absent
- X39 is Asn, Ser or absent
- X40 is He or absent
- X41 is Thr or absent
- X42 is Gin or absent
- R 2 is -NH 2 or -OH.
- a GIP analogue of the invention is represented by the general Formula II:
- R 1 is Hy-, Ac or pG!u
- X2 is Aib or Gly
- X7 is Thr, lie or Ser
- X10 is Tyr, Leu or Ser
- X1 1 is Ser or Leu
- X13 is Ala, Tyr or Aib
- X14 is Leu
- X15 is Asp or Glu
- X16 is Ser, Glu or Lys
- X17 is He or Lys
- X19 is Gin, Lys, Ala or Glu
- X20 is Lys or Arg
- X21 is Ala or Glu
- X23 is Val or lie
- X24 is Asn or Glu
- X27 is Leu, Glu, Ser, Lys or Val
- X28 is Aib, Ala, Ser or Arg
- X29 is Aib, Glu, Gly or Lys
- X30 is Lys, Gly or absent
- Y1 is 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, Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser or absent; and
- R 2 is -NH 2 or -OH.
- a GIP analogue of the invention is represented by the general Formula II':
- R 1 is Hy-, Ac or pGlu
- X2 is Aib or Gly
- X7 is Thr, lie or Ser
- X10 is Tyr or Leu
- X11 is Ser or Leu
- X12 is lie or Lys
- X13 is Ala, Tyr or Aib
- X15 is Asp or Glu
- X16 is Ser, Glu or Lys
- X19 is Gin or Ala
- X20 is Lys, His or Arg
- X21 is Ala, Asp or Glu
- X23 is Val or lie
- X24 is Asn, Lys or Glu
- X27 is Leu, Glu, Val or lie;
- X28 is Aib, Ala, Ser or Arg;
- X29 is Gin, Aib, Ala, Gly or Lys
- X30 is Lys, Gly or absent
- Y1 is 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, Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser or absent; and
- R 2 is -NH 2 or -OH.
- a GIP analogue of the invention is represented by the general Formula 11(a):
- R 1 is Hy-, Ac or pGlu
- X2 is Aib or Gly
- X7 is Thr, lie or Ser
- X10 is Tyr, Leu or Ser
- X11 is Ser or Leu
- X13 is Ala, Tyr or Aib
- X15 is Asp or Glu
- X16 is Ser, Glu or Lys
- X17 is lie or Lys
- X19 is Gin, Lys, Ala or Glu
- X20 is Lys or Arg
- X21 is Ala or Glu
- X23 is Val or lie
- X24 is Asn or Glu
- X27 is Leu, Glu, Ser, Lys or Val
- X28 is Aib, Ala, Ser or Arg
- X29 is Aib, Glu or Lys
- X30 is Lys, Gly or absent;
- Y1 is 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, Pro-Ser-Ser-Giy-Ala-Pro-Pro-Ser or absent;
- R 2 is -NH 2 or -OH.
- a GIP analogue of the invention is represented by the general Formula ll(a)':
- R is Hy-, Ac or pGlu
- X2 is Aib or Gly
- X7 is Thr, lie or Ser
- X10 is Tyr or Leu
- X11 is Ser or Leu
- X13 is Ala, Tyr or Aib
- X15 is Asp or Glu
- X16 is Ser, Glu or Lys
- X19 is Gln, Lys, Ala or Glu
- X20 is Lys, His or Arg
- X21 is Ala, Asp or Glu
- X23 is Val or lie
- X24 is Asn, Lys or Glu
- X27 is Leu, Glu, Val or lie
- X28 is Aib, Ala, Ser or Arg
- X29 is Gin, Aib, Ala, or Gly;
- X30 is Lys, Gly or absent
- Y1 is 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, Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser or absent; and
- R 2 is -NH 2 or -OH.
- a GIP analogue of the invention is represented by the general Formula !l(b): R 1 - Tyr- Aib-Glu-Gly-Thr-Phe-X7-Ser-Asp-Tyr-Ser-lle-X13-X14-X15-Lys-X17-Ala-
- R 1 is Hy-, Ac or pGlu
- X7 is Thr or Ser
- X13 is Ala, Tyr or Aib
- X14 is Leu
- X15 is Asp or Glu
- X17 is He or Lys
- X20 is Lys or Arg
- X21 is Ala or Glu
- X23 is Val or lie
- X24 is Asn or Glu
- X27 is Leu or Val
- X29 is Aib or Gly
- X30 is Lys, Gly or absent
- Y1 is 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, Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser or absent; and
- R 2 is -NH 2 or -OH.
- a GIP analogue of the invention is represented by the general Formula ll(b)':
- R 1 is Hy-, Ac or pGlu
- X7 is Thr or Ser
- X13 is Ala or Tyr
- X15 is Asp or Glu
- X16 is Lys or Ser
- X20 is Lys, His or Arg
- X21 is Ala, Asp or Glu
- X23 is Val or He
- X27 is Leu, Glu or Val
- X28 is Arg or Ser
- X30 is Lys, Gly or absent
- Y1 is 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, Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser or absent; and
- R 2 is -NH 2 or -OH.
- a GIP analogue of the invention is represented by the general Formula ll(c):
- R 1 is Hy-, Ac or pGlu
- X7 is Thr or Ser
- X13 is Aib or Tyr ;
- X15 is Asp or Glu
- X16 is Glu, Lys or Ser
- X20 is Lys, His or Arg
- X21 is Ala, Asp or Glu
- X24 is Glu or Asn
- X27 is Leu, Glu or Val
- X29 is Gin or Aib
- X30 is Lys, Gly or absent
- Y1 is Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser, Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser,
- R 2 is -NH 2 or -OH.
- a GIP analogue of the invention is represented by the general Formula 11(d):
- R 1 is Hy-, Ac or pGlu
- X7 is Thr or Ser
- X13 is Aib or Tyr
- X15 is Asp or Glu
- X16 is Glu, Lys or Ser
- X20 is Lys, His or Arg
- X27 is Leu, Glu or Val
- X30 is Lys, Gly or absent
- Y1 is Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser, Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser,
- R 2 is -NH 2 or -OH.
- the Isoleucine at position 7 of native GIP appears to provide significant selectivity for the GIP receptor.
- a small polar residue (e.g. Thr or Ser) at position 7 may increase potency and/or selectivity at the GLP-1 receptor.
- substitution of Met found in position 14 of native GIP with a hydrophobic residue like leucine is important for enhancing GLP-1 receptor activity and so increase potency and/or selectivity at the GLP-1 receptor.
- the substitution of Met at position 14 with leucine also reduces the potential for oxidation, so increasing the chemical stability of the compounds.
- the non-conservative and non-obvious substitution of lie for Lys in position 17 may enhance GLP-1 receptor activity and in addition provide a handle for acylation to prolong half life of the peptide.
- histidine at position 18 of native GIP appears to provide significant selectivity for the GIP receptor.
- a non-conservative substitution of histidine in position 18 with a small hydrophobic residue may increase potency and/or selectivity at the GLP-1 receptor.
- truncation of the C-terminal of native GIP may be performed without affecting the GIP receptor activity.
- the truncation can be of any length (1-13 amino acids) down to a 29 amino acid GIP peptide.
- 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 or Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser at or after position 29 or at or after position 30 of a native GIP or a GIP analogue may increase GLP1 receptor activity.
- Aib in amino acid position 2 may render GIP peptide having from 42 amino acids down to 29 amino acids resistant to DPP-IV cleavage.
- Aib in amino acid position 13 and/or 29 will enhance the stability of the peptide towards enzymatic degradation.
- the Aib mayenhance the helicity of the peptide and hence enhance the GLP-1 receptor activity.
- Nail in position 22 may also render the peptide stable to enzymatic degradation.
- the GIP analogue of the invention comprises: Glu at position 24 and/or Ala at position 21 , truncated or full length, which may be combined with any of the following:
- Aib at position 2 Thr at position 7, Leu at position 14, Lys at position 17, Ala at position 18, Ala at position 19, truncated or full length; Aib at position 2, Thr at position 7, Leu at position 14, Lys at position 17, Ala at position 18, Ala at position 19, (Aib at position 13 and/or 29), truncated or full length;
- Aib at position 2 Thr at position 7, Leu at position 14, Lys at position 17, Ala at position 18, Gin at position 19, (Aib at position 13 and/or 29), truncated or full length.
- R 1 is Hy-, Ac or pGlu
- X1 is His or Tyr
- X2 is Ala, Aib or Gly
- X3 is Glu or Asp
- X7 is Thr, Ser or lie
- X9 is Asp or Glu
- X10 is Tyr, Leu or Ser
- X11 is Ser or Leu
- X13 is Ala, Tyr or Aib
- X14 is Met, Leu or Ser
- X15 is Asp or Glu
- X16 is Lys, Gly, Ser or Glu
- X17 is He, Lys, Gin, Arg or Glu
- X19 is Gin, Ala, Glu or Lys
- X20 is Gin, Lys or Arg
- X21 is Asp, Ala or Glu
- X22 is Phe or 1 Nal
- X23 is Val, lie or Leu
- X24 is Asn, Glu, Arg or Lys
- X27 is Leu, Val, lie, Lys, Glu or Ser;
- X28 is Ala, Ser, Arg or Aib;
- X29 is Gin, Aib, Glu, Lys, Gly or Tyr;
- X30 is Lys, Gly, Pro or absent
- X31 is Gly, Pro, Ser, Glu or absent
- X32 is Lys, Ser or absent
- X33 is Lys, Ser, Glu or absent
- X34 is Asn, Gly, Ala, Lys or absent;
- X35 is Asp, Ala, Pro, Glu or absent
- X36 is Trp, Pro, Lys or absent
- X37 is Lys, Pro, Glu or absent
- X38 is His, Pro, Ser, Lys or absent
- X39 is Asn, Ser or absent
- X40 is He or absent
- X41 is Thr or absent
- X42 is Gin or absent
- R 2 is -NH 2 or -OH.
- the GIP analogue of embodiment 1 wherein the GIP analogue is represented by the general Formula l(a):
- R 1 is Hy-, Ac or pGlu
- XI is His or Tyr
- X2 is Ala, Aib or Gly
- X3 is Glu or Asp
- X7 is Thr, Ser or lie
- X9 is Asp or Glu
- X10 is Tyr, Leu or Ser
- XI I is Ser or Leu
- X13 is Ala, Tyr or Aib
- X14 is Met, Leu or Ser
- X15 is Asp or Glu
- X16 is Lys, Gly, Ser or Glu
- X17 is lie, Lys, Gin, Arg or Glu;
- X19 is Gin, Ala, Glu or Lys
- X20 is Gin, Lys or Arg
- X21 is Asp, Ala or Glu
- X22 is Phe or 1 Nal
- X23 is Val, lie or Leu ;
- X24 is Asn, Glu, Arg or Lys
- X27 is Leu, Val, He, Lys, Glu or Ser
- X28 is Ala, Ser, Arg or Aib;
- X29 is Gin, Aib, Glu, Lys or Tyr;
- X30 is Lys, Gly, Pro or absent
- X31 is Gly, Pro, Ser, Glu or absent;
- X32 is Lys, Ser or absent;
- X33 is Lys, Ser, Glu or absent
- X34 is Asn, Gly, Ala, Lys or absent;
- X35 is Asp, Ala, Pro, Glu or absent
- X36 is Trp, Pro, Lys or absent
- X37 is Lys, Pro, Glu or absent
- X38 is His, Pro, Ser, Lys or absent
- X39 is Asn, Ser or absent
- X40 is He or absent
- X41 is Thr or absent
- X42 is Gin or absent; and R 2 is -NH 2 or -OH.
- R is Hy-, Ac or pGlu
- XI is His or Tyr
- X2 is Ala, Aib or Gly
- X3 is Glu or Asp
- X7 is Thr or Ser
- X9 is Asp or Glu
- X10 is Tyr, Leu or Ser
- XI I is Ser or Leu
- X13 is Ala, Tyr or Aib
- X14 is Met, Leu or Ser
- X15 is Asp or Glu
- X16 is Lys, Gly, Ser or Glu
- X17 is lie, Lys, Gin, Arg or Glu;
- X19 is Gin, Ala, Glu or Lys
- X20 is Gin, Lys or Arg
- X21 is Asp, Ala or Glu
- X22 is Phe or 1 Nal
- X23 is Val, He or Leu
- X24 is Asn, Glu, Arg or Lys
- X27 is Leu, Val, He, Lys or Ser
- X28 is Ala or Aib
- X29 is Gin, Gly, Aib or Tyr
- X30 is Lys, Gly, Pro or absent
- X31 is Gly, Pro, Ser, Glu or absent
- X32 is Lys, Ser or absent
- X33 is Lys, Ser, Glu or absent
- X34 is Asn, Gly, Ala, Lys or absent
- X35 is Asp, Ala, Pro, Glu or absent
- X36 is Trp, Pro, Lys or absent
- X37 is Lys, Pro, Glu or absent
- X38 is His, Pro, Ser, Lys or absent
- X39 is Asn, Ser or absent
- X40 is lie or absent
- X41 is Thr or absent
- X42 is Gin or absent
- R 1 is Hy-, Ac or pGlu
- X2 is Aib or Gly
- X7 is Thr, lie or Ser
- X10 is Tyr, Leu or Ser
- X1 1 is Ser or Leu
- X13 is Ala, Tyr or Aib
- X14 is Leu
- X15 is Asp or Glu
- X16 is Ser, Glu or Lys
- X17 is lie or Lys
- X19 is Gin, Lys, Ala or Glu
- X20 is Lys or Arg
- X21 is Ala or Glu
- X23 is Val or lie
- X24 is Asn or Glu
- X27 is Leu, Glu, Ser, Lys or Val
- X28 is Aib, Ala, Ser or Arg
- X29 is Aib, Glu, Gly or Lys
- X30 is Lys, Gly or absent;
- Y1 is 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, Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser or absent;
- R 2 is -NH 2 or -OH.
- R 1 is Hy-, Ac or pGlu
- X2 is Aib or Gly
- X7 is Thr, lie or Ser
- X10 is Tyr, Leu or Ser
- X11 is Ser or Leu
- X13 is Ala, Tyr or Aib
- X14 is Leu
- X15 is Asp or Glu
- X16 is Ser, Glu or Lys
- X17 is He or Lys
- X19 is Gin, Lys, Ala or Glu
- X20 is Lys or Arg
- X21 is Ala or Glu
- X23 is Val or He
- X24 is Asn or Glu
- X27 is Leu, Glu, Ser, Lys or Val
- X28 is Aib, Ala, Ser or Arg
- X29 is Aib, Glu or Lys
- X30 is Lys, Gly or absent
- Y1 is G!y-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, Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser or absent; and
- R 2 is -NH 2 or -OH. 6.
- R 1 is Hy-, Ac or pGlu
- X7 is Thr or Ser
- X13 is Ala, Tyr or Aib
- X14 is Leu
- X15 is Asp or Glu
- X17 is He or Lys
- X20 is Lys or Arg
- X21 is Ala or Glu
- X23 is Val or He
- X24 is Asn or Glu
- X27 is Leu or Val
- X29 is Aib or Gly
- X30 is Lys, Gly or absent
- Y1 is Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser, Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser,
- R 2 is -NH 2 or -OH.
- R 1 is Hy-, Ac or pGlu
- X2 is Ala, Aib or Gly
- X3 is Glu or Asp
- X7 is Thr, Ser or lie;
- X9 is Asp or Glu;
- X10 is Tyr, Leu or Ser
- X11 is Ser or Leu
- X12 is He or Lys
- X13 is Ala, Tyr or Aib
- X14 is Met, Leu or Ser
- X15 is Asp or Glu
- X16 is Lys, Gly, Ser or Glu
- X19 is Gin, Ala, Glu or Lys
- X20 is Gin, Lys, Arg or His
- X21 is Asp, Ala or Glu
- X22 is Phe oM Nal
- X23 is Val, lie or Leu
- X24 is Asn, Glu, Arg or Lys
- X27 is Leu, Val, lie, Lys, Glu or Ser;
- X28 is Ala, Ser, Arg or Aib;
- X29 is Gin, Aib, Lys, Gly or Ala;
- X30 is Lys, Gly, Pro or absent
- X31 is Gly, Pro, Ser, Glu or absent
- X32 is Lys, Ser or absent
- X33 is Lys, Ser, Glu or absent
- X34 is Asn, Gly, Ala, Lys or absent;
- X35 is Asp, Ala, Pro, Glu or absent
- X36 is Trp, Pro, Lys or absent
- X37 is Lys, Pro, Glu or absent
- X38 is His, Pro, Ser, Lys or absent
- X39 is Asn, Ser or absent
- X40 is lie or absent
- X41 is Thr or absent
- X42 is Gin or absent
- R 2 is -NH 2 or -OH.
- R 1 is Hy-, Ac or pGlu
- X2 is Ala, Aib or Gly
- X3 is Glu or Asp
- X7 is Thr, Ser or He
- X9 is Asp or Glu
- X10 is Tyr, Leu or Ser
- X11 is Ser or Leu
- X12 is lie or Lys
- X13 is Ala, Tyr or Aib
- X14 is Leu or Ser
- X15 is Asp or Glu
- X16 is Lys, Gly, Ser or Glu
- X19 is Gin, Ala, Glu or Lys
- X20 is Gin, Lys, Arg or His
- X21 is Asp, Ala or Glu
- X22 is Phe or 1 Nal
- X23 is Val, lie or Leu ;
- X24 is Asn, Glu, Arg or Lys
- X27 is Leu, Val, lie, Lys, Glu or Ser;
- X28 is Ala, Ser, Arg or Aib;
- X29 is Gin, Aib, Lys, Gly or Ala;
- X30 is Lys, Gly, Pro or absent
- X31 is Gly, Pro, Ser, Glu or absent
- X32 is Lys, Ser or absent
- X33 is Lys, Ser, Glu or absent
- X34 is Asn, Gly, Ala, Lys or absent;
- X35 is Asp, Ala, Pro, Glu or absent
- X36 is Trp, Pro, Lys or absent
- X37 is Lys, Pro, Glu or absent
- X38 is His, Pro, Ser, Lys or absent;
- X39 is Asn, Ser or absent;
- X40 is lie or absent
- X41 is Thr or absent
- X42 is Gin or absent
- R 2 is -NH 2 or -OH.
- R 1 is Hy-, Ac or pGlu
- X2 is Ala, Aib or Gly
- X3 is Glu or Asp
- X7 is Thr or Ser
- X9 is Asp or Glu
- X10 is Tyr or Leu
- X1 1 is Ser or Leu
- X12 is lie or Lys
- X13 is Ala, Tyr or Aib
- X14 is Leu or Ser
- X15 is Asp or Glu
- X16 is Lys, Ser or Glu
- X19 is Gin, Ala, Glu or Lys
- X20 is Gin, Lys, Arg or His
- X21 is Asp, Ala or Glu
- X23 is Val, lie or Leu
- X24 is Asn, Glu, Arg or Lys
- X27 is Leu, Glu, Val or lie
- X28 is Ala, Ser, Arg or Aib;
- X29 is Gin, Gly, Aib or Ala
- X30 is Lys, Gly, Pro or absent
- X31 is Gly, Pro, Ser, Glu or absent; X32 s Lys, Ser or absent;
- X40 s lie or absent
- R 2 is -NH 2 or -OH.
- R 1 is Hy-, Ac or pGlu
- X2 is Aib or Gly
- X7 is Thr, lie or Ser
- X10 is Tyr or Leu
- X1 1 is Ser or Leu
- X12 is lie or Lys
- X13 is Ala, Tyr or Aib
- X15 is Asp or Glu
- X16 is Ser, Glu or Lys
- X19 is Gin or Ala
- X20 is Lys, His or Arg
- X21 is Ala, Asp or Glu
- X23 is Val or lie
- X24 is Asn, Lys or Glu
- X27 is Leu, Glu, Val or lie
- X28 is Aib, Ala, Ser or Arg
- X29 is Gin, Aib, Ala, Gly or Lys; X30 is Lys, Gly or absent;
- Y1 is 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, Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser or absent; and
- R 2 is -NH 2 or -OH.
- R 1 is Hy-, Ac or pGlu
- X2 is Aib or Gly
- X7 is Thr, lie or Ser
- X10 is Tyr or Leu
- X1 1 is Ser or Leu
- X13 is Ala, Tyr or Aib
- X15 is Asp or Glu
- X16 is Ser, Glu or Lys
- X19 is Gin, Lys, Ala or Glu
- X20 is Lys, His or Arg
- X21 is Ala, Asp or Glu
- X23 is Val or lie
- X24 is Asn, Lys or Glu
- X27 is Leu, Glu, Val or lie
- X28 is Aib, Ala, Ser or Arg
- X29 is Gin, Aib, Ala, or Gly;
- X30 is Lys, Gly or absent
- Y1 is 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, Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser or absent; and
- R 2 is -NH 2 or -OH. 12.
- R 1 is Hy-, Ac or pGlu
- X7 is Thr or Ser
- X13 is Ala, Tyr or Aib
- X15 is Asp or Glu
- X16 is Lys, Glu or Ser
- X20 is Lys, His or Arg
- X21 is Ala, Asp or Glu
- X23 is Val or lie
- X27 is Leu, Glu or Val
- X28 is Arg or Ser
- X30 is Lys, Gly or absent
- Y1 is 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, Pro-Ser-Ser-G!y-Ala-Pro-Pro-Ser or absent; and
- R 2 is -NH 2 or -OH.
- R 1 is Hy-, Ac or pGlu
- X7 is Thr or Ser
- X13 is Ala, Aib or Tyr
- X15 is Asp or Glu
- X 6 is Glu, Lys or Ser
- X20 is Lys, His or Arg
- X21 is Ala, Asp or Glu
- X24 is Glu or Asn
- X27 is Leu, Glu or Val
- X29 is Gin or Aib
- X30 is Lys, Gly or absent
- Y1 is 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, Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser or absent; and
- R 2 is -NH 2 or -OH.
- R 1 is Hy-, Ac or pGlu
- X7 is Thr or Ser
- X13 is Ala, Aib or Tyr
- X15 is Asp or Glu
- X16 is Glu, Lys or Ser
- X20 is Lys, His or Arg
- X27 is Leu, Glu or Val
- X30 is Lys, Gly or absent
- Y1 is 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, Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser or absent; and
- R 2 is -NH 2 or -OH.
- AAHDFVEWLLSAGPSSGAPPPS-NH 2 AAHDFVEWLLSAGPSSGAPPPS-NH 2 ;
- a pharmaceutical composition comprising a GIP analogue of any one of the preceding embodiments, or a salt, solvate or derivative thereof, in admixture with a carrier.
- GIP analogue of any one of embodiments 1 to 30 for the preparation of a medicament for the treatment and/or prevention of diabetes or a diabetes related disorder.
- diabetes related disorder is selected from insulin resistance, glucose intolerance, increased fasting glucose, pre-diabetes, type 1 diabetes, type 2 diabetes, gestational diabetes hypertension, dyslipidemia, or a combination thereof.
- diabetes related disorder is selected from atherosclerosis, arteriosclerosis, coronary heart disease, peripheral artery disease and stroke; or is associated with a condition selected from atherogenic dyslipidemia, blood fat disorders, elevated blood pressure, hypertension, a prothrombotic state, and proinflammatory state, or a combination thereof.
- embodiment 39 wherein the blood fat disorder is selected from high triglycerides, low HDL cholesterol, high LDL cholesterol, and plaque buildup in artery walls, or a combination thereof.
- prothrombotic state is selected from high fibrinogen levels in the blood and high plasminogen activator inhibitor- 1 levels in the blood.
- the obesity related disorder is selected from obesity linked inflammation, obesity linked gallbladder disease and obesity induced sleep apnea, or is associated with a condition selected from atherogenic dyslipidemia, blood fat disorders, elevated blood pressure, hypertension, a prothrombotic state, and a proinflammatory state, or a
- a nucleic acid molecule comprising a nucleic acid sequence encoding a GIP analogue of any one of embodiments 1 to 30.
- An expression vector comprising the nucleic acid sequence of embodiment 44, in combination with control sequences to direct its expression.
- nucleic acid molecule according to embodiment 44, an expression vector according to embodiment 45 or a host cell according to embodiment 46, in the preparation of a medicament for the treatment and/or prevention of a metabolic disorder.
- a method of treating a stomach and/or bowel-related disorder in a patient in need thereof by administering an effective amount a GIP analogue of any one of embodiments 1 to 30, a nucleic acid molecule according to embodiment 44, an expression vector according to embodiment 45, or a host cell according to embodiment 46.
- a method of treatment and/or prevention of a metabolic disease or disorder in a patient in need thereof comprising administering to said patient an effective amount of the GIP analogue of any one of embodiments 1 to 30, a nucleic acid molecule according to embodiment 44, an expression vector according to embodiment 45, or a host cell according to embodiment 46.
- a method of treatment and/or prevention of a diabetes related disorder in a patient in need thereof comprising the step of administering to said patient an effective amount of the GIP analogue of any one of embodiments 1 to 30, a nucleic acid molecule according to embodiment 44, an expression vector according to embodiment 45, or a host cell according to embodiment 46.
- a method of treatment and/or prevention of an obesity related disorder in a patient in need thereof comprising the step of administering to said patient an effective amount of the GIP analogue of any one of embodiments 1 to 30, a nucleic acid molecule according to embodiment 44, an expression vector according to embodiment 45, or a host cell according to embodiment 46.
- diabetes related disorder is selected from insulin resistance, glucose intolerance, increased fasting glucose, pre-diabetes, type 1 diabetes, type 2 diabetes, gestational diabetes hypertension, dyslipidemia, or a combination thereof.
- diabetes related disorder is selected from atherosclerosis, arteriosclerosis, coronary heart disease, peripheral artery disease and stroke; or is associated with a condition selected from atherogenic dyslipidemia, blood fat disorders, elevated blood pressure, hypertension, a prothrombotic state, and a proinflammatory state, or a
- the blood fat disorder is selected from high triglyceride level, low HDL cholesterol level, high LDL cholesterol level, plaque buildup in artery walls, or a combination thereof.
- prothrombotic state is selected from high fibrinogen levels in the blood and high plasminogen activator inhibitor- 1 levels in the blood.
- 61 The method of embodiment 55, wherein the obesity related disorder is selected from obesity linked inflammation, obesity linked gallbladder disease and obesity induced sleep apnea.
- 62. A therapeutic kit comprising a GIP analogue according to any one of embodiments 1 to 30, a nucleic acid molecule according to embodiment 44, an expression vector according to embodiment 45, or a host cell according to embodiment 46, each optionally in combination with a pharmaceutically acceptable carrier.
- a device comprising a GIP analogue according to any one of embodiments 1 to 30, a nucleic acid molecule according to embodiment 44, an expression vector according to embodiment 45, or a host cell according to embodiment 46, for delivery of the GIP analogue to a subject.
- a pharmaceutical composition comprising the GIP analogue of any one of embodiments 1 to 30 for use in treating a stomach and bowel-related disorder in a patient in need thereof.
- a pharmaceutical composition comprising the GIP analogue of any one of embodiments 1 to 30 for use in treatment and/or prevention of a metabolic disease or disorder in a patient in need thereof.
- a pharmaceutical composition comprising the GIP analogue of any one of embodiments 1 to 30 for use in treatment and/or prevention of a diabetes related disorder in a patient in need thereof.
- a pharmaceutical composition comprising the GIP analogue of any one of embodiments 1 to 30 for use in treatment and/or prevention of an obesity related disorder in a patient in need thereof.
- diabetes related disorder is selected from insulin resistance, glucose intolerance, increased fasting glucose, p re-diabetes, type 1 diabetes, type 2 diabetes, gestational diabetes hypertension and dyslipidemia, or a combination thereof.
- the diabetes related disorder is selected from atherosclerosis, arteriosclerosis, coronary heart disease, peripheral artery disease and stroke; or is 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.
- composition of embodiment 70, wherein the blood fat disorder is selected from high triglyceride level, low HDL cholesterol level, high LDL cholesterol level, plaque buildup in artery walls, or a combination thereof.
- composition of embodiment 70, wherein the prothrombotic state is selected from high fibrinogen levels in the blood, and high plasminogen activator inhibitor- 1 levels in the blood.
- composition of embodiment 70, wherein the proinflammatory state is an elevated C-reactive protein level in the blood.
- composition of embodiment 68, wherein the obesity related disorder is selected from obesity linked inflammation, obesity linked gallbladder disease, and obesity induced sleep apnea.
- residues X30 to X42 may be present or absent. They are not present or absent independently of one another. If any one of these residues is absent, then all residues C-terminus of that residue are also absent.
- residues which can be absent are X42; X41 -X42; X40-X41-X42; X39-X40-X41 -X42; X38-X39-X40-X41 -X42; X37-X38-X39-X40-X41 -X42; X36-X37-X38-X39-X40-X41 -X42; X35-X36-X37-X38-X39-X40-X41 -X42; X34-X35-X36-X37-X38-X39-X40-X41-X42; X33-X34-X35-X36-X37-X38-X39-X40- X41-X42; X32-X33-X34-X35-X36-X37-X38-X39-X40- X41-X42; X32-X33-X34-X35-X36-X37-X38-X39-X40-X41
- residue XN is present (where N is an integer between 30 and 42) then residue X(N-1 ) is also present.
- the amino acid sequence X1-X29 has no more than 6 amino acid differences from the sequence Y-Aib-EGTFTSDYSIYLDKKAQRAFVEWLLAQ (SEQ ID NO: 70).
- the amino acid sequence X1-X29 may, for example, have no more than 5, 4, 3, 2 or 1 amino acid differences from that sequence.
- the amino acid sequence X1-X29 has no more than 6 amino acid differences from the sequence Y-Aib-EGTFTSDYSIYLEKKAAKEFVEWLLSA (SEQ ID NO: 71 ).
- the amino acid sequence X1-X29 may, for example, have no more than 5, 4, 3, 2 or 1 amino acid differences from that sequence.
- amino acid sequence X1-X29 has no more than 5 amino acid differences from the sequence Y-Aib-EGTFTSDYSIYLDEKAAKEFIEWLESA (SEQ ID NO: 72).
- the amino acid sequence X1-X29 may, for example, have no more than 4, 3, 2 or 1 amino acid differences from that sequence.
- Figure 1 Effect of Compounds 32 and 33 on glucose tolerance.
- FIG. 5 Blood glucose (A) and plasma insulin (B) on day 13.
- FIG. 6 Blood glucose (A) and plasma insulin (B) on day 21.
- the mice were injected with vehicle, liraglutide or test substance 2 hours prior to the blood sampling.
- mice and rats 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).
- mammals such as humans, primates, livestock animals (e.g., bovines, porcines), companion animals (e.g., canines, felines) and 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 refers to a substance (ligand) that activates the receptor type in question.
- sequences disclosed herein are sequences incorporating an "Hy-" moiety at the amino terminus (N-terminus) of the sequence, and either an "- OH" moiety or an "-NH 2 " moiety at the carboxy terminus (C-terminus) of the sequence.
- conservative substitution means that an amino acid residue belonging to a certain position of the native human GIP peptide sequence has been exchanged with an amino acid residue belonging to the same group (I, II, III, IV, V, 1 , 2, 3) as defined in the following table:
- a “non-conservative" substitution as used herein means any other substitution of an amino acid residue of the native human GIP sequence, e.g. such as substituting with a non-protein amino acid (Sar, Nle, Aib, 1 al) or substituting with an amino acid which does not belong to the same group.
- the peptide conjugate of the invention may comprise functional fragments or variants thereof that have at most 34, 33, 32, 31 30, 29, 28, 27, 26, 25, 24, 23, 22, 21 , 20, 19, 18, 17, 16, 15, 14, 13, 12, 1 1 , 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid substitutions compared to one or more of the specific sequences recited below.
- Preferred 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. In either case, 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. Typically the compounds have activity at both the GLP-1 and GIP receptors.
- EC 50 values may be used as a numerical measure of agonist potency at a given receptor.
- An EC 50 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 EC 50 [GLP-1 R] lower than the EC 50 [GLP-1 R] of native glucagon in a particular assay may be
- the EC 50 GLP-1 -R and/or EC 50 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, or below 0.005 nM, e.g.
- the EC 50 value of a compound in a given assay may be assessed relative to the EC 50 of human GIP.
- the ratio of the EC 50 value of the test compound to the EC 50 value of wild type human GIP (EC 50 [test compound] / EC 50 [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 EC 50 value of the test compound to the EC 50 value of wild type human GIP (EC 50 [test compound] / EC 50 [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 EC 50 values at the two receptors for the test compound and for human GIP.
- the test compound has an EC 50 [GIP] / EC 50 [GLP-1] which is greater than the equivalent ratio for GIP in the same assays.
- the GIP analogue compounds of the present invention have one or more amino acid substitutions, deletions, inversions, or additions compared with native GIP and as defined above. This definition also includes the synonym terms GIP mimetics and/or GIP-GLP1 agonists. Further, the analogue of the present invention may additionally have chemical modification of one or more of its amino acid side groups, a-carbon atoms, terminal amino group, or terminal carboxylic acid group. A chemical modification includes, but is not limited to, adding chemical moieties, creating new bonds, and removing chemical moieties.
- Modifications at amino acid side groups include, without limitation, acylation of lysine ⁇ -amino groups, N-alkylation of arginine, histidine, or lysine, alkylation of glutamic or aspartic carboxylic acid groups, and deamidation of glutamine or asparagine.
- Modifications of the terminal amino include, without limitation, the des-amino, follower alkyl, N-di-lower alkyl, and N-acyl modifications.
- Modifications of the terminal carboxy group include, without limitation, the amide, lower alkyl amide, dialkyl amide, and lower alkyl ester modifications.
- Preferably herein lower alkyl is CrC 4 alkyl.
- one or more side groups, or terminal groups may be protected by protective groups known to the ordinarily-skilled peptide chemist.
- the a-carbon of an amino acid may be mono- or di-methylated.
- GIP analogue compounds of the present invention are described below, where said compounds may be modified at the N-terminus and C-terminus as described for R1 and R2, and include a
Abstract
Description
Claims
Priority Applications (17)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1020147033952A KR102184241B1 (en) | 2012-05-03 | 2013-05-03 | Gip-glp-1 dual agonist compounds and methods |
EP13720931.8A EP2844669B1 (en) | 2012-05-03 | 2013-05-03 | Gip-glp-1 dual agonist compounds and methods |
SG11201407137PA SG11201407137PA (en) | 2012-05-03 | 2013-05-03 | Gip-glp-1 dual agonist compounds and methods |
AU2013255751A AU2013255751B2 (en) | 2012-05-03 | 2013-05-03 | GIP-GLP-1 dual agonist compounds and methods |
MX2014013318A MX356641B (en) | 2012-05-03 | 2013-05-03 | Gip-glp-1 dual agonist compounds and methods. |
CA2872314A CA2872314C (en) | 2012-05-03 | 2013-05-03 | Gip-glp-1 dual agonist compounds and methods |
BR112014027348-0A BR112014027348B1 (en) | 2012-05-03 | 2013-05-03 | GIP-GLP-1 DOUBLE AGONIST COMPOUNDS AND METHODS |
JP2015509461A JP6228187B2 (en) | 2012-05-03 | 2013-05-03 | GIP-GLP-1 dual agonist compounds and methods |
CN201380032714.4A CN104470948B (en) | 2012-05-03 | 2013-05-03 | GIP-GLP-1 double agonists compound and method |
US14/398,260 US10100097B2 (en) | 2012-05-03 | 2013-05-03 | GIP-GLP-1 dual agonist compounds and methods |
EA201491918A EA028665B1 (en) | 2012-05-03 | 2013-05-03 | Gip-glp-1 dual agonist compounds and methods |
IN2304MUN2014 IN2014MN02304A (en) | 2012-05-03 | 2013-05-03 | |
NZ702333A NZ702333A (en) | 2012-05-03 | 2013-05-03 | Gip-glp-1 dual agonist compounds and methods |
IL235463A IL235463A0 (en) | 2012-05-03 | 2014-11-02 | Gip-glp-1 dual agonist compounds and methods |
PH12014502452A PH12014502452A1 (en) | 2012-05-03 | 2014-11-03 | Gip-glp-1 dual agonist compounds and methods |
HK15108788.2A HK1208232A1 (en) | 2012-05-03 | 2015-09-09 | Gip-glp-1 dual agonist compounds and methods gip-glp-1 |
US16/121,745 US20190135886A1 (en) | 2012-05-03 | 2018-09-05 | Gip-glp-1 dual agonist compounds and methods |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201261642439P | 2012-05-03 | 2012-05-03 | |
US61/642,439 | 2012-05-03 | ||
US201361765561P | 2013-02-15 | 2013-02-15 | |
US61/765,561 | 2013-02-15 |
Related Child Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US14/398,260 A-371-Of-International US10100097B2 (en) | 2012-05-03 | 2013-05-03 | GIP-GLP-1 dual agonist compounds and methods |
US16/121,745 Division US20190135886A1 (en) | 2012-05-03 | 2018-09-05 | Gip-glp-1 dual agonist compounds and methods |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2013164483A1 true WO2013164483A1 (en) | 2013-11-07 |
Family
ID=48325702
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2013/059319 WO2013164483A1 (en) | 2012-05-03 | 2013-05-03 | Gip-glp-1 dual agonist compounds and methods |
Country Status (20)
Country | Link |
---|---|
US (2) | US10100097B2 (en) |
EP (1) | EP2844669B1 (en) |
JP (1) | JP6228187B2 (en) |
KR (1) | KR102184241B1 (en) |
CN (1) | CN104470948B (en) |
AR (1) | AR090937A1 (en) |
AU (1) | AU2013255751B2 (en) |
BR (1) | BR112014027348B1 (en) |
CA (1) | CA2872314C (en) |
EA (1) | EA028665B1 (en) |
HK (1) | HK1208232A1 (en) |
IL (1) | IL235463A0 (en) |
IN (1) | IN2014MN02304A (en) |
MX (1) | MX356641B (en) |
NZ (1) | NZ702333A (en) |
PH (1) | PH12014502452A1 (en) |
SG (1) | SG11201407137PA (en) |
TR (1) | TR201815338T4 (en) |
TW (1) | TWI689515B (en) |
WO (1) | WO2013164483A1 (en) |
Cited By (47)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2014096179A1 (en) * | 2012-12-19 | 2014-06-26 | Novo Nordisk A/S | Novel glp-1 receptor agonists with cholesterol efflux activity |
WO2015081891A1 (en) | 2013-12-06 | 2015-06-11 | Baikang (Suzhou) Co., Ltd | Bioreversable promoieties for nitrogen-containing and hydroxyl-containing drugs |
WO2015067715A3 (en) * | 2013-11-06 | 2015-10-15 | Zealand Pharma A/S | Gip-glp-1 dual agonist compounds and methods |
US9200051B2 (en) | 2013-05-28 | 2015-12-01 | Takeda Pharmaceutical Company Limited | Peptide compound |
WO2016111971A1 (en) | 2015-01-09 | 2016-07-14 | Eli Lilly And Company | Gip and glp-1 co-agonist compounds |
WO2016066744A3 (en) * | 2014-10-29 | 2016-09-01 | Zealand Pharma A/S | Gip agonist compounds and methods |
JP2017503474A (en) * | 2013-11-06 | 2017-02-02 | ジーランド ファーマ アクティーゼルスカブ | Glucagon-GLP-1-GIP triple agonist compound |
WO2017060500A1 (en) | 2015-10-07 | 2017-04-13 | Cyprumed Gmbh | Pharmaceutical formulations for the oral delivery of peptide drugs |
WO2017074715A1 (en) | 2015-10-26 | 2017-05-04 | Eli Lilly And Company | Glucagon receptor agonists |
US9896495B2 (en) | 2013-10-17 | 2018-02-20 | Zealand Pharma A/S | Acylated glucagon analogues |
WO2018065634A1 (en) | 2016-10-07 | 2018-04-12 | Cyprumed Gmbh | Pharmaceutical compositions for the nasal delivery of peptide or protein drugs |
US9975939B2 (en) | 2012-09-17 | 2018-05-22 | Zealand Pharma A/S | Glucagon analogues |
US9988429B2 (en) | 2013-10-17 | 2018-06-05 | Zealand Pharma A/S | Glucagon analogues |
WO2018104263A1 (en) | 2016-12-06 | 2018-06-14 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods of enhancing the potency of incretin-based drugs in subjects in need thereof |
WO2018104718A1 (en) * | 2016-12-05 | 2018-06-14 | Lancaster University Business Enterprises Limited | Treatment of neurological diseases |
US10004786B2 (en) | 2009-07-13 | 2018-06-26 | Zealand Pharma A/S | Acylated glucagon analogues |
WO2018181864A1 (en) | 2017-03-31 | 2018-10-04 | Takeda Pharmaceutical Company Limited | Gip receptor activating peptide |
US10100097B2 (en) | 2012-05-03 | 2018-10-16 | Zealand Pharma A/S | GIP-GLP-1 dual agonist compounds and methods |
US10253079B2 (en) | 2012-12-21 | 2019-04-09 | Sanofi | Functionalized Exendin-4 derivatives |
US10336802B2 (en) | 2015-04-16 | 2019-07-02 | Zealand Pharma A/S | Acylated glucagon analogue |
WO2019140030A1 (en) | 2018-01-12 | 2019-07-18 | Eli Lilly And Company | Combination therapy |
WO2019193204A1 (en) | 2018-04-06 | 2019-10-10 | Cyprumed Gmbh | Pharmaceutical compositions for the transmucosal delivery of therapeutic peptides and proteins |
US10442847B2 (en) | 2012-07-23 | 2019-10-15 | Zealand Pharma A/S | Glucagon analogues |
WO2019211451A1 (en) | 2018-05-04 | 2019-11-07 | Novo Nordisk A/S | Gip derivatives and uses thereof |
US10501516B2 (en) | 2016-05-24 | 2019-12-10 | Takeda Pharmaceutical Company Limited | Peptide compound |
WO2020023388A1 (en) | 2018-07-23 | 2020-01-30 | Eli Lilly And Company | Method of using a gip/glp1 co-agonist for diabetes |
WO2020023386A1 (en) | 2018-07-23 | 2020-01-30 | Eli Lilly And Company | Gip/glp1 co-agonist compounds |
WO2020067557A3 (en) * | 2018-09-24 | 2020-07-30 | Takeda Pharmaceutical Company Limited | Gip receptor agonist peptide compounds and uses thereof |
US10758592B2 (en) | 2012-10-09 | 2020-09-01 | Sanofi | Exendin-4 derivatives as dual GLP1/glucagon agonists |
WO2021021877A1 (en) | 2019-08-01 | 2021-02-04 | Eli Lilly And Company | Gipr-agonist compounds |
WO2021034815A1 (en) | 2019-08-19 | 2021-02-25 | Eli Lilly And Company | Methods of making incretin analogs |
WO2021066600A1 (en) | 2019-10-04 | 2021-04-08 | 한미약품 주식회사 | Glucagon, composition comprising glp-1 receptor and gip receptor dual agonist and therapeutic use thereof |
WO2021068251A1 (en) | 2019-10-08 | 2021-04-15 | 江苏诺泰澳赛诺生物制药股份有限公司 | Gip and glp-1 dual agonist polypeptide compound, pharmaceutically acceptable salt of same, and uses thereof |
WO2021094259A1 (en) | 2019-11-11 | 2021-05-20 | Boehringer Ingelheim International Gmbh | Npy2 receptor agonists |
WO2021150673A1 (en) | 2020-01-23 | 2021-07-29 | Eli Lilly And Company | Gip/glp1 co-agonist compounds |
WO2021260530A1 (en) | 2020-06-22 | 2021-12-30 | Sun Pharmaceutical Industries Limited | Long acting glp-1/gip dual agonists |
WO2022018186A1 (en) | 2020-07-22 | 2022-01-27 | Novo Nordisk A/S | Co-agonists at glp-1 and gip receptors suitable for oral delivery |
WO2022018185A1 (en) | 2020-07-22 | 2022-01-27 | Novo Nordisk A/S | Glp-1 and gip receptor co-agonists |
WO2022029231A1 (en) | 2020-08-07 | 2022-02-10 | Boehringer Ingelheim International Gmbh | Soluble npy2 receptor agonists |
WO2022049310A1 (en) | 2020-09-07 | 2022-03-10 | Cyprumed Gmbh | Improved pharmaceutical formulations of glp-1 receptor agonists |
WO2022079639A1 (en) | 2020-10-17 | 2022-04-21 | Sun Pharmaceutical Industries Limited | Glp-1/gip dual agonists |
WO2022235991A1 (en) | 2021-05-07 | 2022-11-10 | Eli Lilly And Company | Erodible tablet |
WO2022253202A1 (en) * | 2021-06-01 | 2022-12-08 | 南京知和医药科技有限公司 | Polypeptide derivative having effect of dual targeted activation of glp-1r and gipr, preparation method therefor, and use thereof |
WO2023139187A1 (en) | 2022-01-20 | 2023-07-27 | Novo Nordisk A/S | Glp-1/gip receptor co-agonist prodrugs and uses thereof |
WO2024050289A1 (en) | 2022-08-29 | 2024-03-07 | Eli Lilly And Company | Compositions for oral delivery |
WO2024059674A1 (en) | 2022-09-15 | 2024-03-21 | Eli Lilly And Company | Gip and glp-1 dual agonist compounds |
RU2816492C2 (en) * | 2019-04-11 | 2024-04-01 | Цзянсу Хэнсох Фармасьютикал Груп Ко., Лтд. | Multi-receptor agonist and medical use thereof |
Families Citing this family (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10577905B2 (en) | 2018-02-12 | 2020-03-03 | Eagle Technology, Llc | Hydrocarbon resource recovery system and RF antenna assembly with latching inner conductor and related methods |
CA3125774A1 (en) * | 2019-01-07 | 2020-07-16 | Vitalixir (Beijing) Co., Ltd | Novel peptides and their therapeutic applications |
US20220168396A1 (en) * | 2019-04-11 | 2022-06-02 | Jiangsu Hansoh Pharmaceutical Group Co., Ltd. | Multi-receptor agonist and medical use thereof |
WO2021093883A1 (en) * | 2019-11-15 | 2021-05-20 | 江苏豪森药业集团有限公司 | Dual receptor-acting agonist compounds and pharmaceutical composition thereof |
WO2022117056A1 (en) * | 2020-12-02 | 2022-06-09 | 南京明德新药研发有限公司 | Lactam-modified polypeptide compounds |
CN114617956B (en) * | 2020-12-10 | 2023-10-03 | 江苏中新医药有限公司 | High-efficiency hypoglycemic protein medicine |
EP4249505A1 (en) * | 2020-12-23 | 2023-09-27 | Zhejiang Doer Biologics Co., Ltd. | Long-acting glucagon derivative |
WO2023030444A1 (en) * | 2021-09-02 | 2023-03-09 | 广东东阳光药业有限公司 | Glp-1/gip dual-targeted polypeptide and fusion protein and applications thereof |
TW202333773A (en) * | 2021-11-12 | 2023-09-01 | 大陸商福建盛迪醫藥有限公司 | Pharmaceutical compositions of glp-1 receptor and gip receptor double agonists and use thereof |
CN116693652B (en) * | 2023-08-02 | 2024-01-05 | 北京惠之衡生物科技有限公司 | GLP-1/GIP receptor dual agonist derivative and preparation method and application thereof |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998008871A1 (en) | 1996-08-30 | 1998-03-05 | Novo Nordisk A/S | Glp-1 derivatives |
WO1998011125A1 (en) | 1996-09-09 | 1998-03-19 | Zealand Pharmaceuticals A/S | Improved solid-phase peptide synthesis and agent for use in such synthesis |
WO2000055119A1 (en) | 1999-03-17 | 2000-09-21 | Novo Nordisk A/S | Method for acylating peptides and novel acylating agents |
WO2000055184A1 (en) | 1999-03-15 | 2000-09-21 | Novo Nordisk A/S | Ion exchange chromatography of proteins and peptides with an organic modifier in the elution step |
WO2010016940A2 (en) * | 2008-08-07 | 2010-02-11 | Ipsen Pharma S.A.S. | Analogues of glucose-dependent insulinotropic polypeptide |
Family Cites Families (77)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NZ202757A (en) | 1981-12-23 | 1985-11-08 | Novo Industri As | Peptides and medicaments |
NZ334595A (en) | 1996-09-09 | 2000-08-25 | Zealand Pharmaceuticals As | Peptide prodrugs containing an alpha-hydroxyacid linker that have increased stability against enzymatic cleavage |
NZ504258A (en) | 1997-11-14 | 2002-12-20 | Amylin Pharmaceuticals Inc | Exendin 3 and 4 agonist compounds for the treatment of diabetes |
EP1950223A3 (en) | 1998-03-09 | 2009-05-13 | Zealand Pharma A/S | Pharmacologically active peptide conjugates having a reduced tendency towards enzymatic hydrolysis |
KR20050037004A (en) | 1998-12-07 | 2005-04-20 | 소시에떼 더 콘세이유 더 레세르세 에 다플리까띠옹 시엔띠피끄, 에스.아.에스. | Analogues of glp-1 |
EP1076066A1 (en) | 1999-07-12 | 2001-02-14 | Zealand Pharmaceuticals A/S | Peptides for lowering blood glucose levels |
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 |
EP1545460A4 (en) | 2001-12-20 | 2005-11-16 | Lilly Co Eli | Insulin molecule having protracted time action |
GB0300571D0 (en) | 2003-01-10 | 2003-02-12 | Imp College Innovations Ltd | Modification of feeding behaviour |
EP1620465A2 (en) | 2003-04-29 | 2006-02-01 | Eli Lilly And Company | Insulin analogs having protracted time action |
EP2494983B1 (en) | 2004-11-12 | 2019-04-24 | Novo Nordisk A/S | Stable formulations of glp-1 |
CN101155828A (en) * | 2005-02-11 | 2008-04-02 | 安米林药品公司 | Gip analog and hybrid polypeptides with selectable properties |
TWI372629B (en) | 2005-03-18 | 2012-09-21 | Novo Nordisk As | Acylated glp-1 compounds |
WO2006121860A2 (en) | 2005-05-06 | 2006-11-16 | Bayer Pharmaceuticals Corporation | Glucagon-like peptide 1 (glp-1) receptor agonists and their pharmacological methods of use |
AU2006258841B2 (en) | 2005-06-13 | 2012-05-03 | 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 |
WO2007056362A2 (en) | 2005-11-07 | 2007-05-18 | Indiana University Research And Technology Corporation | Glucagon analogs exhibiting physiological solubility and stability |
WO2007081824A2 (en) | 2006-01-06 | 2007-07-19 | Case Western Reserve University | Fibrillation resistant proteins |
EP1991574B1 (en) | 2006-02-22 | 2016-10-12 | Merck Sharp & Dohme Corp. | Oxyntomodulin derivatives |
WO2007109354A2 (en) * | 2006-03-21 | 2007-09-27 | Amylin Pharmaceuticals, Inc. | Peptide-peptidase inhibitor conjugates and methods of using same |
JP5622390B2 (en) | 2006-07-18 | 2014-11-12 | サノフイ | Anti-EPHA2 antagonist antibody for cancer treatment |
ITMI20061607A1 (en) | 2006-08-09 | 2008-02-10 | Maria Vincenza Carriero | PEPTIDES WITH PHARMACOLOGICAL ACTIVITY |
WO2008023050A1 (en) * | 2006-08-25 | 2008-02-28 | Novo Nordisk A/S | Acylated exendin-4 compounds |
EP2074140B8 (en) | 2006-10-04 | 2015-10-28 | Case Western Reserve University | Fibrillation-resistant insulin and insulin analogues |
TWI428346B (en) | 2006-12-13 | 2014-03-01 | Imp Innovations Ltd | Novel compounds and their effects on feeding behaviour |
EA017849B1 (en) | 2007-02-15 | 2013-03-29 | Индиана Юниверсити Рисерч Энд Текнолоджи Корпорейшн | Glucagon/glp-1 receptor co-agonists |
EP2025684A1 (en) | 2007-08-15 | 2009-02-18 | Zealand Pharma A/S | Glucagon analogues |
JP5385266B2 (en) | 2007-06-15 | 2014-01-08 | ジーランド ファーマ アクティーゼルスカブ | Glucagon analog |
US8946148B2 (en) | 2007-11-20 | 2015-02-03 | Ambrx, Inc. | Modified insulin polypeptides and their uses |
EP2229406B1 (en) | 2008-01-09 | 2015-04-22 | Sanofi-Aventis Deutschland GmbH | Novel insulin derivatives having an extremely delayed time-action profile |
DE102008003566A1 (en) | 2008-01-09 | 2009-07-16 | Sanofi-Aventis Deutschland Gmbh | New insulin analogs useful for treating diabetes |
DE102008003568A1 (en) | 2008-01-09 | 2009-07-16 | Sanofi-Aventis Deutschland Gmbh | New insulin analogs useful for treating diabetes |
KR20100111682A (en) | 2008-01-09 | 2010-10-15 | 사노피-아벤티스 도이칠란트 게엠베하 | Novel insulin derivatives having an extremely delayed time-action profile |
US8993516B2 (en) | 2008-04-14 | 2015-03-31 | Case Western Reserve University | Meal-time insulin analogues of enhanced stability |
CA2722168A1 (en) | 2008-04-22 | 2009-10-29 | Case Western Reserve University | 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 |
ES2579502T3 (en) | 2008-06-17 | 2016-08-11 | Indiana University Research And Technology Corporation | Glucagon / GLP-1 receptor coagonists |
ES2650038T3 (en) | 2008-06-17 | 2018-01-16 | Indiana University Research And Technology Corporation | Mixed agonists based on GIP for the treatment of metabolic disorders and obesity |
PL219335B1 (en) | 2008-07-04 | 2015-04-30 | Inst Biotechnologii I Antybiotyków | New slow-release insulin analogues |
KR20110061552A (en) | 2008-07-31 | 2011-06-09 | 케이스 웨스턴 리저브 유니버시티 | Halogen-stabilized insulin |
CN102149411A (en) | 2008-09-12 | 2011-08-10 | 诺沃—诺迪斯克有限公司 | Method of acylating a peptide or protein |
US8642540B2 (en) | 2008-12-15 | 2014-02-04 | Zealand Pharma A/S | Glucagon analogues |
PL2370462T3 (en) | 2008-12-15 | 2015-01-30 | Zealand Pharma As | Glucagon analogues |
EA020497B1 (en) | 2008-12-15 | 2014-11-28 | Зилэнд Фарма А/С | Glucagon analogues |
CA2747109A1 (en) | 2008-12-15 | 2010-06-24 | Zealand Pharma A/S | Glucagon analogues |
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 |
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 |
JP5887265B2 (en) | 2009-06-16 | 2016-03-16 | インディアナ・ユニバーシティ・リサーチ・アンド・テクノロジー・コーポレーション | GIP receptor active glucagon compound |
EA022816B1 (en) | 2009-07-13 | 2016-03-31 | Зилэнд Фарма А/С | Acylated glucagon analogues |
CN102791731B (en) | 2009-12-16 | 2016-04-20 | 诺沃—诺迪斯克有限公司 | GLP-1 sum analogous to general Dedekind sum |
MX342409B (en) | 2010-01-20 | 2016-09-28 | Zealand Pharma As | Treatment of cardiac conditions. |
RU2012136450A (en) | 2010-01-27 | 2014-03-10 | Индиана Юниверсити Рисерч Энд Текнолоджи Корпорейшн | CONJUGATES GLUCAGON ANTAGONIST - GIP AGONIST AND COMPOSITIONS FOR TREATMENT OF METABOLIC DISORDERS AND OBESITY |
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 |
AU2011247824B2 (en) | 2010-04-27 | 2014-02-13 | Betta Pharmaceuticals Co., Ltd | Glucagon-like peptide-1 analogue and use thereof |
UY33462A (en) | 2010-06-23 | 2012-01-31 | Zealand Pharma As | GLUCAGON ANALOGS |
CA2802897A1 (en) | 2010-06-24 | 2011-12-29 | Zealand Pharma A/S | Glucagon analogues |
US9006178B2 (en) | 2010-11-09 | 2015-04-14 | Novo Nordisk A/S | Double-acylated GLP-1 derivatives with a linker |
AR085086A1 (en) | 2011-01-20 | 2013-09-11 | Zealand Pharma As | USE OF ACILATED GLUCAGON ANALOGS |
RU2013145013A (en) | 2011-03-28 | 2015-05-10 | Ново Нордиск А/С | NEW GLUCAGON ANALOGUES |
CA2832811A1 (en) | 2011-04-12 | 2012-10-18 | 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 |
US9453062B2 (en) * | 2011-06-10 | 2016-09-27 | Beijing Hanmi Pharmaceutical Co., Ltd. | Glucose dependent insulinotropic polypeptide analogs, pharmaceutical compositions and use thereof |
JP6352806B2 (en) | 2011-09-23 | 2018-07-04 | ノヴォ ノルディスク アー/エス | New glucagon analogues |
EP2793931A2 (en) | 2011-12-23 | 2014-10-29 | Zealand Pharma A/S | Glucagon analogues |
WO2013164483A1 (en) | 2012-05-03 | 2013-11-07 | Zealand Pharma A/S | Gip-glp-1 dual agonist compounds and methods |
PL2875043T3 (en) | 2012-07-23 | 2017-06-30 | Zealand Pharma A/S | Glucagon analogues |
TWI608013B (en) | 2012-09-17 | 2017-12-11 | 西蘭製藥公司 | Glucagon analogues |
SG11201602965WA (en) | 2013-10-17 | 2016-05-30 | Zealand Pharma As | Acylated glucagon analogues |
US9988429B2 (en) | 2013-10-17 | 2018-06-05 | Zealand Pharma A/S | Glucagon analogues |
US10093713B2 (en) | 2013-11-06 | 2018-10-09 | Zealand Pharma A/S | GIP-GLP-1 dual agonist compounds and methods |
MX2016010599A (en) | 2014-02-18 | 2016-11-18 | Novo Nordisk As | Stable glucagon analogues and use for treatment of hypoglycaemia. |
WO2016166289A1 (en) | 2015-04-16 | 2016-10-20 | Zealand Pharma A/S | Acylated glucagon analogue |
-
2013
- 2013-05-03 WO PCT/EP2013/059319 patent/WO2013164483A1/en active Application Filing
- 2013-05-03 NZ NZ702333A patent/NZ702333A/en unknown
- 2013-05-03 US US14/398,260 patent/US10100097B2/en active Active
- 2013-05-03 EP EP13720931.8A patent/EP2844669B1/en active Active
- 2013-05-03 IN IN2304MUN2014 patent/IN2014MN02304A/en unknown
- 2013-05-03 TR TR2018/15338T patent/TR201815338T4/en unknown
- 2013-05-03 EA EA201491918A patent/EA028665B1/en not_active IP Right Cessation
- 2013-05-03 AR ARP130101524A patent/AR090937A1/en unknown
- 2013-05-03 MX MX2014013318A patent/MX356641B/en active IP Right Grant
- 2013-05-03 BR BR112014027348-0A patent/BR112014027348B1/en active IP Right Grant
- 2013-05-03 CA CA2872314A patent/CA2872314C/en active Active
- 2013-05-03 TW TW102115949A patent/TWI689515B/en active
- 2013-05-03 CN CN201380032714.4A patent/CN104470948B/en active Active
- 2013-05-03 JP JP2015509461A patent/JP6228187B2/en active Active
- 2013-05-03 SG SG11201407137PA patent/SG11201407137PA/en unknown
- 2013-05-03 KR KR1020147033952A patent/KR102184241B1/en active IP Right Grant
- 2013-05-03 AU AU2013255751A patent/AU2013255751B2/en active Active
-
2014
- 2014-11-02 IL IL235463A patent/IL235463A0/en unknown
- 2014-11-03 PH PH12014502452A patent/PH12014502452A1/en unknown
-
2015
- 2015-09-09 HK HK15108788.2A patent/HK1208232A1/en unknown
-
2018
- 2018-09-05 US US16/121,745 patent/US20190135886A1/en not_active Abandoned
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998008871A1 (en) | 1996-08-30 | 1998-03-05 | Novo Nordisk A/S | Glp-1 derivatives |
WO1998011125A1 (en) | 1996-09-09 | 1998-03-19 | Zealand Pharmaceuticals A/S | Improved solid-phase peptide synthesis and agent for use in such synthesis |
WO2000055184A1 (en) | 1999-03-15 | 2000-09-21 | Novo Nordisk A/S | Ion exchange chromatography of proteins and peptides with an organic modifier in the elution step |
WO2000055119A1 (en) | 1999-03-17 | 2000-09-21 | Novo Nordisk A/S | Method for acylating peptides and novel acylating agents |
WO2010016940A2 (en) * | 2008-08-07 | 2010-02-11 | Ipsen Pharma S.A.S. | Analogues of glucose-dependent insulinotropic polypeptide |
Non-Patent Citations (16)
Title |
---|
A. R. GENNARO: "Remington's Pharmaceutical Sciences", 1985, MACK PUBLISHING CO |
ALFONSO R. GENNARO: "Remington's Pharmaceutical Sciences,17th edition.", 1985, MARK PUBLISHING COMPANY |
ALPESHKUMAR K. MALDE ET AL: "Understanding interactions of gastric inhibitory polypeptide (GIP) with its G-protein coupled receptor through NMR and molecular modeling", JOURNAL OF PEPTIDE SCIENCE, vol. 13, no. 5, 1 May 2007 (2007-05-01), pages 287 - 300, XP055077705, ISSN: 1075-2617, DOI: 10.1002/psc.839 * |
DRUCKER, DJ; NAUCK, MA, LANCET, vol. 368, 2006, pages 1696 - 705 |
FARILLA, L, ENDOCRINOLOGY, vol. 14, no. 4, 2003, pages 5149 - 58 |
FIELDS, G.B. ET AL.: "Synthetic Peptides", 2002, OXFORD UNIVERSITY PRESS, article "Principles and Practice of Solid-Phase Peptide Synthesis" |
GAULT, VA, CLINICAL SCIENCE, vol. 121, 2011, pages 107 - 117 |
GREEN B D ET AL: "STRUCTURALLY MODIFIED ANALOGUES OF GLUCAGON-LIKE PEPTIDE-1 (GLP-1) AND GLUCOSE-DEPENDENT INSULINOTROPIC POLYPEPTIDE (GIP) AS FUTURE ANTIDIABETIC AGENTS", CURRENT PHARMACEUTICAL DESIGN, BENTHAM SCIENCE PUBLISHERS, NL, vol. 10, no. 29, 1 January 2004 (2004-01-01), pages 3651 - 3662, XP009068381, ISSN: 1381-6128, DOI: 10.2174/1381612043382774 * |
IRWIN NIGEL ET AL: "Antidiabetic potential of two novel fatty acid derivatised, N-terminally modified analogues of glucose-dependent insulinotropic polypeptide (GIP): N-AcGIP(LysPAL(16)) and N-AcGIP(LysPAL(37))", BIOLOGICAL CHEMISTRY, WALTER DE GRUYTER GMBH & CO, BERLIN, DE, vol. 386, no. 7, 1 July 2005 (2005-07-01), pages 679 - 687, XP002428433, ISSN: 1431-6730, DOI: 10.1515/BC.2005.079 * |
KNUDSEN ET AL., J. MED CHEM., vol. 43, 2000, pages 1664 - 1669 |
MADSEN ET AL., J. MED. CHEM., no. 50, 2007, pages 6126 - 32 |
MATTHIAS, TSCHOP ORAL PRESENTATION AT ADA (AMERICAN DIABETES ASSOCIATION, 2011 |
RUNGE STEFFEN ET AL: "Differential structural properties of GLP-1 and exendin-4 determine their relative affinity for the GLP-1 receptor N-terminal extracellular domain", BIOCHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 46, no. 19, 15 May 2007 (2007-05-15), pages 5830 - 5840, XP009095139, ISSN: 0006-2960, DOI: 10.1021/BI062309M * |
SUSANNE MANHART ET AL: "Structure-function analysis of a series of novel GIP analogues containing different helical length linkers", BIOCHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 42, no. 10, 18 March 2003 (2003-03-18), pages 3081 - 3088, XP002661510, ISSN: 0006-2960, [retrieved on 20030220], DOI: 10.1021/BI026868E * |
VICTOR A. GAULT ET AL: "Administration of an acylated GLP-1 and GIP preparation provides added beneficial glucose-lowering and insulinotropic actions over single incretins in mice with Type 2 diabetes and obesity", CLINICAL SCIENCE, vol. 84, no. 3, 1 August 2011 (2011-08-01), pages 331 - 117, XP055077821, ISSN: 0143-5221, DOI: 10.1016/j.mce.2008.08.012 * |
WEIDENMAIER, SD, PLOS ONE, vol. 5, no. 3, 2010, pages E9590 |
Cited By (115)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10004786B2 (en) | 2009-07-13 | 2018-06-26 | Zealand Pharma A/S | Acylated glucagon analogues |
US10100097B2 (en) | 2012-05-03 | 2018-10-16 | Zealand Pharma A/S | GIP-GLP-1 dual agonist compounds and methods |
US11795204B2 (en) | 2012-07-23 | 2023-10-24 | Zealand Pharma A/S | Glucagon analogues |
US10442847B2 (en) | 2012-07-23 | 2019-10-15 | Zealand Pharma A/S | Glucagon analogues |
US10253081B2 (en) | 2012-09-17 | 2019-04-09 | Zealand Pharma A/S | Glucagon analogues |
US9975939B2 (en) | 2012-09-17 | 2018-05-22 | Zealand Pharma A/S | Glucagon analogues |
US10758592B2 (en) | 2012-10-09 | 2020-09-01 | Sanofi | Exendin-4 derivatives as dual GLP1/glucagon agonists |
WO2014096179A1 (en) * | 2012-12-19 | 2014-06-26 | Novo Nordisk A/S | Novel glp-1 receptor agonists with cholesterol efflux activity |
US10253079B2 (en) | 2012-12-21 | 2019-04-09 | Sanofi | Functionalized Exendin-4 derivatives |
US10087229B2 (en) | 2013-05-28 | 2018-10-02 | Takeda Pharmaceutical Company Limited | Peptide compound |
US9200051B2 (en) | 2013-05-28 | 2015-12-01 | Takeda Pharmaceutical Company Limited | Peptide compound |
US9988429B2 (en) | 2013-10-17 | 2018-06-05 | Zealand Pharma A/S | Glucagon analogues |
US11091528B2 (en) | 2013-10-17 | 2021-08-17 | Zealand Pharma A/S | Acylated glucagon analogues |
US11034747B2 (en) | 2013-10-17 | 2021-06-15 | Zealand Pharma A/S | Glucagon analogues and methods of use |
US11884713B2 (en) | 2013-10-17 | 2024-01-30 | Zealand Pharma A/S | Acylated glucagon analogues |
US10457714B2 (en) | 2013-10-17 | 2019-10-29 | Zealand Pharma A/S | Acylated glucagon analogues |
US9896495B2 (en) | 2013-10-17 | 2018-02-20 | Zealand Pharma A/S | Acylated glucagon analogues |
US11111285B2 (en) | 2013-11-06 | 2021-09-07 | Zealand Pharma A/S | Glucagon-GLP-1-GIP triple agonist compounds |
JP2020045362A (en) * | 2013-11-06 | 2020-03-26 | ジーランド ファーマ アクティーゼルスカブ | Glucagon-glp-1-gip triple agonist compounds |
EA035466B1 (en) * | 2013-11-06 | 2020-06-22 | Зилэнд Фарма А/С | Gip-glp-1 dual agonist compounds and methods |
AU2014345569B2 (en) * | 2013-11-06 | 2020-08-13 | Zealand Pharma A/S | GIP-GLP-1 dual agonist compounds and methods |
EA035466B9 (en) * | 2013-11-06 | 2020-08-17 | Зилэнд Фарма А/С | Gip-glp-1 dual agonist compounds and methods |
US11008375B2 (en) | 2013-11-06 | 2021-05-18 | Zealand Pharma A/S | GIP-GLP-1 dual agonist compounds and methods |
US10131702B2 (en) | 2013-11-06 | 2018-11-20 | Zealand Pharma A/S | Glucagon-GLP-1-GIP triple agonist compounds |
JP2017503474A (en) * | 2013-11-06 | 2017-02-02 | ジーランド ファーマ アクティーゼルスカブ | Glucagon-GLP-1-GIP triple agonist compound |
CN105849122A (en) * | 2013-11-06 | 2016-08-10 | 西兰制药公司 | GIP-GLP-1 dual agonist compounds and methods |
WO2015067715A3 (en) * | 2013-11-06 | 2015-10-15 | Zealand Pharma A/S | Gip-glp-1 dual agonist compounds and methods |
US10093713B2 (en) | 2013-11-06 | 2018-10-09 | Zealand Pharma A/S | GIP-GLP-1 dual agonist compounds and methods |
WO2015081891A1 (en) | 2013-12-06 | 2015-06-11 | Baikang (Suzhou) Co., Ltd | Bioreversable promoieties for nitrogen-containing and hydroxyl-containing drugs |
AU2015340586B2 (en) * | 2014-10-29 | 2020-04-30 | Zealand Pharma A/S | GIP agonist compounds and methods |
EP3985016A1 (en) * | 2014-10-29 | 2022-04-20 | Zealand Pharma A/S | Gip agonist compounds and methods |
TWI705973B (en) * | 2014-10-29 | 2020-10-01 | 丹麥商西蘭製藥公司 | Gip agonist compounds and methods |
US11001619B2 (en) | 2014-10-29 | 2021-05-11 | Zealand Pharma A/S | GIP agonist compounds and methods |
KR102620911B1 (en) | 2014-10-29 | 2024-01-05 | 질랜드 파마 에이/에스 | Gip agonist compounds and methods |
KR20170075779A (en) * | 2014-10-29 | 2017-07-03 | 질랜드 파마 에이/에스 | Gip agonist compounds and methods |
CN107001439A (en) * | 2014-10-29 | 2017-08-01 | 西兰制药公司 | GIP agonist compounds and method |
RU2716985C2 (en) * | 2014-10-29 | 2020-03-17 | Зилэнд Фарма А/С | Gip agonist compounds and methods |
US10253078B2 (en) | 2014-10-29 | 2019-04-09 | Zealand Pharma A/S | GIP agonist compounds and methods |
JP2021138740A (en) * | 2014-10-29 | 2021-09-16 | ジーランド ファーマ アクティーゼルスカブ | GIP agonist compounds and methods |
CN107001439B (en) * | 2014-10-29 | 2021-12-21 | 西兰制药公司 | GIP agonist compounds and methods |
JP2018500282A (en) * | 2014-10-29 | 2018-01-11 | ジーランド ファーマ アクティーゼルスカブ | GIP agonist compounds and methods |
US11814417B2 (en) | 2014-10-29 | 2023-11-14 | Zealand Pharma A/S | GIP agonist compounds and methods |
WO2016066744A3 (en) * | 2014-10-29 | 2016-09-01 | Zealand Pharma A/S | Gip agonist compounds and methods |
JP7312215B2 (en) | 2014-10-29 | 2023-07-20 | ジーランド ファーマ アクティーゼルスカブ | GIP agonist compounds and methods |
US9474780B2 (en) | 2015-01-09 | 2016-10-25 | Eli Lilly And Company | GIP and GLP-1 co-agonist compounds |
CN107207576A (en) * | 2015-01-09 | 2017-09-26 | 伊莱利利公司 | GIP and the co-agonists compounds of GLP 1 |
CN112608377A (en) * | 2015-01-09 | 2021-04-06 | 伊莱利利公司 | GIP and GLP-1 co-agonist compounds |
JP2019203000A (en) * | 2015-01-09 | 2019-11-28 | イーライ リリー アンド カンパニー | Gip and glp-1 co-agonist compound |
AU2016205435B2 (en) * | 2015-01-09 | 2018-03-29 | Eli Lilly And Company | GIP and GLP-1 co-agonist compounds |
EP3597662A1 (en) | 2015-01-09 | 2020-01-22 | Eli Lilly and Company | Gip and glp-1 co-agonist compounds |
KR102330764B1 (en) | 2015-01-09 | 2021-11-25 | 일라이 릴리 앤드 캄파니 | Gip and glp-1 co-agonist compounds |
JP2018052933A (en) * | 2015-01-09 | 2018-04-05 | イーライ リリー アンド カンパニー | Gip and glp-1 co-agonist compounds |
KR101957620B1 (en) | 2015-01-09 | 2019-03-13 | 일라이 릴리 앤드 캄파니 | Gip and glp-1 co-agonist compounds |
CN112608377B (en) * | 2015-01-09 | 2024-02-13 | 伊莱利利公司 | GIP and GLP-1 co-agonist compounds |
CN107207576B (en) * | 2015-01-09 | 2020-11-24 | 伊莱利利公司 | GIP and GLP-1 co-agonist compounds |
EA035055B1 (en) * | 2015-01-09 | 2020-04-22 | Эли Лилли Энд Компани | Gip and glp-1 co-agonist compounds |
JP2017507124A (en) * | 2015-01-09 | 2017-03-16 | イーライ リリー アンド カンパニー | GIP and GLP-1 co-agonist compounds |
KR20170092661A (en) * | 2015-01-09 | 2017-08-11 | 일라이 릴리 앤드 캄파니 | Gip and glp-1 co-agonist compounds |
WO2016111971A1 (en) | 2015-01-09 | 2016-07-14 | Eli Lilly And Company | Gip and glp-1 co-agonist compounds |
KR20190026967A (en) * | 2015-01-09 | 2019-03-13 | 일라이 릴리 앤드 캄파니 | Gip and glp-1 co-agonist compounds |
EA031591B1 (en) * | 2015-01-09 | 2019-01-31 | Эли Лилли Энд Компани | Gip and glp-1 co-agonist compounds |
US10336802B2 (en) | 2015-04-16 | 2019-07-02 | Zealand Pharma A/S | Acylated glucagon analogue |
US11274136B2 (en) | 2015-04-16 | 2022-03-15 | Zealand Pharma A/S | Acylated glucagon analogue |
WO2017060500A1 (en) | 2015-10-07 | 2017-04-13 | Cyprumed Gmbh | Pharmaceutical formulations for the oral delivery of peptide drugs |
WO2017074715A1 (en) | 2015-10-26 | 2017-05-04 | Eli Lilly And Company | Glucagon receptor agonists |
US9764004B2 (en) | 2015-10-26 | 2017-09-19 | Eli Lilly And Company | Glucagon receptor agonists |
US9884093B2 (en) | 2015-10-26 | 2018-02-06 | Eli Lilly And Company | Glucagon receptor agonists |
WO2017074714A1 (en) | 2015-10-26 | 2017-05-04 | Eli Lilly And Company | Glucagon receptor agonists |
US10501516B2 (en) | 2016-05-24 | 2019-12-10 | Takeda Pharmaceutical Company Limited | Peptide compound |
WO2018065634A1 (en) | 2016-10-07 | 2018-04-12 | Cyprumed Gmbh | Pharmaceutical compositions for the nasal delivery of peptide or protein drugs |
WO2018104718A1 (en) * | 2016-12-05 | 2018-06-14 | Lancaster University Business Enterprises Limited | Treatment of neurological diseases |
US11220534B2 (en) | 2016-12-05 | 2022-01-11 | Lancaster University Business Enterprises Limited | Treatment of neurological diseases |
US11851468B2 (en) | 2016-12-05 | 2023-12-26 | University Of Lancaster | Treatment of neurological diseases |
WO2018104263A1 (en) | 2016-12-06 | 2018-06-14 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods of enhancing the potency of incretin-based drugs in subjects in need thereof |
US10435445B2 (en) | 2017-03-31 | 2019-10-08 | Takeda Pharmaceutical Company Limited | Peptide compound |
WO2018181864A1 (en) | 2017-03-31 | 2018-10-04 | Takeda Pharmaceutical Company Limited | Gip receptor activating peptide |
US11174301B2 (en) | 2017-03-31 | 2021-11-16 | Takeda Pharmaceutical Company Limited | Peptide compound |
WO2019140030A1 (en) | 2018-01-12 | 2019-07-18 | Eli Lilly And Company | Combination therapy |
WO2019193204A1 (en) | 2018-04-06 | 2019-10-10 | Cyprumed Gmbh | Pharmaceutical compositions for the transmucosal delivery of therapeutic peptides and proteins |
US10604555B2 (en) | 2018-05-04 | 2020-03-31 | Novo Nordisk A/S | GIP derivatives and uses thereof |
AU2019263674B2 (en) * | 2018-05-04 | 2023-03-02 | Novo Nordisk A/S | GIP derivatives and uses thereof |
KR20210005700A (en) * | 2018-05-04 | 2021-01-14 | 노보 노르디스크 에이/에스 | GIP derivatives and uses thereof |
US11633459B2 (en) | 2018-05-04 | 2023-04-25 | Novo Nordisk A/S | GIP derivatives and uses thereof |
WO2019211451A1 (en) | 2018-05-04 | 2019-11-07 | Novo Nordisk A/S | Gip derivatives and uses thereof |
KR102379958B1 (en) | 2018-05-04 | 2022-04-01 | 노보 노르디스크 에이/에스 | GIP derivatives and uses thereof |
TWI707865B (en) * | 2018-05-04 | 2020-10-21 | 丹麥商諾佛 儂迪克股份有限公司 | Gip derivatives and uses thereof |
US11084861B2 (en) | 2018-07-23 | 2021-08-10 | Eli Lilly And Company | GIP/GLP1 co-agonist compounds |
KR102351313B1 (en) | 2018-07-23 | 2022-01-17 | 일라이 릴리 앤드 캄파니 | GIP/GLP1 co-agonist compounds |
KR20210016632A (en) * | 2018-07-23 | 2021-02-16 | 일라이 릴리 앤드 캄파니 | GIP/GLP1 coagonist compound |
WO2020023386A1 (en) | 2018-07-23 | 2020-01-30 | Eli Lilly And Company | Gip/glp1 co-agonist compounds |
WO2020023388A1 (en) | 2018-07-23 | 2020-01-30 | Eli Lilly And Company | Method of using a gip/glp1 co-agonist for diabetes |
WO2020067557A3 (en) * | 2018-09-24 | 2020-07-30 | Takeda Pharmaceutical Company Limited | Gip receptor agonist peptide compounds and uses thereof |
RU2816492C2 (en) * | 2019-04-11 | 2024-04-01 | Цзянсу Хэнсох Фармасьютикал Груп Ко., Лтд. | Multi-receptor agonist and medical use thereof |
US11897926B2 (en) | 2019-08-01 | 2024-02-13 | Eli Lilly And Company | GIPR-agonist compounds |
US11254721B2 (en) | 2019-08-01 | 2022-02-22 | Eli Lilly And Company | GIPR-agonist compounds |
WO2021021877A1 (en) | 2019-08-01 | 2021-02-04 | Eli Lilly And Company | Gipr-agonist compounds |
WO2021034815A1 (en) | 2019-08-19 | 2021-02-25 | Eli Lilly And Company | Methods of making incretin analogs |
WO2021066600A1 (en) | 2019-10-04 | 2021-04-08 | 한미약품 주식회사 | Glucagon, composition comprising glp-1 receptor and gip receptor dual agonist and therapeutic use thereof |
WO2021068251A1 (en) | 2019-10-08 | 2021-04-15 | 江苏诺泰澳赛诺生物制药股份有限公司 | Gip and glp-1 dual agonist polypeptide compound, pharmaceutically acceptable salt of same, and uses thereof |
WO2021094259A1 (en) | 2019-11-11 | 2021-05-20 | Boehringer Ingelheim International Gmbh | Npy2 receptor agonists |
TWI770781B (en) * | 2020-01-23 | 2022-07-11 | 美商美國禮來大藥廠 | Gip/glp1 co-agonist compounds |
WO2021150673A1 (en) | 2020-01-23 | 2021-07-29 | Eli Lilly And Company | Gip/glp1 co-agonist compounds |
WO2021260530A1 (en) | 2020-06-22 | 2021-12-30 | Sun Pharmaceutical Industries Limited | Long acting glp-1/gip dual agonists |
WO2022018186A1 (en) | 2020-07-22 | 2022-01-27 | Novo Nordisk A/S | Co-agonists at glp-1 and gip receptors suitable for oral delivery |
US11779648B2 (en) | 2020-07-22 | 2023-10-10 | Novo Nordisk A/S | Co-agonists at GLP-1 and GIP receptors suitable for oral delivery |
WO2022018185A1 (en) | 2020-07-22 | 2022-01-27 | Novo Nordisk A/S | Glp-1 and gip receptor co-agonists |
WO2022029231A1 (en) | 2020-08-07 | 2022-02-10 | Boehringer Ingelheim International Gmbh | Soluble npy2 receptor agonists |
WO2022049310A1 (en) | 2020-09-07 | 2022-03-10 | Cyprumed Gmbh | Improved pharmaceutical formulations of glp-1 receptor agonists |
WO2022079639A1 (en) | 2020-10-17 | 2022-04-21 | Sun Pharmaceutical Industries Limited | Glp-1/gip dual agonists |
WO2022235991A1 (en) | 2021-05-07 | 2022-11-10 | Eli Lilly And Company | Erodible tablet |
WO2022253202A1 (en) * | 2021-06-01 | 2022-12-08 | 南京知和医药科技有限公司 | Polypeptide derivative having effect of dual targeted activation of glp-1r and gipr, preparation method therefor, and use thereof |
US11840560B2 (en) | 2022-01-20 | 2023-12-12 | Novo Nordisk A/S | Prodrugs and uses thereof |
WO2023139187A1 (en) | 2022-01-20 | 2023-07-27 | Novo Nordisk A/S | Glp-1/gip receptor co-agonist prodrugs and uses thereof |
WO2024050289A1 (en) | 2022-08-29 | 2024-03-07 | Eli Lilly And Company | Compositions for oral delivery |
WO2024059674A1 (en) | 2022-09-15 | 2024-03-21 | Eli Lilly And Company | Gip and glp-1 dual agonist compounds |
Also Published As
Publication number | Publication date |
---|---|
US20190135886A1 (en) | 2019-05-09 |
NZ702333A (en) | 2017-06-30 |
EP2844669B1 (en) | 2018-08-01 |
IL235463A0 (en) | 2014-12-31 |
KR102184241B1 (en) | 2020-12-01 |
PH12014502452A1 (en) | 2015-02-02 |
KR20150003910A (en) | 2015-01-09 |
BR112014027348B1 (en) | 2022-12-20 |
CN104470948B (en) | 2018-06-15 |
AU2013255751A1 (en) | 2014-12-18 |
TR201815338T4 (en) | 2018-11-21 |
TWI689515B (en) | 2020-04-01 |
BR112014027348A2 (en) | 2017-06-27 |
CA2872314C (en) | 2021-08-31 |
IN2014MN02304A (en) | 2015-08-07 |
HK1208232A1 (en) | 2016-02-26 |
MX2014013318A (en) | 2015-09-28 |
JP2015517459A (en) | 2015-06-22 |
JP6228187B2 (en) | 2017-11-08 |
AU2013255751B2 (en) | 2017-10-05 |
EA028665B1 (en) | 2017-12-29 |
US10100097B2 (en) | 2018-10-16 |
TW201348252A (en) | 2013-12-01 |
CN104470948A (en) | 2015-03-25 |
SG11201407137PA (en) | 2014-11-27 |
CA2872314A1 (en) | 2013-11-07 |
US20150299281A1 (en) | 2015-10-22 |
EA201491918A1 (en) | 2015-07-30 |
EP2844669A1 (en) | 2015-03-11 |
MX356641B (en) | 2018-06-07 |
AR090937A1 (en) | 2014-12-17 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20190135886A1 (en) | Gip-glp-1 dual agonist compounds and methods | |
US11008375B2 (en) | GIP-GLP-1 dual agonist compounds and methods | |
US11111285B2 (en) | Glucagon-GLP-1-GIP triple agonist compounds | |
US10253078B2 (en) | GIP agonist compounds and methods | |
AU2014345569A1 (en) | GIP-GLP-1 dual agonist compounds and methods |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 13720931 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 2015509461 Country of ref document: JP Kind code of ref document: A Ref document number: 2872314 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 14398260 Country of ref document: US |
|
WWE | Wipo information: entry into national phase |
Ref document number: 235463 Country of ref document: IL |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: MX/A/2014/013318 Country of ref document: MX |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2013720931 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 201491918 Country of ref document: EA |
|
WWE | Wipo information: entry into national phase |
Ref document number: IDP00201407408 Country of ref document: ID |
|
ENP | Entry into the national phase |
Ref document number: 20147033952 Country of ref document: KR Kind code of ref document: A |
|
REG | Reference to national code |
Ref country code: BR Ref legal event code: B01A Ref document number: 112014027348 Country of ref document: BR |
|
ENP | Entry into the national phase |
Ref document number: 2013255751 Country of ref document: AU Date of ref document: 20130503 Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: 112014027348 Country of ref document: BR Kind code of ref document: A2 Effective date: 20141031 |