US20140206608A1 - Exendin-4 Derivatives - Google Patents

Exendin-4 Derivatives Download PDF

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US20140206608A1
US20140206608A1 US14/135,756 US201314135756A US2014206608A1 US 20140206608 A1 US20140206608 A1 US 20140206608A1 US 201314135756 A US201314135756 A US 201314135756A US 2014206608 A1 US2014206608 A1 US 2014206608A1
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carboxy
butyryl
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amino acid
acid residue
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Torsten HAACK
Michael Wagner
Bernd Henkel
Siegfried Stengelin
Andreas EVERS
Martin Lorenz
Katrin LORENZ
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Sanofi SA
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Definitions

  • the present invention relates to exendin-4 peptide analogues which activate the glucagon-like peptide 1 (GLP-1) and the glucose-dependent insulinotropic polypeptide (GIP) receptor and optionally the glucagon receptor (GCG) and their medical use, for example in the treatment of disorders of the metabolic syndrome, including diabetes and obesity, as well as reduction of excess food intake.
  • GLP-1 glucagon-like peptide 1
  • GIP glucose-dependent insulinotropic polypeptide
  • GCG glucagon receptor
  • Exendin-4 is a 39 amino acid peptide which is produced by the salivary glands of the Gila monster (Heloderma suspectum) (Eng J. et al., J. Biol. Chem., 267: 7402-05, 1992). Exendin-4 is an activator of the glucagon-like peptide-1 (GLP-1) receptor, whereas it shows only very low activation of the GIP receptor and does not activate the glucagon receptor (see Table 1).
  • GLP-1 glucagon-like peptide-1
  • Exendin-4 shares many of the glucoregulatory actions observed with GLP-1. Clinical and non-clinical studies have shown that exendin-4 has several beneficial antidiabetic properties including a glucose dependent enhancement in insulin synthesis and secretion, glucose dependent suppression of glucagon secretion, slowing down gastric emptying, reduction of food intake and body weight, and an increase in beta-cell mass and markers of beta cell function (Gentilella R et al., Diabetes Obes Metab., 11:544-56, 2009; Norris S L et al., Diabet Med., 26:837-46, 2009; Bunck M C et al., Diabetes Care., 34:2041-7, 2011).
  • exendin-4 is more resistant to cleavage by dipeptidyl peptidase-4 (DPP4) resulting in a longer half-life and duration of action in vivo (Eng J., Diabetes, 45 (Suppl 2):152A (abstract 554), 1996; Deacon C F, Horm Metab Res, 36: 761-5, 2004).
  • DPP4 dipeptidyl peptidase-4
  • Exendin-4 was also shown to be much more stable towards degradation by neutral endopeptidase (NEP), when compared to GLP-1, glucagon or oxyntomodulin (Druce M R et al., Endocrinology, 150(4), 1712-1721, 2009).
  • NEP neutral endopeptidase
  • exendin-4 is chemically labile due to methionine oxdiation in position 14 (Hargrove D M et al., Regul. Pept., 141: 113-9, 2007) as well as deamidation and isomerization of asparagine in position 28 (WO 2004/035623).
  • amino acid sequence of exendin-4 is shown as SEQ ID NO: 1:
  • amino acid sequence of GLP-1(7-36)-amide is shown as SEQ ID NO: 2:
  • Liraglutide is a marketed chemically modified GLP-1 analogue in which, among other modifications, a fatty acid is linked to a lysine in position 20 leading to a prolonged duration of action (Drucker D J et al, Nature Drug Disc. Rev. 9, 267-268, 2010; Buse, J B et al., Lancet, 374:39-47, 2009).
  • the amino acid sequence of Liraglutide is shown as SEQ ID NO: 3:
  • GIP glucose-dependent insulinotropic polypeptide
  • GIP and GLP-1 are the two gut enteroendocrine cell-derived hormones accounting for the incretin effect, which accounts for over 70% of the insulin response to an oral glucose challenge (Baggio L L, Drucker D J. Biology of incretins: GLP-1 and GIP. Gastroenterology 2007; 132: 2131-2157).
  • GIP's amino acid sequence is shown as SEQ ID NO: 4:
  • Glucagon is a 29-amino acid peptide which is released into the bloodstream when circulating glucose is low. Glucagon's amino acid sequence is shown in SEQ ID NO: 5:
  • hypoglycemia when blood glucose levels drop below normal, glucagon signals the liver to break down glycogen and release glucose, causing an increase of blood glucose levels to reach a normal level. Hypoglycemia is a common side effect of insulin treated patients with hyperglycemia (elevated blood glucose levels) due to diabetes. Thus, glucagon's most predominant role in glucose regulation is to counteract insulin action and maintain blood glucose levels.
  • GLP-1 receptor agonists such as GLP-1, Liraglutide and exendin-4
  • FPG and PPG fasting and postprandial glucose
  • GLP-1 and GIP receptors dual activation of the GLP-1 and GIP receptors, e.g. by combining the actions of GLP-1 and GIP in one preparation, leads to a therapeutic principle with significantly better reduction of blood glucose levels, increased insulin secretion and reduced body weight in mice with T2DM and obesity compared to the marketed GLP-1 agonist liraglutide (e.g. VA Gault et al., Clin Sci (Lond), 121, 107-117, 2011).
  • Native GLP-1 and GIP were proven in humans following co-infusion to interact in an additive manner with a significantly increased insulinotropic effect compared to GLP-1 alone (MA Nauck et al., J. Clin. Endocrinol. Metab., 76, 912-917, 1993).
  • Compounds of this invention are exendin-4 derivatives, which show agonistic activity at the GLP-1 and the GIP receptor and optionally the glucagon receptor and which have—among others—preferably the following modifications: Tyr at position 1 and Ile at position 12.
  • Peptides which bind and activate both the GIP and the GLP-1 receptor and optionally the glucagon receptor, and improve glycaemic control, suppress body weight gain and reduce food intake are described in patent applications WO 2011/119657 A1, WO 2012/138941 A1, WO 2010/011439 A2, WO 2010/148089 A1, WO 2011/094337 A1, WO 2012/088116 A2, the contents of which are herein incorporated by reference. These applications disclose that mixed agonists of the GLP-1 receptor, the GIP receptor and optionally the glucagon receptor can be designed as analogues of the native GIP or glucagon sequences.
  • Exendin-4 peptide analogues comprising leucine in position 10 and glutamine in position 13.
  • Krstenansky et al. show the importance of residues 10 to 13 of glucagon for its receptor interactions and activation of adenylate cyclase.
  • residues Tyr10 and Tyr13 are replaced by leucine in position 10 and glutamine, a non-aromatic polar amino acid, in position 13.
  • exendin-4 derivatives with potentially improved biophysical properties as solubility or aggregation behavior in solution.
  • the non-conservative replacement of an aromatic amino acid with a polar amino acid in position 13 of an exendin-4 analogue surprisingly leads to peptides with high activity on the GIP receptor and optionally on the glucagon receptor.
  • compounds of this invention are exendin-4 derivatives which show high activity on the GLP-1 receptor and the GIP receptor with only 4 to 6 amino acids replaced compared to exendin-4.
  • the replacement of the amino acids in position 1, 2, 12 and 14 in combination with the substitution with a fatty acid leads to exendin-4 derivatives which are potent GLP-1 receptor, GIP receptor and—optionally—glucagon receptor agonists and show potentially an improved enzymatic stability, for example versus trypsin, plasmin or ⁇ -chymotrypsin, leading to improved in vivo properties as half life and clearance, as shown in Examples 6 and 7 as well as in Tables 8 and 9.
  • exendin-4 analogs which potently activate the GLP-1 and the GIP receptor and optionally the glucagon receptor.
  • methionine at position 14 is replaced by an amino acid carrying an —NH 2 group in the side-chain, which is further substituted with a lipophilic side-chain (e.g. a fatty acid optionally combined with a linker).
  • the invention provides a peptidic compound having the formula (I):
  • the compounds of the invention are GLP-1 and GIP receptor agonists and optionally glucagon receptor agonists as determined by the observation that they are capable of stimulating intracellular cAMP formation.
  • In vitro potency determination in cellular assays of agonists is quantified by determining the concentrations that cause 50% activation of maximal response (EC 50 ) as described in Methods.
  • the invention therefore provides a peptidic compound having the formula (I):
  • the peptidic compound particularly with a lysine at position 14 which is further substituted with a lipophilic residue, exhibits a relative activity of at least 0.07%, preferably at least 0.1%, more preferably at least 0.14%, more preferably at least 0.35% and even more preferably at least 0.4% compared to that of GLP-1(7-36) at the GLP-1 receptor.
  • the peptidic compound particularly with a lysine at position 14 which is further substituted with a lipophilic residue, exhibits a relative activity of at least 0.1%, preferably at least 0.2%, more preferably at least 0.3%, more preferably at least 0.4% and even more preferably at least 0.5% compared to that of natural glucagon at the glucagon receptor.
  • the term “activity” as used herein preferably refers to the capability of a compound to activate the human GLP-1 receptor, the human GIP receptor and optionally the human glucagon receptor. More preferably the term “activity” as used herein refers to the capability of a compound to stimulate intracellular cAMP formation.
  • the term “relative activity” as used herein is understood to refer to the capability of a compound to activate a receptor in a certain ratio as compared to another receptor agonist or as compared to another receptor. The activation of the receptors by the agonists (e.g. by measuring the cAMP level) is determined as described herein, e.g. as described in the examples.
  • the compounds of the invention have an EC 50 for hGLP-1 receptor of 500 pM or less, preferably of 200 pM or less; more preferably of 150 pM or less, more preferably of 100 pM or less, more preferably of 90 pM or less, more preferably of 80 pM or less, more preferably of 70 pM or less, more preferably of 60 pM or less, more preferably of 50 pM or less, more preferably of 40 pM or less, more preferably of 30 pM or less, and more preferably of 20 pM or less.
  • the compounds of the invention have an EC 50 for hGIP receptor of 500 pM or less, preferably of 200 pM or less; more preferably of 150 pM or less, more preferably of 100 pM or less, more preferably of 90 pM or less, more preferably of 80 pM or less, more preferably of 70 pM or less, more preferably of 60 pM or less, more preferably of 50 pM or less, more preferably of 40 pM or less, more preferably of 30 pM or less, and more preferably of 20 pM or less.
  • the compounds of the invention have optionally an EC 50 for hGlucagon receptor of 500 pM or less, preferably of 200 pM or less; more preferably of 150 pM or less, more preferably of 100 pM or less, more preferably of 90 pM or less, more preferably of 80 pM or less, more preferably of 70 pM or less, more preferably of 60 pM or less, more preferably of 50 pM or less, more preferably of 40 pM or less, more preferably of 30 pM or less, and more preferably of 20 pM or less.
  • an EC 50 for hGlucagon receptor of 500 pM or less, preferably of 200 pM or less; more preferably of 150 pM or less, more preferably of 100 pM or less, more preferably of 90 pM or less, more preferably of 80 pM or less, more preferably of 70 pM or less, more preferably of 60 pM or less, more preferably of 50 pM or
  • the compounds of the invention have an EC 50 for hGLP-1 receptor of 500 pM or less, preferably of 200 pM or less; more preferably of 150 pM or less, more preferably of 100 pM or less, more preferably of 90 pM or less, more preferably of 80 pM or less, more preferably of 70 pM or less, more preferably of 60 pM or less, more preferably of 50 pM or less, more preferably of 40 pM or less, more preferably of 30 pM or less, and more preferably of 20 pM or less, and/or an EC 50 for hGIP receptor of 500 pM or less, preferably of 200 pM or less; more preferably of 150 pM or less, more preferably of 100 pM or less, more preferably of 90 pM or less, more preferably of 80 pM or less, more preferably of 70 pM or less, more preferably of 60 pM or less, more preferably of 50 p
  • the EC 50 for both receptors is 500 pM or less, more preferably 200 pM or less, more preferably 150 pM or less, more preferably 100 pM or less, more preferably 90 pM or less, more preferably 80 pM or less, more preferably 70 pM or less, more preferably 60 pM or less, more preferably 50 pM or less, more preferably 40 pM or less, more preferably 30 pM or less, more preferably 20 pM or less.
  • the EC 50 for all three receptors is 500 pM or less, more preferably 200 pM or less, more preferably 150 pM or less, more preferably 100 pM or less, more preferably 90 pM or less, more preferably 80 pM or less, more preferably 70 pM or less, more preferably 60 pM or less, more preferably 50 pM or less, more preferably 40 pM or less, more preferably 30 pM or less, more preferably 20 pM or less.
  • the EC 50 for hGLP-1 receptor, hGIP receptor and hGlucagon receptor may be determined as described in the Methods herein and as used to generate the results described in Example 5.
  • the compounds of the invention have the ability to reduce the intestinal passage, to increase the gastric content and/or to reduce the food intake of a patient. These activities of the compounds of the invention can be assessed in animal models known to the skilled person and also described herein in the Methods. The results of such experiments are described in Examples 11 and 12.
  • Preferred compounds of the invention may increase the gastric content of mice, preferably of female NMRI-mice, if administered as a single dose, preferably subcutaneous dose, of 0.02 mg/kg body weight by at least 25%, more preferably by at least 30%, more preferably by at least 40%, more preferably by at least 50%, more preferably by at least 60%, more preferably by at least 70%, more preferably by at least 80%.
  • this result is measured 1 h after administration of the respective compound and 30 mins after administration of a bolus, and/or reduces intestinal passage of mice, preferably of female NMRI-mice, if administered as a single dose, preferably subcutaneous dose, of 0.02 mg/kg body weight at least by 45%; more preferably by at least 50%, more preferably by at least 55%, more preferably by at least 60%, and more preferably at least 65%; and/or reduces food intake of mice, preferably of female NMRI-mice, over a period of 22 h, if administered as a single dose, preferably subcutaneous dose of 0.01 mg/kg body weight by at least 10%, more preferably 15%, and more preferably 20%.
  • the compounds of the invention have the ability to reduce blood glucose level, and/or to reduce HbA1c levels of a patient. These activities of the compounds of the invention can be assessed in animal models known to the skilled person and also described herein in the Methods. The results of such experiments are described in Examples 9 and 10.
  • Preferred compounds of the invention may reduce blood glucose level of mice, preferably in female leptin-receptor deficient diabetic db/db mice over a period of 24 h, if administered as a single dose, preferably subcutaneous dose, of 0.01 mg/kg body weight by at least 4 mmol/L; more preferably by at least 6 mmol/L, more preferably by at least 8 mmol/L. If the dose is increased to 0.1 mg/kg body weight a more pronounced reduction of blood glucose levels can be observed in mice over a period of 24 h, if administered as a single dose, preferably subcutaneous dose.
  • the compounds of the invention lead to a reduction by at least 7 mmol/L; more preferably by at least 9 mmol/L, more preferably by at least 11 mmol/L.
  • the compounds of the invention preferably reduce the increase of HbA1c levels of mice over a period of 4 weeks, if administered at a daily dose of 0.01 mg/kg to about the ignition value.
  • the compounds of the invention also have the ability to reduce body weight of a patient. These activities of the compounds of the invention can be assessed in animal models known to the skilled person and also described herein in the Methods and in Example 8.
  • peptidic compounds of the formula (I), particularly those with a lysine (or close analogs) at position 14 which is further substituted with a lipophilic residue showed very potent GLP-1 and GIP receptor activation; additionally in combination with amino acids like Gln in position 3 also very potent glucagon receptor activation can be provided.
  • compounds of the invention preferably have a high solubility at acidic and/or physiological pH values, e.g., at pH 4.5 and/or at pH 7.4 at 25° C., in another embodiment at least 0.5 mg/ml and in a particular embodiment at least 1.0 mg/ml.
  • compounds of the invention preferably have a high stability when stored in solution.
  • Preferred assay conditions for determining the stability is storage for 7 days at 25° C. in solution at pH 4.5 or pH 7.4. The remaining amount of peptide is determined by chromatographic analyses as described in Methods and Examples.
  • the remaining peptide amount is at least 80%, more preferably at least 85%, even more preferably at least 90% and even more preferably at least 95%.
  • the compounds of the present invention comprise a peptide moiety Z (formula II) which is a linear sequence of 39-40 amino carboxylic acids, particularly ⁇ -amino carboxylic acids linked by peptide, i.e. carboxamide, bonds.
  • position X14 represents an amino acid residue with a functionalized —NH 2 side chain group, such as functionalized Lys, Orn, Dab, or Dap, more preferably functionalized Lys and X40 is absent or represents Lys.
  • a functionalized —NH 2 side chain group such as functionalized Lys, Orn, Dab, or Dap, more preferably functionalized Lys and X40 is absent or represents Lys.
  • An amino acid residue with an —NH 2 side chain group may be functionalized in that at least one H atom of the —NH 2 side chain group is replaced by —C(O)—R 5 , —C(O)O—R 5 , —C(O)NH—R 5 , —S(O)2-R5 or R 5 , preferably by —C(O)—R 5 , wherein R 5 is a moiety comprising up to 50 or up to 100 carbon atoms and optionally heteroatoms selected from halogen, N, O, S and/or P.
  • R 5 may comprise a lipophilic moiety, e.g. an acyclic linear or branched saturated hydrocarbon group, wherein R 5 particularly comprises an acyclic linear or branched (C 4 -C 30 ) saturated or unsaturated hydrocarbon group, and/or a cyclic saturated, unsaturated or aromatic group, particularly a mono-, bi-, or tricyclic group comprising 4 to 14 carbon atoms and 0, 1, or 2 heteroatoms selected from N, O, and S, e.g.
  • a lipophilic moiety e.g. an acyclic linear or branched saturated hydrocarbon group, wherein R 5 particularly comprises an acyclic linear or branched (C 4 -C 30 ) saturated or unsaturated hydrocarbon group, and/or a cyclic saturated, unsaturated or aromatic group, particularly a mono-, bi-, or tricyclic group comprising 4 to 14 carbon atoms and 0, 1, or 2 heteroatoms selected from N, O, and S, e.g.
  • cyclohexyl phenyl, biphenyl, chromanyl, phenanthrenyl or naphthyl, wherein the acyclic or cyclic group may be unsubstituted or substituted e.g. by halogen, —OH and/or CO 2 H.
  • R 5 may comprise a lipophilic moiety, e.g. an acyclic linear or branched (C 12 -C 22 ) saturated or unsaturated hydrocarbon group.
  • the lipophilic moiety may be attached to the —NH 2 side chain group by a linker in all stereoisomeric forms, e.g. a linker comprising one or more, e.g. 2, 3 or 4, amino acid linker groups such as ⁇ -aminobutyric acid (GABA), ⁇ -aminohexanoic acid ( ⁇ -Ahx), ⁇ -Glu and/or ⁇ -Ala.
  • the lipophilic moiety is attached to the —NH 2 side chain group by a linker.
  • the lipophilic moiety is directly attached to the —NH 2 side chain group.
  • amino acid linker groups are ( ⁇ -Ala) 1-4 , ( ⁇ -Glu) 1-4 , ( ⁇ -Ahx) 1-4 , or (GABA) 1-4 .
  • Preferred amino acid linker groups are 8-Ala, ⁇ -Glu, ⁇ -Ala- ⁇ -Ala and ⁇ -Glu- ⁇ -Glu.
  • —C(O)—R 5 groups are listed in the following Table 3, which are selected from the group consisting of (S)-4-Carboxy-4-hexadecanoylamino-butyryl-, (S)-4-Carboxy-4-octadecanoylamino-butyryl-, 4-Hexadecanoylamino-butyryl-, 4- ⁇ 3-[(R)-2,5,7,8-tetramethyl-2-((4R,8R)-4,8,12-trimethyl-tridecyl)-chroman-6-yloxycarbonyl]-propionylamino ⁇ -butyryl-, 4-octadecanoylamino-butyryl-, 4-((Z)-octadec-9-enoylamino)-butyryl-, 6-[(4,4-Diphenyl-cyclohexyloxy)-hydroxy-phosphoryloxy]-hexanoyl-, Hexadecan
  • stereoisomers particularly enantiomers of these groups, either S- or R-enantiomers.
  • R in Table 3 is intended to mean the attachment site of —C(O)—R 5 at the peptide back bone, i.e. particularly the ⁇ -amino group of Lys.
  • the invention relates to peptidic compounds of Formula (I) as defined above, wherein X14 represents an amino acid residue selected from Lys, Orn, Dab and Dap, wherein the —NH 2 side chain group is functionalized by —C(O)—R 5 , X40 represents an amino acid residue selected from Lys, Orn, Dab and Dap, wherein the —NH 2 side chain group can be functionalized by —C(O)—R 5 , and R 5 is a lipophilic moiety selected from an acyclic linear or branched (C 4 -C 30 ) saturated or unsaturated hydrocarbon group, and/or a cyclic saturated, unsaturated or aromatic group, wherein the lipophilic moiety may be attached to the —NH 2 side chain group by a linker selected from ( ⁇ -Ala) 1-4 , ( ⁇ -Glu) 1-4 , ( ⁇ -Ahx) 1-4 , or (GABA) 1-4 in all stereoisomeric forms.
  • a linker selected from (
  • X14 represents an amino acid residue with a functionalized —NH 2 side chain group, such as functionalized Lys, Orn, Dab or Dap, wherein at least one H atom of the —NH 2 side chain group is replaced by —C(O)—R 5 , which is selected from the group consisting of the substituents according to Table 3 above.
  • a functionalized —NH 2 side chain group such as functionalized Lys, Orn, Dab or Dap
  • X14 represents an amino acid residue selected from Lys, Orn, Dab and Dap, wherein the —NH 2 side chain group is functionalized by —C(O)—R 5
  • X40 represents an amino acid residue selected from Lys, Orn, Dab and Dap, wherein the —NH 2 side chain group can be functionalized by —C(O)—R 5
  • —C(O)—R 5 is selected from the group consisting of the substituents according to Table 3 above.
  • position X14 and/or X40 in formula (II) represents Lysine (Lys).
  • Lys at position 14 and optionally at position 40 is functionalized, e.g. with a group —C(O)R 5 as described above.
  • X40 is absent and X14 is Lys functionalized with —C(O)—R 5 , —C(O)O—R 5 , —C(O)NH—R 5 , —S(O) 2 —R 5 or R 5 , preferably by —C(O)—R 5 , wherein R 5 is as defined above.
  • X14 is Lys functionalized with C(O)—R 5 , wherein R 5 is selected from the group consisting of (S)-4-carboxy-4-hexadecanoylamino-butyryl ( ⁇ E-x53), (S)-4-carboxy-4-octadecanoylamino-butyryl ( ⁇ E-x70), 4-hexadecanoylamino-butyryl (GABA-x53), 4- ⁇ 3-[(R)-2,5,7,8-tetramethyl-2-((4R,8R)-4,8,12-tri methyl-tridecyl)-chroman-6-yloxycarbonyl]-propionylamino ⁇ -butyryl-(GABA-x60), 4-octadecanoylamino-butyryl (GABA-x70), 4-((Z)-octadec-9-enoylamino)-butyryl (GABA-x74), 6-[(4,4--
  • X14 is Lys functionalized with C(O)—R 5 , wherein R 5 is selected from the group consisting of (S)-4-carboxy-4-hexadecanoylamino-butyryl ( ⁇ E-x53) and (S)-4-carboxy-4-octadecanoylamino-butyryl ( ⁇ E-x70).
  • a further embodiment relates to a group of compounds, wherein
  • a further embodiment relates to a group of compounds, wherein
  • a further embodiment relates to a group of compounds, wherein
  • a further embodiment relates to a group of compounds, wherein
  • a further embodiment relates to a group of compounds, wherein
  • a further embodiment relates to a group of compounds, wherein
  • a further embodiment relates to a group of compounds, wherein
  • a further embodiment relates to a group of compounds, wherein
  • a further embodiment relates to a group of compounds, wherein
  • a further embodiment relates to a group of compounds, wherein
  • a further embodiment relates to a group of compounds, wherein
  • a further embodiment relates to a group of compounds, wherein
  • a further embodiment relates to a group of compounds, wherein
  • a further embodiment relates to a group of compounds, wherein
  • a further embodiment relates to a group of compounds, wherein
  • a further embodiment relates to a group of compounds, wherein
  • a further embodiment relates to a group of compounds, wherein
  • a further embodiment relates to a group of compounds, wherein
  • a further embodiment relates to a group of compounds, wherein
  • a further embodiment relates to a group of compounds, wherein
  • a further embodiment relates to a group of compounds, wherein
  • a further embodiment relates to a group of compounds, wherein
  • a further embodiment relates to a group of compounds, wherein
  • peptidic compounds of formula (I) are the compounds of SEQ ID NO: 8-13 as well as salts and solvates thereof.
  • peptidic compounds of formula (I) are the compounds of SEQ ID NO: 8-10 and 13 as well as salts and solvates thereof.
  • the invention further provides a nucleic acid (which may be DNA or RNA) encoding said compound, an expression vector comprising such a nucleic acid, and a host cell containing such a nucleic acid or expression vector.
  • a nucleic acid which may be DNA or RNA
  • the present invention provides a composition comprising a compound of the invention in admixture with a carrier.
  • the composition is a pharmaceutically acceptable composition and the carrier is a pharmaceutically acceptable carrier.
  • the compound of the invention may be in the form of a salt, e.g. a pharmaceutically acceptable salt or a solvate, e.g. a hydrate.
  • the present invention provides a composition for use in a method of medical treatment, particularly in human medicine.
  • the nucleic acid or the expression vector may be used as therapeutic aguponents, e.g. in gene therapy.
  • the compounds of formula (I) are suitable for therapeutic application without an additionally therapeutically effective agent. In other embodiments, however, the compounds are used together with at least one additional therapeutically active agent, as described in “combination therapy”.
  • the compounds of formula (I) are particularly suitable for the treatment or prevention of diseases or disorders caused by, associated with and/or accompanied by disturbances in carbohydrate and/or lipid metabolism, e.g. for the treatment or prevention of hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, obesity and metabolic syndrome. Further, the compounds of the invention are particularly suitable for the treatment or prevention of degenerative diseases, particularly neurodegenerative diseases.
  • the compounds described find use, inter alia, in preventing weight gain or promoting weight loss.
  • preventing is meant inhibiting or reducing when compared to the absence of treatment, and is not necessarily meant to imply complete cessation of a disorder.
  • the compounds of the invention may cause a decrease in food intake and/or increase in energy expenditure, resulting in the observed effect on body weight.
  • the compounds of the invention may have a beneficial effect on circulating cholesterol levels, being capable of improving lipid levels, particularly LDL, as well as HDL levels (e.g. increasing HDL/LDL ratio).
  • the compounds of the invention can be used for direct or indirect therapy of any condition caused or characterised by excess body weight, such as the treatment and/or prevention of obesity, morbid obesity, obesity linked inflammation, obesity linked gallbladder disease, obesity induced sleep apnea. They may also be used for treatment and prevention of the metabolic syndrome, diabetes, hypertension, atherogenic dyslipidemia, atherosclerosis, arteriosclerosis, coronary heart disease, or stroke. Their effects in these conditions may be as a result of or associated with their effect on body weight, or may be independent thereof.
  • Preferred medical uses include delaying or preventing disease progression in type 2 diabetes, treating metabolic syndrome, treating obesity or preventing overweight, for decreasing food intake, increase energy expenditure, reducing body weight, delaying the progression from impaired glucose tolerance (IGT) to type 2 diabetes; delaying the progression from type 2 diabetes to insulin-requiring diabetes; regulating appetite; inducing satiety; preventing weight regain after successful weight loss; treating a disease or state related to overweight or obesity; treating bulimia; treating binge eating; treating atherosclerosis, hypertension, type 2 diabetes, IGT, dyslipidemia, coronary heart disease, hepatic steatosis, treatment of beta-blocker poisoning, use for inhibition of the motility of the gastrointestinal tract, useful in connection with investigations of the gastrointestinal tract using techniques such as X-ray, CT- and NMR-scanning.
  • ITT impaired glucose tolerance
  • Further preferred medical uses include treatment or prevention of degenerative disorders, particularly neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, ataxia, e.g spinocerebellar ataxia, Kennedy disease, myotonic dystrophy, Lewy body dementia, multi-systemic atrophy, amyotrophic lateral sclerosis, primary lateral sclerosis, spinal muscular atrophy, prion-associated diseases, e.g.
  • neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, ataxia, e.g spinocerebellar ataxia, Kennedy disease, myotonic dystrophy, Lewy body dementia, multi-systemic atrophy, amyotrophic lateral sclerosis, primary lateral sclerosis, spinal muscular atrophy, prion-associated diseases, e.g.
  • Creutzfeldt-Jacob disease multiple sclerosis, telangiectasia, Batten disease, corticobasal degeneration, subacute combined degeneration of spinal cord, Tabes dorsalis, Tay-Sachs disease, toxic encephalopathy, infantile Refsum disease, Refsum disease, neuroacanthocytosis, Niemann-Pick disease, Lyme disease, Machado-Joseph disease, Sandhoff disease, Shy-Drager syndrome, wobbly hedgehog syndrome, proteopathy, cerebral ⁇ -amyloid angiopathy, retinal ganglion cell degeneration in glaucoma, synucleinopathies, tauopathies, frontotemporal lobar degeneration (FTLD), dementia, cadasil syndrome, hereditary cerebral hemorrhage with amyloidosis, Alexander disease, seipinopathies, familial amyloidotic neuropathy, senile systemic amyloidosis, serpinopathies, AL (light chain) amyloido
  • Further medical uses include treatment of bone related disorders, such as osteoporosis or osteoarthritis, etc., where increased bone formation and decreased bone resorption might be beneficial.
  • amino acid sequences of the present invention contain the conventional one letter and three letter codes for naturally occuring amino acids, as well as generally accepted three letter codes for other amino acids, such as Aib ( ⁇ -aminoisobutyric acid), Orn (ornithin), Dab (2,4-diamino butyric acid), Dap (2,3-diamino propionic acid), Nle (norleucine), GABA ( ⁇ -aminobutyric acid) or Ahx ( ⁇ -aminohexanoic acid).
  • Aib ⁇ -aminoisobutyric acid
  • Orn ornithin
  • Dab 2,4-diamino butyric acid
  • Dap 2,3-diamino propionic acid
  • Nle nodeucine
  • GABA ⁇ -aminobutyric acid
  • Ahx ⁇ -aminohexanoic acid
  • native exendin-4 refers to native exendin-4 having the sequence HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-NH 2 (SEQ ID NO: 1).
  • the invention provides peptidic compounds as defined above.
  • the peptidic compounds of the present invention comprise a linear backbone of amino carboxylic acids linked by peptide, i.e. carboxamide bonds.
  • the amino carboxylic acids are ⁇ -amino carboxylic acids and more preferably L- ⁇ -amino carboxylic acids, unless indicated otherwise.
  • the peptidic compounds preferably comprise a backbone sequence of 39-40 amino carboxylic acids.
  • the peptidic compounds of the present invention may have unmodified side-chains, but carry at least one modification at one of the side chains.
  • sequence of the peptidic moiety (II) differs from native exendin-4 at least at one of those positions which are stated to allow variation.
  • Amino acids within the peptide moiety (II) can be considered to be numbered consecutively from 0 to 40 in the conventional N-terminal to C-terminal direction.
  • Reference to a “position” within peptidic moiety (II) should be constructed accordingly, as should reference to positions within native exendin-4 and other molecules, e.g., in exendin-4, His is at position 1, Gly at position 2, . . . , Met at position 14, . . . and Ser at position 39.
  • amino acid residues at position 14 and optionally at position 40, having a side chain with an —NH 2 group, e.g. Lys, Orn, Dab or Dap are conjugated to a functional group, e.g. acyl groups.
  • a functional group e.g. acyl groups.
  • one or more selected amino acids of the peptides in the present invention may carry a covalent attachment at their side chains. In some cases those attachments may be lipophilic. These lipophilic side chain attachments have the potential to reduce in vivo clearance of the peptides thus increasing their in vivo half-lives.
  • the lipophilic attachment may consist of a lipophilic moiety which can be a branched or unbranched, aliphatic or unsaturated acyclic moiety and/or a cyclic moiety selected from one or several aliphatic or unsaturated homocycles or heterocycles, aromatic condensed or non-condensed homocycles or heterocycles, ether linkages, unsaturated bonds and substituents, e.g. hydroxy and/or carboxy groups.
  • the lipophilic moiety may be attached to the peptide either by alkylation, reductive amination or by an amide bond, a carbamate or a sulfonamide bond in case of amino acids carrying an amino group at their side chain.
  • Nonlimiting examples of lipophilic moieties that can be attached to amino acid side chains include fatty acids, e.g. C 8-30 fatty acids such as palmitic acid, myristic acid, stearic acid and oleic acid, and/or cyclic groups as described above or derivatives thereof.
  • linkers between the amino acid of the peptide and the lipophilic attachment.
  • linkers are ⁇ -alanine, ⁇ -glutamic acid, ⁇ -glutamic acid, ⁇ -aminobutyric acid and/or ⁇ -aminohexanoic acid or dipeptides, such as ⁇ -Ala- ⁇ -Ala (also abbreviated ⁇ A- ⁇ A herein) and/or ⁇ -Glu- ⁇ -Glu (also abbreviated ⁇ E- ⁇ E herein) in all their stereo-isomer forms (S and R enantiomers).
  • a side chain attachment is palmitic acid which is covalently linked to the ⁇ -amino group of glutamic acid forming an amide bond.
  • the ⁇ -carboxy group of this substituted glutamic acid can form an amide bond with the side chain amino group of a lysine within the peptide.
  • the present invention provides a composition
  • a composition comprising a compound of the invention as described herein, or a salt or solvate thereof, in admixture with a carrier.
  • the invention also provides the use of a compound of the present invention for use as a medicament, particularly for the treatment of a condition as described below.
  • the invention also provides a composition wherein the composition is a pharmaceutically acceptable composition, and the carrier is a pharmaceutically acceptable carrier.
  • peptides that are described in this invention. These methods include but are not limited to synthetic approaches and recombinant gene expression. Thus, one way of preparing these peptides is the synthesis in solution or on a solid support and subsequent isolation and purification. A different way of preparing the peptides is gene expression in a host cell in which a DNA sequence encoding the peptide has been introduced. Alternatively, the gene expression can be achieved without utilizing a cell system. The methods described above may also be combined in any way.
  • a preferred way to prepare the peptides of the present invention is solid phase synthesis on a suitable resin.
  • Solid phase peptide synthesis is a well established methodology (see for example: Stewart and Young, Solid Phase Peptide Synthesis, Pierce Chemical Co., Rockford, III., 1984; E. Atherton and R. C. Sheppard, Solid Phase Peptide Synthesis. A Practical Approach, Oxford-IRL Press, New York, 1989).
  • Solid phase synthesis is initiated by attaching an N-terminally protected amino acid with its carboxy terminus to an inert solid support carrying a cleavable linker.
  • This solid support can be any polymer that allows coupling of the initial amino acid, e.g.
  • trityl resin a chlorotrityl resin, a Wang resin or a Rink resin in which the linkage of the carboxy group (or carboxamide for Rink resin) to the resin is sensitive to acid (when Fmoc strategy is used).
  • the polymer support must be stable under the conditions used to deprotect the ⁇ -amino group during the peptide synthesis.
  • the ⁇ -amino protecting group of this amino acid is removed.
  • the remaining protected amino acids are then coupled one after the other in the order represented by the peptide sequence using appropriate amide coupling reagents, for example BOP, HBTU, HATU or DIC (N,N′-diisopropylcarbodiimide)/HOBt (1-hydroxybenzotriazol), wherein BOP, HBTU and HATU are used with tertiary amine bases.
  • the liberated N-terminus can be functionalized with groups other than amino acids, for example carboxylic acids, etc.
  • a lysine may be protected with an ivDde ([1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)-3-methylbutyl) protecting group (S. R. Chhabra et al., Tetrahedron Lett. 39, (1998), 1603) which is labile to a very nucleophilic base, for example 4% hydrazine in DMF (dimethyl formamide).
  • the ivDde group can be selectively removed using 4% hydrazine in DMF and the corresponding free amino group can then be further modified, e.g. by acylation.
  • the lysine can alternatively be coupled to a protected amino acid and the amino group of this amino acid can then be deprotected resulting in another free amino group which can be acylated or attached to further amino acids.
  • peptide is cleaved from the resin. This can be achieved by using King's cocktail (D. S. King, C. G. Fields, G. B. Fields, Int. J. Peptide Protein Res. 36, 1990, 255-266).
  • the raw material can then be purified by chromatography, e.g. preparative RP-HPLC, if necessary.
  • the term “potency” or “in vitro potency” is a measure for the ability of a compound to activate the receptors for GLP-1, GIP or glucagon in a cell-based assay. Numerically, it is expressed as the “EC50 value”, which is the effective concentration of a compound that induces a half maximal increase of response (e.g. formation of intracellular cAMP) in a dose-response experiment.
  • the compounds of the invention are agonists for the receptors for GLP-1 and for GIP as well as optionally the glucagon receptor (e.g. “dual or trigonal agonists”).
  • glucagon receptor e.g. “dual or trigonal agonists”.
  • Such peptides that are GIP/GLP-1 co-agonists, or GIP/GLP-1/glucagon tri-agonists may provide therapeutic benefit to address a clinical need for targeting the metabolic syndrome by allowing simultaneous treatment of diabetes and obesity.
  • Metabolic syndrome is a combination of medical disorders that, when occurring together, increase the risk of developing type 2 diabetes, as well as atherosclerotic vascular disease, e.g. heart disease and stroke.
  • Defining medical parameters for the metabolic syndrome include diabetes mellitus, impaired glucose tolerance, raised fasting glucose, insulin resistance, urinary albumin secretion, central obesity, hypertension, elevated triglycerides, elevated LDL cholesterol and reduced HDL cholesterol.
  • Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health and life expectancy and due to its increasing prevalence in adults and children it has become one of the leading preventable causes of death in modern world. It increases the likelihood of various other diseases, including heart disease, type 2 diabetes, obstructive sleep apnea, certain types of cancer, as well as osteoarthritis, and it is most commonly caused by a combination of excess food intake, reduced energy expenditure, as well as genetic susceptibility.
  • Diabetes mellitus often simply called diabetes, is a group of metabolic diseases in which a person has high blood sugar levels, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced.
  • the most common types of diabetes are: (1) type 1 diabetes, where the body fails to produce insulin; (2) type 2 diabetes, where the body fails to use insulin properly, combined with an increase in insulin deficiency over time, and (3) gestational diabetes, where women develop diabetes due to their pregnancy. All forms of diabetes increase the risk of long-term complications, which typically develop after many years.
  • macrovascular disease arising from atherosclerosis of larger blood vessels
  • microvascular disease arising from damage of small blood vessels.
  • macrovascular disease conditions are ischemic heart disease, myocardial infarction, stroke and peripheral vascular disease.
  • microvascular diseases are diabetic retinopathy, diabetic nephropathy, as well as diabetic neuropathy.
  • the receptors for GLP-1 and GIP as well as glucagon are members of the family of 7-transmembrane-spanning, heterotrimeric G-protein coupled receptors. They are structurally related to each other and share not only a significant level of sequence identity, but have also similar mechanisms of ligand recognition and intracellular signaling pathways.
  • GLP-1, GIP and glucagon share regions of high sequence identity/similarity.
  • GLP-1 and glucagon are produced from a common precursor, preproglucagon, which is differentially processed in a tissue-specific manner to yield e.g. GLP-1 in intestinal endocrine cells and glucagon in alpha cells of pancreatic islets.
  • GIP is derived from a larger proGIP prohormone precursor and is synthesized and released from K-cells located in the small intestine.
  • the peptidic incretin hormones GLP-1 and GIP are secreted by intestinal endocrine cells in response to food and account for up to 70% of meal-stimulated insulin secretion.
  • targeting of the GLP-1 receptor with suitable agonists offers an attractive approach for treatment of metabolic disorders, including diabetes.
  • the receptor for GLP-1 is distributed widely, being found mainly in pancreatic islets, brain, heart, kidney and the gastrointestinal tract. In the pancreas, GLP-1 acts in a strictly glucose-dependent manner by increasing secretion of insulin from beta cells.
  • GIP GLP-1 receptors
  • the receptor for GIP is broadly expressed in peripheral tissues including pancreatic islets, adipose tissue, stomach, small intestine, heart, bone, lung, kidney, testis, adrenal cortex, pituitary, endothelial cells, trachea, spleen, thymus, thyroid and brain.
  • pancreatic B-cell express the highest levels of the receptor for GIP in humans.
  • GIP-receptor mediated signaling could be impaired in patients with T2DM but GIP-action is shown to be reversible and could be restored with improvement of the diabetic status.
  • the stimulation of insulin secretion by both incretin hormones, GIP and GLP-1 is strictly glucosed-dependent ensuring a fail-safe mechanism associated with at low risk for hypoglycemia.
  • GLP-1 and GIP have been shown to promote glucose sensitivity, neogenesis, proliferation, transcription of proinsulin and hypertrophy, as well as antiapoptosis.
  • a peptide with dual agonistic activity for the GLP-1 and the GIP receptor could be anticipated to have additive or synergistic anti-diabetic benefit.
  • Other relevant effects of GLP-1 beyond the pancreas include delayed gastric emptying, increased satiety, decreased food intake, reduction of body weight, as well as neuroprotective and cardioprotective effects. In patients with type 2 diabetes, such extrapancreatic effects could be particularly important considering the high rates of comorbidities like obesity and cardiovascular disease.
  • Further GIP actions in peripheral tissues beyond the pancreas comprise increased bone formation and decreased bone resorption as well as neuroprotective effects which might be beneficial for the treatment of osteoporosis and cognitive defects like Alzheimer's disease.
  • Glucagon is a 29 amino acid peptide hormone that is produced by pancreatic alpha cells and released into the bloodstream when circulating glucose is low.
  • An important physiological role of glucagon is to stimulate glucose output in the liver, which is a process providing the major counterregulatory mechanism for insulin in maintaining glucose homeostasis in vivo.
  • Glucagon receptors are however also expressed in extrahepatic tissues such as kidney, heart, adipocytes, lymphoblasts, brain, retina, adrenal gland and gastrointestinal tract, suggesting a broader physiological role beyond glucose homeostasis. Accordingly, recent studies have reported that glucagon has therapeutically positive effects on energy management, including stimulation of energy expenditure and thermogenesis, accompanied by reduction of food intake and body weight loss. Altogether, stimulation of glucagon receptors might be useful in the treatment of obesity and the metabolic syndrome.
  • Oxyntomodulin is a peptide hormone consisting of glucagon with an eight amino acids encompassing C-terminal extension. Like GLP-1 and glucagon, it is preformed in preproglucagon and cleaved and secreted in a tissue-specific manner by endocrinal cells of the small bowel. Oxyntomodulin is known to stimulate both, the receptors for GLP-1 and glucagon and is therefore the prototype of a dual agonist.
  • GLP-1 and GIP are known for their anti-diabetic effects
  • GLP-1 and glucagon are both known for their food intake-suppressing effects
  • glucagon is also a mediator of additional energy expenditure, it is conceivable that a combination of the activities of the two or three hormones in one molecule can yield a powerful medication for treatment of the metabolic syndrome and in particular its components diabetes and obesity.
  • the compounds of the invention may be used for treatment of glucose intolerance, insulin resistance, pre-diabetes, increased fasting glucose, type 2 diabetes, hypertension, dyslipidemia, arteriosclerosis, coronary heart disease, peripheral artery disease, stroke or any combination of these individual disease components.
  • they may be used for control of appetite, feeding and calory intake, increase of energy expenditure, prevention of weight gain, promotion of weight loss, reduction of excess body weight and altogether treatment of obesity, including morbid obesity.
  • the effects of the compounds of the invention may be mediated in whole or in part via an effect on body weight, or independent thereof.
  • diseases to be treated are neurodegenerative diseases such as Alzheimer's disease or Parkinson's disease, or other degenerative diseases as described above.
  • exendin-4 Compared to GLP-1, glucagon and oxyntomodulin, exendin-4 has beneficial physicochemical properties, such as solubility and stability in solution and under physiological conditions (including enzymatic stability towards degradation by enzymes, such as DPP-4 or NEP), which results in a longer duration of action in vivo. Therefore, exendin-4 might serve as good starting scaffold to obtain exendin-4 analogs with dual or even triple pharmacologies, e.g., GLP-1/GIP and optionally in addition glucagon agonism.
  • exendin-4 has been shown to be chemically labile due to methionine oxdiation in position 14 as well as deamidation and isomerization of asparagine in position 28. Therefore, stability might be further improved by substitution of methionine at position 14 and the avoidance of sequences that are known to be prone to degradation via aspartimide formation, especially Asp-Gly or Asn-Gly at positions 28 and 29.
  • composition indicates a mixture containing ingredients that are compatible when mixed and which may be administered.
  • a pharmaceutical composition may include one or more medicinal drugs. Additionally, the pharmaceutical composition may include carriers, buffers, acidifying agents, alkalizing agents, solvents, adjuvants, tonicity adjusters, emollients, expanders, preservatives, physical and chemical stabilizers e.g. surfactants, antioxidants and other components, whether these are considered active or inactive ingredients.
  • Guidance for the skilled in preparing pharmaceutical compositions may be found, for example, in Remington: The Science and Practice of Pharmacy, (20th ed.) ed. A. R. Gennaro A. R., 2000, Lippencott Williams & Wilkins and in R. C. Rowe et al (Ed), Handbook of Pharmaceutical Excipients, PhP, May 2013 update.
  • exendin-4 peptide derivatives of the present invention, or salts thereof, are administered in conjunction with an acceptable pharmaceutical carrier, diluent, or excipient as part of a pharmaceutical composition.
  • a “pharmaceutically acceptable carrier” is a carrier which is physiologically acceptable (e.g. physiologically acceptable pH) while retaining the therapeutic properties of the substance with which it is administered.
  • Standard acceptable pharmaceutical carriers and their formulations are known to one skilled in the art and described, for example, in Remington: The Science and Practice of Pharmacy, (20th ed.) ed. A. R. Gennaro A. R., 2000, Lippencott Williams & Wilkins and in R. C. Rowe et al (Ed), Handbook of Pharmaceutical excipients, PhP, May 2013 update.
  • One exemplary pharmaceutically acceptable carrier is physiological saline solution.
  • carriers are selected from the group of buffers (e.g. citrate/citric acid), acidifying agents (e.g. hydrochloric acid), alkalizing agents (e.g. sodium hydroxide), preservatives (e.g. phenol), co-solvents (e.g. polyethylene glycol 400), tonicity adjusters (e.g. mannitol), stabilizers (e.g. surfactant, antioxidants, amino acids).
  • buffers e.g. citrate/citric acid
  • acidifying agents e.g. hydrochloric acid
  • alkalizing agents e.g. sodium hydroxide
  • preservatives e.g. phenol
  • co-solvents e.g. polyethylene glycol 400
  • tonicity adjusters e.g. mannitol
  • stabilizers e.g. surfactant, antioxidants, amino acids
  • Concentrations used are in a range that is physiologically acceptable.
  • Acceptable pharmaceutical carriers or diluents include those used in formulations suitable for oral, rectal, nasal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, and transdermal) administration.
  • the compounds of the present invention will typically be administered parenterally.
  • pharmaceutically acceptable salt means salts of the compounds of the invention which are safe and effective for use in mammals.
  • Pharmaceutically acceptable salts may include, but are not limited to, acid addition salts and basic salts.
  • acid addition salts include chloride, sulfate, hydrogen sulfate, (hydrogen) phosphate, acetate, citrate, tosylate or mesylate salts.
  • basic salts include salts with inorganic cations, e.g. alkaline or alkaline earth metal salts such as sodium, potassium, magnesium or calcium salts and salts with organic cations such as amine salts. Further examples of pharmaceutically acceptable salts are described in Remington: The Science and Practice of Pharmacy, (20th ed.) ed.
  • solvate means complexes of the compounds of the invention or salts thereof with solvent molecules, e.g. organic solvent molecules and/or water.
  • the exendin-4 derivative in monomeric or oligomeric form.
  • terapéuticaally effective amount of a compound refers to a nontoxic but sufficient amount of the compound to provide the desired effect.
  • the amount of a compound of the formula I necessary to achieve the desired biological effect depends on a number of factors, for example the specific compound chosen, the intended use, the mode of administration and the clinical condition of the patient.
  • An appropriate “effective” amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation
  • the “therapeutically effective amount” of a compound of the formula (I) is about 0.01 to 50 mg/dose, preferably 0.1 to 10 mg/dose.
  • compositions of the invention are those suitable for parenteral (for example subcutaneous, intramuscular, intradermal or intravenous), oral, rectal, topical and peroral (for example sublingual) administration, although the most suitable mode of administration depends in each individual case on the nature and severity of the condition to be treated and on the nature of the compound of formula I used in each case.
  • Suitable pharmaceutical compositions may be in the form of separate units, for example capsules, tablets and powders in vials or ampoules, each of which contains a defined amount of the compound; as powders or granules; as solution or suspension in an aqueous or nonaqueous liquid; or as an oil-in-water or water-in-oil emulsion. It may be provided in single or multiple dose injectable form, for example in the form of a pen.
  • the compositions may, as already mentioned, be prepared by any suitable pharmaceutical method which includes a step in which the active ingredient and the carrier (which may consist of one or more additional ingredients) are brought into contact.
  • the pharmaceutical composition may be provided together with a device for application, for example together with a syringe, an injection pen or an autoinjector.
  • a device for application for example together with a syringe, an injection pen or an autoinjector.
  • Such devices may be provided separate from a pharmaceutical composition or prefilled with the pharmaceutical composition.
  • the compounds of the present invention can be widely combined with other pharmacologically active compounds, such as all drugs mentioned in the Rote Liste 2012 and/or the Rote Liste 2013, e.g. with all antidiabetics mentioned in the Rote Liste 2012, chapter 12, and/or the Rote Liste 2013, chapter 12, all weight-reducing agents or appetite suppressants mentioned in the Rote Liste 2012, chapter 1, and/or the Rote Liste 2013, chapter 1, all lipid-lowering agents mentioned in the Rote Liste 2012, chapter 58, and/or the Rote Liste 2013, chapter 58, all antihypertensives and nephroprotectives, mentioned in the Rote Liste 2012 and/or the Rote Liste 2013, or all diuretics mentioned in the Rote Liste 2012, chapter 36, and/or the Rote Liste 2013, chapter 36.
  • the active ingredient combinations can be used especially for a synergistic improvement in action. They can be applied either by separate administration of the active ingredients to the patient or in the form of combination products in which a plurality of active ingredients are present in one pharmaceutical preparation. When the active ingredients are administered by separate administration of the active ingredients, this can be done simultaneously or successively.
  • active substances which are suitable for such combinations include in particular those which for example potentiate the therapeutic effect of one or more active substances with respect to one of the indications mentioned and/or which allow the dosage of one or more active substances to be reduced.
  • Therapeutic agents which are suitable for combinations include, for example, antidiabetic agents such as:
  • Insulin and Insulin derivatives for example: Glargine/Lantus®, 270-330U/mL of insulin glargine (EP 2387989 A), 300U/mL of insulin glargine (EP 2387989 A), Glulisin/Apidra®, Detemir/Levemir®, Lispro/Humalog®/Liprolog®, Degludec/DegludecPlus, Aspart, basal insulin and analogues (e.g.
  • Exubera® Nasulin®, Afrezza, Tregopil, TPM 02, Capsulin, Oral-lyn®, Cobalamin® oral insulin, ORMD-0801, NN1953, NN1954, NN1956, VIAtab, Oshadi oral insulin). Additionally included are also those insulin derivatives which are bonded to albumin or another protein by a bifunctional linker.
  • GLP-1, GLP-1 analogues and GLP-1 receptor agonists for example: Lixisenatide/AVE0010/ZP10/Lyxumia, Exenatide/Exendin-4/Byetta/Bydureon/ITCA 650/AC-2993, Liraglutide/Victoza, Semaglutide, Taspoglutide, Syncria/Albiglutide, Dulaglutide, rExendin-4, CJC-1134-PC, PB-1023, TTP-054, Langlenatide/HM-112600, CM-3, GLP-1 Eligen, ORMD-0901, NN-9924, NN-9926, NN-9927, Nodexen, Viador-GLP-1, CVX-096, ZYOG-1, ZYD-1, GSK-2374697, DA-3091, MAR-701, MAR709, ZP-2929, ZP-3022, TT-401, BHM-034. MOD-6030, CAM
  • DPP-4 inhibitors for example: Alogliptin/Nesina, Trajenta/Linagliptin/BI-1356/Ondero/Trajenta/Tradjenta/Trayenta/Tradzenta, Saxagliptin/Onglyza, Sitagliptin/Januvia/Xelevia/Tesave/Janumet/Velmetia, Galvus/Vildagliptin, Anagliptin, Gemigliptin, Teneligliptin, Melogliptin, Trelagliptin, DA-1229, Omarigliptin/MK-3102, KM-223, Evogliptin, ARI-2243, PBL-1427, Pinoxacin.
  • Alogliptin/Nesina Trajenta/Linagliptin/BI-1356/Ondero/Trajenta/Tradjenta/Trayenta/Tradzenta
  • SGLT2 inhibitors for example: Invokana/Canaglifozin, Forxiga/Dapagliflozin, Remoglifozin, Sergliflozin, Empagliflozin, Ipragliflozin, Tofogliflozin, Luseogliflozin, LX-4211, Ertuglifozin/PF-04971729, RO-4998452, EGT-0001442, KGA-3235/DSP-3235, LIK066, SBM-TFC-039,
  • Biguanides e.g. Metformin, Buformin, Phenformin
  • Thiazolidinediones e.g. Pioglitazone, Rivoglitazone, Rosiglitazone, Troglitazone
  • dual PPAR agonists e.g. Aleglitazar, Muraglitazar, Tesaglitazar
  • Sulfonylureas e.g. Tolbutamide, Glibenclamide, Glimepiride/Amaryl, Glipizide
  • Meglitinides e.g. Nateglinide, Repaglinide, Mitiglinide
  • Alpha-glucosidase inhibitors e.g. Acarbose, Miglitol, Voglibose
  • Amylin and Amylin analogues e.g. Pramlintide, Symlin.
  • GPR119 agonists e.g. GSK-263A, PSN-821, MBX-2982, APD-597, ZYG-19, DS-8500
  • GPR40 agonists e.g. Fasiglifam/TAK-875, TUG-424, P-1736, JTT-851, GW9508.
  • Suitable combination partners are: Cycloset, inhibitors of 11-beta-HSD (e.g. LY2523199, BMS770767, RG-4929, BMS816336, AZD-8329, HSD-016, BI-135585), activators of glucokinase (e.g. TTP-399, AMG-151, TAK-329, GKM-001), inhibitors of DGAT (e.g. LCQ-908), inhibitors of protein tyrosinephosphatase 1 (e.g.
  • Trodusquemine inhibitors of glucose-6-phosphatase, inhibitors of fructose-1,6-bisphosphatase, inhibitors of glycogen phosphorylase, inhibitors of phosphoenol pyruvate carboxykinase, inhibitors of glycogen synthase kinase, inhibitors of pyruvate dehydrokinase, alpha2-antagonists, CCR-2 antagonists, SGLT-1 inhibitors (e.g. LX-2761).
  • One or more lipid lowering agents are also suitable as combination partners, such as for example: HMG-CoA-reductase inhibitors (e.g. Simvastatin, Atorvastatin), fibrates (e.g. Bezafibrate, Fenofibrate), nicotinic acid and the derivatives thereof (e.g. Niacin), PPAR-(alpha, gamma or alpha/gamma) agonists or modulators (e.g. Aleglitazar), PPAR-delta agonists, ACAT inhibitors (e.g. Avasimibe), cholesterol absorption inhibitors (e.g. Ezetimibe), Bile acid-binding substances (e.g. Cholestyramine), ileal bile acid transport inhibitors, MTP inhibitors, or modulators of PCSK9.
  • HMG-CoA-reductase inhibitors e.g. Simvastatin, Atorvastatin
  • fibrates e.g. Bezafib
  • HDL-raising compounds such as: CETP inhibitors (e.g. Torcetrapib, Anacetrapid, Dalcetrapid, Evacetrapid, JTT-302, DRL-17822, TA-8995) or ABC1 regulators.
  • CETP inhibitors e.g. Torcetrapib, Anacetrapid, Dalcetrapid, Evacetrapid, JTT-302, DRL-17822, TA-8995
  • ABC1 regulators e.g., ABC1 regulators.
  • Suitable combination partners are one or more active substances for the treatment of obesity, such as for example: Sibutramine, Tesofensine, Orlistat, antagonists of the cannabinoid-1 receptor, MCH-1 receptor antagonists, MC4 receptor agonists, NPY5 or NPY2 antagonists (e.g. Velneperit), beta-3-agonists, leptin or leptin mimetics, agonists of the 5HT2c receptor (e.g. Lorcaserin), or the combinations of bupropione/naltrexone, bupropione/zonisamide, bupropione/phentermine or pramlintide/metreleptin.
  • active substances for the treatment of obesity such as for example: Sibutramine, Tesofensine, Orlistat, antagonists of the cannabinoid-1 receptor, MCH-1 receptor antagonists, MC4 receptor agonists, NPY5 or NPY2 antagonists (e.g. Velneperit), beta-3-agonists,
  • gastrointestinal peptides such as Peptide YY 3-36 (PYY3-36) or analogues thereof, pancreatic polypeptide (PP) or analogues thereof.
  • Glucagon receptor agonists or antagonists GIP receptor agonists or antagonists, ghrelin antagonists or inverse agonists, Xenin and analogues thereof.
  • angiotensin II receptor antagonists e.g. telmisartan, candesartan, valsartan, losartan, eprosartan, irbesartan, olmesartan, tasosartan, azilsartan
  • ACE inhibitors e.g. telmisartan, candesartan, valsartan, losartan, eprosartan, irbesartan, olmesartan, tasosartan, azilsartan
  • ACE inhibitors e.g. telmisartan, candesartan, valsartan, losartan, eprosartan, irbesartan, olmesartan, tasosartan, azilsartan
  • ACE inhibitors e.g. telmisartan, candesartan, valsartan, losartan, eprosartan, irbe
  • this invention relates to the use of a compound according to the invention or a physiologically acceptable salt thereof combined with at least one of the active substances described above as a combination partner, for preparing a medicament which is suitable for the treatment or prevention of diseases or conditions which can be affected by binding to the receptors for GLP-1 and glucagon and by modulating their activity.
  • This is preferably a disease in the context of the metabolic syndrome, particularly one of the diseases or conditions listed above, most particularly diabetes or obesity or complications thereof.
  • the use of the compound according to the invention, or a physiologically acceptable salt thereof, in combination with another active substance may take place simultaneously or at staggered times, but particularly within a short space of time. If they are administered simultaneously, the two active substances are given to the patient together; if they are used at staggered times, the two active substances are given to the patient within a period of less than or equal to 12 hours, but particularly less than or equal to 6 hours.
  • this invention relates to a medicament which comprises a compound according to the invention or a physiologically acceptable salt of such a compound and at least one of the active substances described above as combination partners, optionally together with one or more inert carriers and/or diluents.
  • the compound according to the invention, or physiologically acceptable salt or solvate thereof, and the additional active substance to be combined therewith may both be present together in one formulation, for example a tablet or capsule, or separately in two identical or different formulations, for example as so-called kit-of-parts.
  • FIG. 1 Effect of s.c. administration of compound SEQ ID NO: 10 at 3 ⁇ g/kg and 10 ⁇ g/kg on body weight in female diet-induced obese (DIO) C57BL/6NCrl mice following 3-weeks chronic treatment once daily. Data are mean ⁇ SEM.
  • FIG. 2 Effect of s.c. administration of compound SEQ ID NO: 10 at 3 ⁇ g/kg and 10 ⁇ g/kg on body weight in female diet-induced obese (DIO) C57BL/6NCrl mice following 3-weeks chronic treatment once daily. Changes in body weight were calculated as relative change from baseline. Data are mean ⁇ SEM.
  • FIG. 3 Effect of 4 weeks of treatment with SEQ ID NO: 10 at 3 and 10 ⁇ g/kg, s.c. on non-fasted glucose in diabetic dbdb-mice, represented as change from baseline (0 mmol/l, day ⁇ 7). Data are mean ⁇ SEM.
  • FIG. 4 Effect of 4 weeks of treatment with SEQ ID NO: 10 at 3 and 10 ⁇ g/kg, s.c. on HbA1c in diabetic dbdb-mice, represented as change from baseline (0%, day ⁇ 7). Data are mean ⁇ SEM.
  • FIG. 6 Effect of 4 weeks of treatment with SEQ ID NO: 10 at 3 and 10 ⁇ g/kg, s.c. on oral glucose tolerance in diabetic dbdb-mice, represented as area under the glucose curve (Glucose-AUC). Data are mean ⁇ SEM.
  • FIG. 7 Effect of treatment with SEQ ID NO: 13 at 3 ⁇ g/kg, s.c. on glucose lowering in non-fasted female diabetic dbdb-mice, represented as change from baseline. Data are mean ⁇ SEM.
  • FIG. 8 Effect of s.c. administration of compound SEQ ID NO: 10, 1, 10 and 100 ⁇ g/kg on gastric emptying and intestinal passage in female NMRI-mice. Data are mean ⁇ SEM.
  • FIG. 9 Effect of s.c. administration of compound SEQ ID NO: 10 at 3 and 10 ⁇ g/kg on 22-hours feed intake in female NMRI-mice. Data are mean ⁇ SEM. *p ⁇ 0.05.
  • Rink-Amide resins (4-(2′,4′-Dimethoxyphenyl-Fmoc-aminomethyl)-phenoxyacetamido-norleucylaminomethyl resin, Merck Biosciences; 4-[(2,4-Dimethoxyphenyl)(Fmoc-amino)methyl]phenoxy acetamido methyl resin, Agilent Technologies) were used for the synthesis of peptide amides with loadings in the range of 0.3-0.4 mmol/g.
  • Fmoc protected natural amino acids were purchased from Protein Technologies Inc., Senn Chemicals, Merck Biosciences, Novabiochem, Iris Biotech or Bachem. The following standard amino acids were used throughout the syntheses: Fmoc-L-Ala-OH, Fmoc-Arg(Pbf)-OH, Fmoc-L-Asn(Trt)-OH, Fmoc-L-Asp(OtBu)-OH, Fmoc-L-Cys(Trt)-OH, Fmoc-L-Gln(Trt)-OH, Fmoc-L-Glu(OtBu)-OH, Fmoc-Gly-OH, Fmoc-L-His(Trt)-OH, Fmoc-L-Ile-OH, Fmoc-L-Leu-OH, Fmoc-L-Lys(Boc)-OH, Fmoc-L-Met-OH, Fmoc-L-
  • the solid phase peptide syntheses were performed for example on a Prelude Peptide Synthesizer (Protein Technologies Inc) or similar automated synthesizer using standard Fmoc chemistry and HBTU/DIPEA activation. DMF was used as the solvent. Deprotection: 20% piperidine/DMF for 2 ⁇ 2.5 min. Washes: 7 ⁇ DMF. Coupling 2:5:10 200 mM AA/500 mM HBTU/2M DIPEA in DMF 2 ⁇ for 20 min. Washes: 5 ⁇ DMF.
  • Fmoc-L-Lys(ivDde)-OH or Fmoc-L-Lys(Mmt)-OH was used in the corresponding position.
  • the ivDde group was removed according to a modified literature procedure (S. R. Chhabra et al., Tetrahedron Lett. 39, (1998), 1603), using 4% hydrazine hydrate in DMF.
  • the Mmt group was removed by repeated treatment with 1% TFA in dichloromethane.
  • the following acylations were carried out by treating the resin with the N-hydroxy succinimide esters of the desired acid or using coupling reagents like HBTU/DIPEA or HOBt/DIC.
  • a Waters LCT Premier Time-of-Flight instrument was used as mass analyser equipped with an electrospray in the positive ion mode.
  • the crude peptides were purified either on an Akta Purifier System or on a Jasco semiprep HPLC System. Preparative RP-C18-HPLC columns of different sizes and with different flow rates were used depending on the amount of crude peptide to be purified. Acetonitrile+0.05 to 0.1% TFA (B) and water+0.05 to 0.1% TFA (A) were employed as eluents. Alternatively, a buffer system consisting of acetonitrile and water with minor amounts of acetic acid was used. Product-containing fractions were collected and lyophilized to obtain the purified product, typically as TFA or acetate salt.
  • the target concentration was 1.0 mg/mL pure compound. Therefore, solutions from solid samples were prepared in different buffer systems with a concentration of 1.0 mg/mL compound based on the previously determined content. HPLC-UV was performed after 2 h of gentle agitation from the supernatant, which was obtained by 20 min of centrifugation at 4000 rpm.
  • solubility was then determined by comparison with the UV peak areas obtained with a stock solution of the peptide at a concentration of 2 mg/mL in pure water or a variable amount of acetonitrile (optical control that all of the compound was dissolved). This analysis also served as starting point (t0) for the stability testing.
  • the amount of soluble degradation products was calculated from the comparison of the sum of the peak areas from all observed impurities reduced by the sum of peak areas observed at t0 (i.e. to determine the amount of newly formed peptide-related species). This value was given in percentual relation to the initial amount of peptide at t0, following the equation:
  • % soluble degradation products ⁇ [(peak area sum of impurities t 7) ⁇ (peak area sum of impurities t 0)] ⁇ 100 ⁇ /peak area peptide t 0
  • This precipitate includes non-soluble degradation products, polymers and/or fibrils, which have been removed from analysis by centrifugation.
  • the chemical stability is expressed as “% remaining peptide”.
  • Agonism of compounds for the receptors was determined by functional assays measuring cAMP response of HEK-293 cell lines stably expressing human GIP, GLP-1 or glucagon receptor.
  • cAMP content of cells was determined using a kit from Cisbio Corp. (cat. no. 62AM4PEC) based on HTRF (Homogenous Time Resolved Fluorescence).
  • HTRF Homogenous Time Resolved Fluorescence
  • cells were split into T175 culture flasks and grown overnight to near confluency in medium (DMEM/10% FBS). Medium was then removed and cells washed with PBS lacking calcium and magnesium, followed by proteinase treatment with accutase (Sigma-Aldrich cat. no. A6964). Detached cells were washed and resuspended in assay buffer (1 ⁇ HBSS; 20 mM HEPES, 0.1% BSA, 2 mM IBMX) and cellular density determined.
  • test compound in assay buffer was added to the wells, followed by incubation for 30 minutes at room temperature.
  • HTRF reagents diluted in lysis buffer (kit components)
  • the plates were incubated for 1 hr, followed by measurement of the fluorescence ratio at 665/620 nm.
  • In vitro potency of agonists was quantified by determining the concentrations that caused 50% activation of maximal response (EC50).
  • mice were dosed 1 mg/kg subcutaneously (s.c.). The mice were sacrificed and blood samples were collected after 0.25, 0.5, 1, 2, 4, 8, 16 and 24 hours post application. Plasma samples were analyzed after protein precipitation via liquid chromatography mass spectrometry (LC/MS). PK parameters and half-life were calculated using WinonLin Version 5.2.1 (non-compartment model).
  • mice Female Gottinger minipigs were dosed 0.1 mg/kg subcutaneously (s.c.). Blood samples were collected after 0.25, 0.5, 1, 2, 4, 8, 24, 32, 48, 56 and 72 hours post application. Plasma samples were analyzed after protein precipitation via liquid chromatography mass spectrometry (LC/MS). PK parameters and half-life were calculated using WinonLin Version 5.2.1 (non-compartment model).
  • Method F AB Sciex API 4000, mass analyser: electrospray positive ion mode
  • mice Female NMRI-mice of a body weight between 20 and 30 g were used. Mice were adapted to housing conditions for at least one week.
  • mice were overnight fasted, while water remained available all the time. On the study day, mice were weighed, single-caged and allowed access to 500 mg of feed for 30 min, while water was removed. At the end of the 30 min feeding period, remaining feed was removed and weighed. Then, the test compound/reference compound or its vehicle in the control group was administered subcutaneously. 60 min later, to allow the compound to reach relevant plasma exposure, a coloured, non-caloric bolus was instilled via gavage into the stomach. After another 30 min, the animals were sacrificed and the stomach and the small intestine prepared. The filled stomach was weighed, emptied, carefully cleaned and dried and reweighed.
  • the stomach content calculated as weight of filled subtracted by the weight of emptied stomach, indicated the degree of gastric emptying.
  • the small intestine was straightened without force and measured in length. Then the distance from the gastric beginning of the gut to the tip of the farthest travelled intestinal content bolus was measured. The intestinal passage was given as ratio in percent of the latter distance and the total length of the small intestine.
  • mice Female NMRI-mice of a body weight between 20 and 30 g were used. Mice were adapted to housing conditions for at least one week and for at least one day single-caged in the assessment equipment, when basal data were recorded simultaneously. On the study day, test product was administered subcutaneously close to the lights-off phase (12 h lights off) and assessment of feed consumption was directly started afterwards. Assessment included continued monitoring over 22 hours, while data are processed as mean over every 30 min. Repetition of this procedure over several days was possible. Restriction of assessment to 22 hours was for practical reasons to allow for reweighing of animals, refilling of feed and water and drug administration between procedures. Results could be assessed as cumulated data over 22 hours or differentiated to 30 min intervals. Comparable data can be obtained for both female and male mice.
  • mice were subcutaneously (s.c.) injected with vehicle solution and weighed for 3 days to acclimate them to the procedures.
  • Acute effect on blood glucose in fed DIO mice initial blood samples were taken just before first administration (s.c.) of vehicle (phosphate buffer solution) or the exendin-4 derivatives at doses of 10, 30 and 100 ⁇ g/kg (dissolved in phosphate puffer), respectively. The volume of administration was 5 mL/kg. The animals had access to water and their corresponding diet during the experiment, food consumption was determined at all time points of blood sampling.
  • vehicle phosphate buffer solution
  • exendin-4 derivatives dissolved in phosphate puffer
  • mice were subcutaneously (s.c.) injected with vehicle solution and weighed for 3 days to acclimate them to the procedures.
  • Subchronic effect on body weight all animals were treated once daily s.c. late afternoon, at the end of the light phase (LD 12:12) with either vehicle or exendin-4 derivatives at the above-mentioned doses for 3 weeks. Body weight was recorded daily.
  • mice Female BKS.Cg-m+/+Leprdb/J (db/db) and BKS.Cg-m+/+Leprdb/+(lean control) mice were obtained from Charles River Laboratories, Germany, at an age of 9-10 weeks. The animals were housed in groups in a specific pathogen-free barrier facility on a 12-h light/dark cycle with free access to water and rodent-standard chow.
  • blood samples were drawn from the tail without anaesthesia and blood glucose (method: d-glucose hexokinase, hemolysate, AU640 Beckman Coulter) and HbA1c level (method: hemolysate, Cobas6000 c501, Roche Diagnostics, Germany) were determined.
  • HbA1c is a glycosylated form of haemoglobin whose level reflects the average level of glucose to which the erythrocyte has been exposed during its lifetime. In mice, HbA1c is a relevant biomarker for the average blood glucose level during the preceding 4 weeks (erythrocyte life span in mouse 47 days).
  • mice 8 week old, female diabetic dbdb-mice of mean non-fasted glucose value of 14.5 mmol/l and a body weight of 37-40 g were used. Mice were individually marked and were adapted to housing conditions for at least one week.
  • mice Female diabetic dbdb-mice of mean non-fasted glucose value of 20-22 mmol/l and a body weight of 42 g+/ ⁇ 0.6 g (SEM) were used. Mice were individually marked and were adapted to housing conditions for at least one week.
  • mice were assigned to groups and cages (4 mice per cage, 8 per group) according to their non-fasted glucose values to ensure even distribution of lower and higher values between groups (stratification).
  • t 0
  • t 0
  • t 0
  • a first blood sample at a tail incision was drawn (baseline). Further blood samples were drawn at the tail incision at 30, 60, 90, 120, 240, 360, and 480 min.
  • the solid phase synthesis was carried out on Novabiochem Rink-Amide resin (4-(2′,4′-Dimethoxyphenyl-Fmoc-aminomethyl)-phenoxyacetamido-norleucylaminomethyl resin), 100-200 mesh, loading of 0.34 mmol/g.
  • the Fmoc-synthesis strategy was applied with HBTU/DIPEA-activation. In position 1 Boc-Tyr(tBu)-OH and in position 14 Fmoc-Lys(ivDde)-OH was used in the solid phase synthesis protocol.
  • the ivDde-group was cleaved from the peptide on resin according to a modified literature procedure (S. R.
  • the solid phase synthesis was carried out on Novabiochem Rink-Amide resin (4-(2′,4′-Dimethoxyphenyl-Fmoc-aminomethyl)-phenoxyacetamido-norleucylaminomethyl resin), 100-200 mesh, loading of 0.34 mmol/g.
  • the Fmoc-synthesis strategy was applied with HBTU/DIPEA-activation. In position 1 Boc-Tyr(tBu)-OH and in position 14 Fmoc-Lys(ivDde)-OH was used in the solid phase synthesis protocol.
  • the ivDde-group was cleaved from the peptide on resin according to a modified literature procedure (S. R.
  • the solid phase synthesis was carried out on Novabiochem Rink-Amide resin (4-(2′,4′-Dimethoxyphenyl-Fmoc-aminomethyl)-phenoxyacetamido-norleucylaminomethyl resin), 100-200 mesh, loading of 0.34 mmol/g.
  • the Fmoc-synthesis strategy was applied with HBTU/DIPEA-activation. In position 1 Boc-Tyr(tBu)-OH and in position 14 Fmoc-Lys(ivDde)-OH was used in the solid phase synthesis protocol.
  • the ivDde-group was cleaved from the peptide on resin according to a modified literature procedure (S. R.
  • Solubility Solubility (pH 4.5) (pH 7.4) (pH 4.5) (pH 7.4) SEQ ID NO: [%] [%] [ ⁇ g/ml] [ ⁇ g/ml] 1 (Exendin-4) 100.0 77.5 933.6 1000 10 99.0 97.0 120.3 >1000 13 Not determined 84.0 688.0 824.0
  • Potencies of peptidic compounds at the GLP-1, GIP and glucagon receptors were determined by exposing cells expressing human glucagon receptor (hGLUC R), human GIP (hGIP R) and human GLP-1 receptor (hGLP-1 R) to the listed compounds at increasing concentrations and measuring the formed cAMP as described in Methods.
  • mice Female obese C57BL/6NCrl mice were treated for 3 weeks once daily subcutaneously in the late afternoon, prior to the end of the light phase (12 h lights on) with 3 ⁇ g/kg and 10 ⁇ g/kg SEQ ID NO: 10 or vehicle. Body weight was recorded daily.
  • SEQ ID NO: 10 prevented an increase of HbA1c in a statistical significant manner compared to vehicle control at the 10 ⁇ g/kg dose ( FIG. 4 ; p ⁇ 0.05, 1-way-ANOVA, followed by Dunnett's post-hoc test).
  • FIG. 5 Treatment with SEQ ID NO: 10 lead to improved oral glucose tolerance ( FIG. 5 ; represented as normalized to 0 mmol/l at 0 min), and reduction of AUC under the glucose curve reached statistical significance at 10 ⁇ g/kg compared to vehicle control ( FIG. 6 ; p ⁇ 0.05, 1-way-ANOVA, followed by Dunnett's post-hoc test).
  • Female dbdb-mice received 3 ⁇ g/kg of SEQ ID NO: 13 or phosphate buffered saline (vehicle control) subcutaneously, at time 0 min.
  • the compound immediately lowered glucose values (baseline at 20-22 mmol/l), reaching the maximal effect of ⁇ 12 mmol/l glucose reduction, at 240 min and keeping it to the end of observation at 480 min ( FIG. 7 ).
  • Female NMRI-mice weighing on average 25-30 g, received 1, 10 and 100 ⁇ g/kg of SEQ ID NO: 10, or phosphate buffered saline (vehicle control) subcutaneously, 30 min prior to the administration of the coloured bolus. 30 min later, the assessment of stomach contents and intestinal passage was done ( FIG. 8 ).
  • SEQ ID NO: 10 reduced intestinal passage by 28, 58 and 64% (p ⁇ 0.0001) and increased remaining gastric contents by 1, 28 and 68% (p ⁇ 0.0001 versus vehicle control, 1-W-ANOVA, followed by Dunnett's post-hoc test) respectively.

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Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9255154B2 (en) 2012-05-08 2016-02-09 Alderbio Holdings, Llc Anti-PCSK9 antibodies and use thereof
US9365632B2 (en) 2012-10-09 2016-06-14 Sanofi Exendin-4 derivatives as dual GLP1/glucagon agonists
US9670261B2 (en) 2012-12-21 2017-06-06 Sanofi Functionalized exendin-4 derivatives
US9694053B2 (en) 2013-12-13 2017-07-04 Sanofi Dual GLP-1/glucagon receptor agonists
US9751926B2 (en) 2013-12-13 2017-09-05 Sanofi Dual GLP-1/GIP receptor agonists
US9750788B2 (en) 2013-12-13 2017-09-05 Sanofi Non-acylated exendin-4 peptide analogues
US9758561B2 (en) 2014-04-07 2017-09-12 Sanofi Dual GLP-1/glucagon receptor agonists derived from exendin-4
US9771406B2 (en) 2014-04-07 2017-09-26 Sanofi Peptidic dual GLP-1/glucagon receptor agonists derived from exendin-4
US9775904B2 (en) 2014-04-07 2017-10-03 Sanofi Exendin-4 derivatives as peptidic dual GLP-1/glucagon receptor agonists
US9789165B2 (en) 2013-12-13 2017-10-17 Sanofi Exendin-4 peptide analogues as dual GLP-1/GIP receptor agonists
US9932381B2 (en) 2014-06-18 2018-04-03 Sanofi Exendin-4 derivatives as selective glucagon receptor agonists
US9982029B2 (en) 2015-07-10 2018-05-29 Sanofi Exendin-4 derivatives as selective peptidic dual GLP-1/glucagon receptor agonists
US10806797B2 (en) 2015-06-05 2020-10-20 Sanofi Prodrugs comprising an GLP-1/glucagon dual agonist linker hyaluronic acid conjugate
US10894076B2 (en) 2015-12-29 2021-01-19 Pegbio Co., Ltd. Composition comprising GLP-1 receptor agonist and glucagon receptor agonist and application thereof
US11160869B2 (en) 2019-08-16 2021-11-02 Applied Molecular Transport Inc. Compositions, formulations and interleukin production and purification
CN114848799A (zh) * 2015-05-28 2022-08-05 免疫新炉有限公司 用于肌肉减少症治疗的包括胰高血糖素样肽-1受体激动剂的药物组合物
US11485753B2 (en) 2012-12-21 2022-11-01 Janssen Pharmaceutica Nv Substituted nucleosides, nucleotides and analogs thereof
US12215133B2 (en) 2021-03-25 2025-02-04 Brightgene Bio-Medical Technology Co., Ltd. GIP and GLP-1 dual receptor agonist, pharmaceutical composition, and use
US12303604B1 (en) 2024-10-16 2025-05-20 Currax Pharmaceuticals Llc Pharmaceutical formulations comprising naltrexone and/or bupropion

Families Citing this family (79)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
UA111305C2 (uk) 2012-12-21 2016-04-11 Пфайзер Інк. Конденсовані лактами арилу та гетероарилу
MX388826B (es) 2013-05-28 2025-03-20 Scohia Pharma Inc Compuesto peptidico.
EA035688B1 (ru) * 2013-11-06 2020-07-27 Зилэнд Фарма А/С Соединения, которые представляют собой тройные агонисты глюкагона, glp-1 и gip
BR112016009889B1 (pt) 2013-11-06 2023-11-28 Zealand Pharma A/S Análogo do gip, composição farmacêutica compreendendo um análogo do gip, ou um sal farmaceuticamente aceitável do mesmo, e seu uso
UA118380C2 (uk) 2014-06-17 2019-01-10 Пфайзер Інк. Заміщені сполуки дигідроізохінолінону
DK3212218T3 (da) 2014-10-29 2021-08-30 Zealand Pharma As GIP-agonistforbindelser og fremgangsmåder
PE20230304A1 (es) 2014-12-30 2023-02-13 Hanmi Pharm Ind Co Ltd Derivados de glucagon como agentes hipoglucemicos y antiobesidad
JOP20200119A1 (ar) 2015-01-09 2017-06-16 Lilly Co Eli مركبات مساعد مشترك من gip وglp-1
US10993993B2 (en) 2015-05-28 2021-05-04 Immunoforge Co., Ltd. Pharmaceutical composition for treating muscle atrophy or sarcopenia including glucagon-like peptide (GLP-1) or GLP-1 receptor agonist
WO2016198624A1 (en) * 2015-06-12 2016-12-15 Sanofi Exendin-4 derivatives as trigonal glp-1/glucagon/gip receptor agonists
CN108025041A (zh) 2015-06-30 2018-05-11 韩美药品株式会社 胰高血糖素衍生物和包含其长效缀合物的组合物
TWI622596B (zh) 2015-10-26 2018-05-01 美國禮來大藥廠 升糖素受體促效劑
PL3389697T3 (pl) 2015-12-14 2021-04-19 Antaros Medical Ab Selektywni agoniści receptora glukagonu zawierający ugrupowanie chelatujące do celów obrazowania
DK3393496T5 (da) 2015-12-23 2024-09-16 Univ Johns Hopkins Long-acting glp-1r agonist as a therapy of neurological and neurodegenerative conditions
HK1258177A1 (en) * 2015-12-31 2019-11-08 Hanmi Pharm. Co., Ltd. Persistent conjugate of triple activator activating glucagon, glp-1 and gip receptor
EA201891946A1 (ru) * 2016-03-10 2019-04-30 Медиммун Лимитед Коагонисты глюкагона и glp-1 для лечения ожирения
CN109477094B (zh) 2016-05-24 2022-04-26 武田药品工业株式会社 肽化合物
SG11201811697SA (en) 2016-06-29 2019-01-30 Hanmi Pharmaceutical Co Ltd Glucagon derivative, conjugate thereof, composition comprising same and therapeutic use thereof
TW201821434A (zh) * 2016-10-10 2018-06-16 法商賽諾菲公司 製備包含親脂性修飾的離胺酸側鏈的肽的方法
US10774127B2 (en) * 2016-10-12 2020-09-15 University Of Copenhagen Peptide dual agonists of GIPR and GLP2R
AR110301A1 (es) * 2016-12-02 2019-03-13 Sanofi Sa Compuestos como agonistas peptídicos de receptores de glp1 / glucagón / gip
AR110300A1 (es) * 2016-12-02 2019-03-13 Sanofi Sa Compuestos como agonistas peptídicos trigonales de los receptores de glp1 / glucagón / gip
TW201832783A (zh) 2016-12-02 2018-09-16 法商賽諾菲公司 包含ｇｌｐ－１／胰高血糖素雙重激動劑、連接子和透明質酸的接合物
US10392366B2 (en) 2017-02-21 2019-08-27 Sanofi Azetidine compounds as GPR119 modulators for the treatment of diabetes, obesity, dyslipidemia and related disorders
JOP20180028A1 (ar) 2017-03-31 2019-01-30 Takeda Pharmaceuticals Co مركب ببتيد
AR112760A1 (es) * 2017-07-19 2019-12-11 Novo Nordisk As Compuestos bifuncionales que comprenden un análogo de glp-1 y un análogo de egf(a)
KR102686854B1 (ko) 2017-08-09 2024-07-18 사노피 지방간 질환 및 지방간염의 치료에서의 glp-1/글루카곤 수용체 작용제
CN115304666B (zh) * 2017-11-24 2025-09-19 浙江道尔生物科技有限公司 一种治疗代谢疾病的胰高血糖素类似物
GB201720187D0 (en) 2017-12-04 2018-01-17 Imperial Innovations Ltd Novel Compounds
DK3774862T3 (da) 2018-04-05 2022-09-05 Sun Pharmaceutical Ind Ltd Nye GLP-1-analoger
CA3096495A1 (en) 2018-04-10 2019-10-17 Sanofi-Aventis Deutschland Gmbh Lixisenatide synthesis with capping
US11560402B2 (en) 2018-04-10 2023-01-24 Sanofi-Aventis Deutschland Gmbh Method for cleavage of solid phase-bound peptides from the solid phase
TWI829687B (zh) 2018-05-07 2024-01-21 丹麥商諾佛 儂迪克股份有限公司 包含glp-1促效劑與n-(8-(2-羥基苯甲醯基)胺基)辛酸之鹽的固體組成物
UY38249A (es) 2018-05-30 2019-12-31 Sanofi Sa Productos conjugados que comprenden un agonista del receptor triple de glp-1/glucagón/gip, un conector y ácido hialurónico
TWI749381B (zh) * 2018-11-01 2021-12-11 美商美國禮來大藥廠 蛋白質酪胺酸-酪胺酸類似物及其使用方法
KR102119188B1 (ko) * 2018-11-13 2020-06-08 이뮤노포지 주식회사 글루카곤 유사 펩타이드-1(glp-1), glp-1 유래 펩타이드, 또는 glp-1 분해 억제제를 포함하는 근감소증 또는 근위축증 치료용 약학 조성물
WO2020130749A1 (ko) * 2018-12-21 2020-06-25 한미약품 주식회사 글루카곤, glp-1 및 gip 수용체 모두에 활성을 갖는 삼중 활성체 및 인슐린을 포함하는 약학 조성물
US20220153853A1 (en) 2018-12-21 2022-05-19 Jiangsu Hengrui Medicine Co., Ltd. Bispecific protein
JP7324530B2 (ja) * 2019-01-07 2023-08-10 鴻緒生物医葯科技（北京）有限公司 新型ポリペプチド及びその治療用途
US20220168396A1 (en) * 2019-04-11 2022-06-02 Jiangsu Hansoh Pharmaceutical Group Co., Ltd. Multi-receptor agonist and medical use thereof
WO2020214012A1 (ko) * 2019-04-19 2020-10-22 한미약품 주식회사 글루카곤, glp-1 및 gip 수용체 모두에 활성을 갖는 삼중 활성체 또는 이의 결합체를 포함하는 고지혈증 예방 또는 치료용 약학적 조성물 및 예방 또는 치료 방법
WO2020214013A1 (ko) * 2019-04-19 2020-10-22 한미약품 주식회사 글루카곤, glp-1 및 gip 수용체 모두에 활성을 갖는 삼중 활성체 또는 이의 결합체의 고지혈증에 대한 치료적 용도
GB201908424D0 (en) 2019-06-12 2019-07-24 Imp College Innovations Ltd Novel compounds
CN111040022B (zh) * 2019-12-23 2021-12-14 万新医药科技(苏州)有限公司 针对胰高血糖素样肽-1受体、胰高血糖素受体、以及抑胃肽受体的三重激动剂
BR112022014397A2 (pt) * 2020-01-23 2022-10-11 Lilly Co Eli Compostos co-agonistas de gip/glp1
MX2022011089A (es) 2020-03-06 2022-10-03 Sanofi Sa Peptidos como agonistas selectivos del receptor de gip.
AU2021250319A1 (en) 2020-03-31 2022-12-01 Antaros Medical Ab Selective GIP receptor agonists comprising a chelating moiety for imaging and therapy purposes
EP4140496A4 (en) * 2020-04-20 2024-05-22 Hanmi Pharm. Co., Ltd. PREVENTIVE OR THERAPEUTIC COMPOSITION FOR HYPERLIPIDEMIA WITH TRIPLE AGONIST ACTING ON GLUCAGON, GLP-1 AND GIP RECEPTORS
JP2023526973A (ja) * 2020-05-29 2023-06-26 北京拓界生物医薬科技有限公司 Ｇｌｐ－１とｇｉｐ受容体二重アゴニスト化合物及びその応用
CN116133677A (zh) * 2020-07-06 2023-05-16 鸿绪生物医药科技（北京）有限公司 新型多肽制剂及其治疗用途
CA3185229A1 (en) * 2020-07-06 2022-01-13 Jie Han Novel polypeptide and therapeutic use thereof
TW202315883A (zh) 2020-07-22 2023-04-16 丹麥商諾佛 儂迪克股份有限公司 適用於口服的glp-1及gip受體共促效劑
WO2022018185A1 (en) 2020-07-22 2022-01-27 Novo Nordisk A/S Glp-1 and gip receptor co-agonists
WO2022034062A1 (en) * 2020-08-12 2022-02-17 Txp Pharma Ag Exendin-4 peptide analogues
JP2023550594A (ja) 2020-10-30 2023-12-04 ノヴォ ノルディスク アー／エス Ｇｌｐ－１、ｇｉｐ、およびグルカゴン受容体三重作動薬
CN114617956B (zh) * 2020-12-10 2023-10-03 江苏中新医药有限公司 一种高效降糖的蛋白质药物
JP2024511107A (ja) * 2021-03-25 2024-03-12 ブライトジーン バイオ－メディカル テクノロジー カンパニー リミテッド Ｇｉｐとｇｌｐ－１の二重受容体作動薬、医薬組成物および使用
CA3219647A1 (en) * 2021-05-26 2022-12-01 The United Bio-Technology (Hengqin) Co., Ltd. Multi agonists and use thereof
WO2022262837A1 (zh) * 2021-06-18 2022-12-22 北京拓界生物医药科技有限公司 胰高血糖素类似物及其医药用途
CN115572326B (zh) * 2021-06-21 2025-01-10 广东东阳光药业股份有限公司 Glp-1、gcg和gip受体的三重激动剂
TW202313667A (zh) * 2021-07-30 2023-04-01 大陸商南京明德新藥研發有限公司 含內醯胺橋的多肽化合物
JP2024536727A (ja) 2021-09-06 2024-10-08 サノフイ 強力で選択的なｇｉｐ受容体アゴニストとしての新規のペプチド
CA3237796A1 (en) * 2021-11-12 2023-05-19 Zhenbin Li Pharmaceutical composition of glp-1 receptor and gip receptor dual agonist, and use thereof
CA3239474A1 (en) * 2021-12-01 2023-06-08 Hua He Pharmaceutical composition of glp-1 and gip receptor dual agonist and use thereof
TW202330584A (zh) 2022-01-20 2023-08-01 丹麥商諾佛 儂迪克股份有限公司 前藥及其用途
CN117603364A (zh) * 2022-09-30 2024-02-27 广西医科大学附属肿瘤医院 一类GLP-1/glucagon/Y2受体三重激动剂及其应用
WO2024165571A2 (en) 2023-02-06 2024-08-15 E-Therapeutics Plc Inhibitors of expression and/or function
KR20250152096A (ko) * 2023-02-24 2025-10-22 아이피2아이피오 이노베이션스 리미티드 화합물
GB202302686D0 (en) * 2023-02-24 2023-04-12 Imperial College Innovations Ltd Novel compounds
AU2024291989A1 (en) * 2023-07-14 2026-01-15 Jiangsu Hengrui Pharmaceuticals Co., Ltd. Glp-1, gip and gcg receptor triagonist and use thereof
CN120329412A (zh) * 2023-11-06 2025-07-18 成都奥达生物科技有限公司 一种三激动剂化合物
WO2025125576A2 (en) 2023-12-15 2025-06-19 E-Therapeutics Plc Inhibitors of expression and/or function
EP4686757A1 (en) 2024-07-31 2026-02-04 e-therapeutics PLC Inhibitors of expression and/or function
WO2025133348A1 (en) 2023-12-22 2025-06-26 E-Therapeutics Plc Inhibitors of expression and/or function
WO2025162423A1 (zh) * 2024-02-02 2025-08-07 杭州先为达生物科技股份有限公司 针对glp-1r、gipr和gcgr的三激动剂
WO2025176999A2 (en) * 2024-02-23 2025-08-28 Ip2Ipo Innovations Limited Novel compounds
WO2025196502A1 (en) 2024-03-20 2025-09-25 North Carolina Agricultural & Technical State University Choline kinase inhibitors as a therapeutic treatment for obesity
WO2025219590A1 (en) 2024-04-19 2025-10-23 Actimed Therapeutics Ltd Beta-blockers for preserving muscle mass, bone density, and cardiac function in weight loss treatments
CN118440155B (zh) * 2024-07-11 2024-11-22 中国药科大学 一种双激动多肽化合物及其医药用途

Family Cites Families (437)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6284727B1 (en) 1993-04-07 2001-09-04 Scios, Inc. Prolonged delivery of peptides
NZ250844A (en) 1993-04-07 1996-03-26 Pfizer Treatment of non-insulin dependant diabetes with peptides; composition
US5424286A (en) 1993-05-24 1995-06-13 Eng; John Exendin-3 and exendin-4 polypeptides, and pharmaceutical compositions comprising same
US5641757A (en) 1994-12-21 1997-06-24 Ortho Pharmaceutical Corporation Stable 2-chloro-2'-deoxyadenosine formulations
CA2262647C (en) 1996-08-08 2007-12-04 Amylin Pharmaceuticals, Inc. Methods for regulating gastrointestinal motility
CA2264243C (en) 1996-08-30 2004-10-05 Novo Nordisk A/S Glp-1 derivatives
US6458924B2 (en) 1996-08-30 2002-10-01 Novo Nordisk A/S Derivatives of GLP-1 analogs
CA2277112C (en) 1997-01-07 2008-08-26 Amylin Pharmaceuticals, Inc. Use of exendins and agonists thereof for the reduction of food intake
US7312196B2 (en) 1997-01-08 2007-12-25 Amylin Pharmaceuticals, Inc. Formulations for amylin agonist peptides
US6410511B2 (en) 1997-01-08 2002-06-25 Amylin Pharmaceuticals, Inc. Formulations for amylin agonist peptides
US6723530B1 (en) 1997-02-05 2004-04-20 Amylin Pharmaceuticals, Inc. Polynucleotides encoding proexendin, and methods and uses thereof
EP1019077B2 (en) 1997-08-08 2010-12-22 Amylin Pharmaceuticals, Inc. Novel exendin agonist compounds
US7157555B1 (en) 1997-08-08 2007-01-02 Amylin Pharmaceuticals, Inc. Exendin agonist compounds
US7220721B1 (en) 1997-11-14 2007-05-22 Amylin Pharmaceuticals, Inc. Exendin agonist peptides
US7223725B1 (en) 1997-11-14 2007-05-29 Amylin Pharmaceuticals, Inc. Exendin agonist compounds
DK1032587T4 (da) 1997-11-14 2013-04-08 Amylin Pharmaceuticals Llc Hidtil ukendte exendinagonist-forbindelser
NZ504258A (en) 1997-11-14 2002-12-20 Amylin Pharmaceuticals Inc Exendin 3 and 4 agonist compounds for the treatment of diabetes
ES2316161T3 (es) 1998-01-09 2009-04-01 Amylin Pharmaceuticals, Inc. Formulaciones para peptidos agonistas de amilina con insulina.
US6703359B1 (en) 1998-02-13 2004-03-09 Amylin Pharmaceuticals, Inc. Inotropic and diuretic effects of exendin and GLP-1
WO1999043708A1 (en) 1998-02-27 1999-09-02 Novo Nordisk A/S Glp-1 derivatives of glp-1 and exendin with protracted profile of action
EP1950223A3 (en) 1998-03-09 2009-05-13 Zealand Pharma A/S Pharmacologically active peptide conjugates having a reduced tendency towards enzymatic hydrolysis
EP1061947B1 (en) 1998-03-13 2004-06-16 Novo Nordisk A/S Stabilized aqueous glucagon solutions comprising detergents
US6998387B1 (en) 1998-03-19 2006-02-14 Amylin Pharmaceuticals, Inc. Human appetite control by glucagon-like peptide receptor binding compounds
ID28617A (id) 1998-06-12 2001-06-21 Bionebraska Inc Peptida jenis-1 glukagon yang meningkatkan respon sel-b terhadap glukosa pada subyek yang mengalami kerusakan toleransi glukosa
CA2339326A1 (en) 1998-08-10 2000-02-24 Josephine Egan Differentiation of non-insulin producing cells into insulin producing cells by glp-1 or exendin-4 and uses thereof
JP2002524514A (ja) 1998-09-17 2002-08-06 イーライ・リリー・アンド・カンパニー タンパク質製剤
US6429197B1 (en) 1998-10-08 2002-08-06 Bionebraska, Inc. Metabolic intervention with GLP-1 or its biologically active analogues to improve the function of the ischemic and reperfused brain
US7259136B2 (en) 1999-04-30 2007-08-21 Amylin Pharmaceuticals, Inc. Compositions and methods for treating peripheral vascular disease
US6284725B1 (en) 1998-10-08 2001-09-04 Bionebraska, Inc. Metabolic intervention with GLP-1 to improve the function of ischemic and reperfused tissue
WO2000037098A1 (en) 1998-12-22 2000-06-29 Eli Lilly And Company Shelf-stable formulation of glucagon-like peptide-1
US7399489B2 (en) 1999-01-14 2008-07-15 Amylin Pharmaceuticals, Inc. Exendin analog formulations
US6902744B1 (en) 1999-01-14 2005-06-07 Amylin Pharmaceuticals, Inc. Exendin agonist formulations and methods of administration thereof
ATE460942T1 (de) 1999-01-14 2010-04-15 Amylin Pharmaceuticals Inc Exendine zur glucagon suppression
US20030087820A1 (en) 1999-01-14 2003-05-08 Young Andrew A. Novel exendin agonist formulations and methods of administration thereof
WO2000055119A1 (en) 1999-03-17 2000-09-21 Novo Nordisk A/S Method for acylating peptides and novel acylating agents
US6451974B1 (en) 1999-03-17 2002-09-17 Novo Nordisk A/S Method of acylating peptides and novel acylating agents
NZ514916A (en) 1999-04-30 2004-06-25 Amylin Pharmaceuticals Inc Exendins and exendin agonists linked to polyethylene glycol polymers
US6924264B1 (en) 1999-04-30 2005-08-02 Amylin Pharmaceuticals, Inc. Modified exendins and exendin agonists
US6849714B1 (en) 1999-05-17 2005-02-01 Conjuchem, Inc. Protection of endogenous therapeutic peptides from peptidase activity through conjugation to blood components
US6514500B1 (en) 1999-10-15 2003-02-04 Conjuchem, Inc. Long lasting synthetic glucagon like peptide {GLP-!}
US6887470B1 (en) 1999-09-10 2005-05-03 Conjuchem, Inc. Protection of endogenous therapeutic peptides from peptidase activity through conjugation to blood components
CA2363712C (en) 1999-05-17 2011-05-10 Conjuchem Inc. Long lasting insulinotropic peptides
US6482799B1 (en) 1999-05-25 2002-11-19 The Regents Of The University Of California Self-preserving multipurpose ophthalmic solutions incorporating a polypeptide antimicrobial
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
US6972319B1 (en) 1999-09-28 2005-12-06 Bayer Pharmaceuticals Corporation Pituitary adenylate cyclase activating peptide (PACAP)receptor 3 (R3) agonists and their pharmacological methods of use
GB9930882D0 (en) 1999-12-30 2000-02-23 Nps Allelix Corp GLP-2 formulations
CA2396157A1 (en) 2000-01-10 2001-07-19 Amylin Pharmaceuticals, Inc. Use of exendins and agonists thereof for modulation of triglyceride levels and treatment of dyslipidemia
CN1487836A (zh) 2000-03-14 2004-04-07 埃米林药品公司 胰高糖素样肽1(7-36)对胃窦幽门十二指肠能动性的影响
CA2380423A1 (en) 2000-05-17 2001-11-22 Bionebraska, Inc. Peptide pharmaceutical formulations
ATE397938T1 (de) 2000-05-19 2008-07-15 Amylin Pharmaceuticals Inc Behandlung des akuten koronaren syndroms mit glp- 1
JP4624642B2 (ja) 2000-08-18 2011-02-02 エミスフェアー・テクノロジーズ・インク 活性剤デリバリー用化合物および組成物
US7507714B2 (en) 2000-09-27 2009-03-24 Bayer Corporation Pituitary adenylate cyclase activating peptide (PACAP) receptor 3 (R3) agonists and their pharmacological methods of use
WO2002034285A2 (en) 2000-10-20 2002-05-02 Coolidge Thomas R Treatment of hibernating myocardium and diabetic cardiomyopathy with a glp-1 peptide
PT1355942E (pt) 2000-12-07 2008-11-21 Lilly Co Eli Proteínas de fusão de glp-1
AU3938402A (en) 2000-12-13 2002-06-24 Lilly Co Eli Chronic treatment regimen using glucagon-like insulinotropic peptides
GB2371227A (en) 2001-01-10 2002-07-24 Grandis Biotech Gmbh Crystallisation - resistant aqueous growth hormone formulations
US6573237B2 (en) 2001-03-16 2003-06-03 Eli Lilly And Company Protein formulations
CN1162446C (zh) 2001-05-10 2004-08-18 上海华谊生物技术有限公司 促胰岛素分泌肽衍生物
EP1542712A2 (en) 2001-06-01 2005-06-22 Eli Lilly And Company Glp-1 formulations with protracted time action
DE60224284T2 (de) 2001-06-28 2008-12-18 Novo Nordisk A/S Stabile formulierung von modifiziertem glp-1
US7858560B2 (en) 2001-07-16 2010-12-28 Caprotec Bioanalytics Gmbh Capture compounds, collections thereof and methods for analyzing the proteome and complex compositions
DE60228972D1 (de) 2001-07-31 2008-10-30 Us Gov Health & Human Serv Glp 1 exendin 4 peptidanaloga und deren verwendungen
MXPA04001560A (es) 2001-08-28 2004-05-17 Lilly Co Eli Premezclas de glp-1 e insulina basal.
WO2003035099A1 (en) 2001-10-19 2003-05-01 Eli Lilly And Company Biphasic mixtures of glp-1 and insulin
CA2484556A1 (en) 2001-12-21 2003-07-24 Human Genome Sciences, Inc. Albumin fusion proteins
JP5424521B2 (ja) 2001-12-21 2014-02-26 ヒューマン ジノーム サイエンシーズ， インコーポレイテッド アルブミン融合タンパク質
US7105489B2 (en) 2002-01-22 2006-09-12 Amylin Pharmaceuticals, Inc. Methods and compositions for treating polycystic ovary syndrome
MXPA04008068A (es) 2002-02-20 2004-11-26 Lilly Co Eli Metodo para administrar moleculas de glp-1.
MXPA04008215A (es) 2002-02-27 2004-11-26 Immunex Corp Formulacion polipeptidica.
WO2003077851A2 (en) 2002-03-11 2003-09-25 Hk Pharmaceuticals, Inc. Compounds and methods for analyzing the proteome
US7141240B2 (en) 2002-03-12 2006-11-28 Cedars-Sinai Medical Center Glucose-dependent insulin-secreting cells transfected with a nucleotide sequence encoding GLP-1
WO2003084563A1 (en) 2002-04-04 2003-10-16 Novo Nordisk A/S Glp-1 agonist and cardiovascular complications
CN1735423A (zh) 2002-04-10 2006-02-15 伊莱利利公司 胃轻瘫的治疗
US6861236B2 (en) 2002-05-24 2005-03-01 Applied Nanosystems B.V. Export and modification of (poly)peptides in the lantibiotic way
US20040037826A1 (en) 2002-06-14 2004-02-26 Michelsen Birgitte Koch Combined use of a modulator of CD3 and a GLP-1 compound
WO2003105897A1 (en) 2002-06-14 2003-12-24 Novo Nordisk A/S Combined use of a modulator of cd3 and a glp-1 compound
DE10227232A1 (de) 2002-06-18 2004-01-15 Aventis Pharma Deutschland Gmbh Saure Insulinzubereitungen mit verbesserter Stabilität
ATE432289T1 (de) 2002-07-04 2009-06-15 Zealand Pharma As Glp-1 und behandlungsmethode für diabetes
CN1665540A (zh) 2002-07-09 2005-09-07 桑多斯股份公司 含1,2－丙二醇的高浓度人生长激素液体制剂
US20070065469A1 (en) 2002-07-09 2007-03-22 Michael Betz Liquid formulations with high concentration of human growth hormone (high) comprising glycine
US20080260838A1 (en) 2003-08-01 2008-10-23 Mannkind Corporation Glucagon-like peptide 1 (glp-1) pharmaceutical formulations
JP4828940B2 (ja) 2002-08-01 2011-11-30 マンカインド コーポレイション 細胞輸送組成物およびこれらの使用
US20040038865A1 (en) 2002-08-01 2004-02-26 Mannkind Corporation Cell transport compositions and uses thereof
US7407955B2 (en) 2002-08-21 2008-08-05 Boehringer Ingelheim Pharma Gmbh & Co., Kg 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
CN105001222B (zh) 2002-08-21 2017-11-07 勃林格殷格翰制药两合公司 8‑[3‑氨基‑哌啶‑1‑基]‑黄嘌呤化合物，其制备方法及作为药物制剂的用途
US7544657B2 (en) 2002-10-02 2009-06-09 Zealand Pharma A/S Stabilized Exendin-4 compounds
US20050209142A1 (en) 2002-11-20 2005-09-22 Goran Bertilsson Compounds and methods for increasing neurogenesis
ATE494904T1 (de) 2002-11-20 2011-01-15 Neuronova Ab Verbindungen und verfahren zur erhöhung der neurogenese
US6969702B2 (en) 2002-11-20 2005-11-29 Neuronova Ab Compounds and methods for increasing neurogenesis
JP2006514035A (ja) 2002-12-17 2006-04-27 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 心不整脈の予防および治療
US20040209803A1 (en) 2002-12-19 2004-10-21 Alain Baron Compositions for the treatment and prevention of nephropathy
US7790681B2 (en) 2002-12-17 2010-09-07 Amylin Pharmaceuticals, Inc. Treatment of cardiac arrhythmias with GLP-1 receptor ligands
GB0300571D0 (en) 2003-01-10 2003-02-12 Imp College Innovations Ltd Modification of feeding behaviour
EP1620118B1 (en) 2003-04-08 2014-06-18 Yeda Research And Development Co., Ltd. Reversible pegylated drugs
WO2004089985A1 (en) 2003-04-11 2004-10-21 Novo Nordisk A/S Stable pharmaceutical compositions
CN1822851B (zh) 2003-05-15 2011-04-13 塔夫茨大学信托人 肽和多肽药物的稳定类似物
US7947261B2 (en) 2003-05-23 2011-05-24 Nektar Therapeutics Conjugates formed from polymer derivatives having particular atom arrangements
LT2644206T (lt) 2003-05-23 2019-05-27 Nektar Therapeutics Peg dariniai, susidedantys iš dviejų peg grandinių
WO2005000222A2 (en) 2003-05-30 2005-01-06 Amylin Pharmaceuticals, Inc. Novel methods and compositions for enhanced transmucosal delivery of peptides and proteins
EP1633390B1 (en) 2003-06-03 2012-01-18 Novo Nordisk A/S Stabilized pharmaceutical glp-1 peptide compositions
CN102940879B (zh) 2003-06-03 2017-06-06 诺沃挪第克公司 稳定化的药物肽组合物
CN1812808B (zh) 2003-06-03 2012-07-04 诺沃挪第克公司 稳定化的药物肽组合物
JP2007524592A (ja) 2003-06-03 2007-08-30 ノボ・ノルデイスク・エー／エス 安定化された薬学的ペプチド組成物
US8921311B2 (en) 2003-08-01 2014-12-30 Mannkind Corporation Method for treating hyperglycemia
EP2107069B1 (en) 2003-08-05 2013-01-16 Novo Nordisk A/S Novel insulin derivatives
MXPA06001814A (es) 2003-08-21 2006-05-04 Novo Nordisk As Separacion de polipeptidos que comprenden un aminoacido racemizado.
WO2005021022A2 (en) 2003-09-01 2005-03-10 Novo Nordisk A/S Stable formulations of peptides
US20060247167A1 (en) 2003-09-01 2006-11-02 Novo Nordisk A/S Stable formulations of peptides
JP2007537981A (ja) 2003-09-19 2007-12-27 ノボ　ノルディスク　アクティーゼルスカブ 新規の血漿タンパク質親和性タグ
WO2005046716A1 (en) 2003-11-13 2005-05-26 Novo Nordisk A/S Soluble pharmaceutical compositions for parenteral administration comprising a glp-1 peptide and a insulin peptide of short time action for treatment of diabetes and bulimia
US20060287221A1 (en) 2003-11-13 2006-12-21 Novo Nordisk A/S Soluble pharmaceutical compositions for parenteral administration comprising a GLP-1 peptide and an insulin peptide of short time action for treatment of diabetes and bulimia
US20050106214A1 (en) 2003-11-14 2005-05-19 Guohua Chen Excipients in drug delivery vehicles
US20050281879A1 (en) 2003-11-14 2005-12-22 Guohua Chen Excipients in drug delivery vehicles
WO2005081619A2 (en) 2003-11-20 2005-09-09 Neuronova Ab Compounds and methods for increasing neurogenesis
BRPI0416743A (pt) 2003-11-20 2007-01-16 Novo Nordisk As formulação farmacêutica, e, métodos de preparar uma formulação de peptìdeo apropriada para uso em um dispositivo de injeção, para reduzir depósitos em equipamento de produção e no produto final, e para reduzir o entupimento de dispositivos de injeção por uma formulação de peptìdeo
AU2004295023A1 (en) 2003-12-03 2005-06-16 Novo Nordisk A/S Single-chain insulin
CN1913925A (zh) 2003-12-10 2007-02-14 尼克塔治疗亚拉巴马公司 含有两组不同聚合物－活性剂缀合物的组合物
US20050143303A1 (en) 2003-12-26 2005-06-30 Nastech Pharmaceutical Company Inc. Intranasal administration of glucose-regulating peptides
US20060210614A1 (en) 2003-12-26 2006-09-21 Nastech Pharmaceutical Company Inc. Method of treatment of a metabolic disease using intranasal administration of exendin peptide
WO2007065156A2 (en) 2005-12-02 2007-06-07 Nastech Pharmaceutical Company Inc. Pharmaceutical formulation for increased epithelial permeability of glucose-regulating peptide
CN1938334A (zh) * 2004-01-30 2007-03-28 瓦拉塔药品公司 Glp－1激动剂和胃泌素化合物的联合使用
KR101427024B1 (ko) 2004-02-11 2014-08-05 아스트라제네카 파마수티컬스 엘피 선택가능한 특성을 갖는 하이브리드 폴리펩티드
EP1789440A4 (en) 2004-02-11 2008-03-12 Amylin Pharmaceuticals Inc REASONS FOR THE FAMILY OF PANCREATIC POLYPEPTIDES AND POLYPEPTIDES CONTAINING THEM
JP2008500281A (ja) 2004-02-11 2008-01-10 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 アミリンファミリーペプチドおよびそれらを作成し使用するための方法
US8076288B2 (en) 2004-02-11 2011-12-13 Amylin Pharmaceuticals, Inc. Hybrid polypeptides having glucose lowering activity
US7399744B2 (en) 2004-03-04 2008-07-15 Amylin Pharmaceuticals, Inc. Methods for affecting body composition
JP5030292B2 (ja) 2004-04-15 2012-09-19 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 ポリマーを基にした持続放出性装置
US7456254B2 (en) 2004-04-15 2008-11-25 Alkermes, Inc. Polymer-based sustained release device
US20060110423A1 (en) 2004-04-15 2006-05-25 Wright Steven G Polymer-based sustained release device
US20090069226A1 (en) 2004-05-28 2009-03-12 Amylin Pharmaceuticals, Inc. Transmucosal delivery of peptides and proteins
WO2005117584A2 (en) 2004-05-28 2005-12-15 Amylin Pharmaceuticals, Inc Improved transmucosal delivery of peptides and proteins
EP1758575A1 (en) 2004-06-11 2007-03-07 Novo Nordisk A/S Counteracting drug-induced obesity using glp-1 agonists
JP5220410B2 (ja) 2004-07-19 2013-06-26 バイオコン・リミテッド インスリン−オリゴマー複合体、その処方物及び使用
JP2008507280A (ja) 2004-07-21 2008-03-13 アンブレツクス・インコーポレイテツド 非天然コードアミノ酸を用いた生合成ポリペプチド
JP2008509153A (ja) 2004-08-03 2008-03-27 バイオレクシス ファーマシューティカル コーポレイション Ｇｌｐ−１を含むトランスフェリン融合タンパク質用いた併用療法
CA2577158A1 (en) 2004-08-16 2006-02-23 Water Un Limited Apparatus and method for cooling of air
JP4965446B2 (ja) 2004-08-31 2012-07-04 ノヴォ ノルディスク アー／エス ペプチド、ポリペプチド及びタンパク質の安定化のためのトリス（ヒドロキシメチル）アミノメタンの使用
DE102004043153B4 (de) 2004-09-03 2013-11-21 Philipps-Universität Marburg Erfindung betreffend GLP-1 und Exendin
WO2006028110A1 (ja) 2004-09-07 2006-03-16 Chugai Seiyaku Kabushiki Kaisha 水溶性ヒアルロン酸修飾物の製造方法
JP2008513384A (ja) 2004-09-17 2008-05-01 ノボ ノルディスク アクティーゼルスカブ インスリンおよびインスリン分泌性ペプチドを含有する医薬組成物
KR101341359B1 (ko) 2004-10-01 2013-12-13 램스코르 인코포레이티드 편리하게 이식가능한 서방형 약물 조성물
WO2006037811A2 (en) 2004-10-07 2006-04-13 Novo Nordisk A/S Protracted exendin-4 compounds
US7595294B2 (en) 2004-10-08 2009-09-29 Transition Therapeutics, Inc. Vasoactive intestinal polypeptide pharmaceuticals
US20090036355A1 (en) 2004-10-13 2009-02-05 Sanjay Bhanot Antisense Modulation of PTP1B Expression
US7442682B2 (en) 2004-10-19 2008-10-28 Nitto Denko Corporation Transepithelial delivery of peptides with incretin hormone activities
EP2494983B1 (en) 2004-11-12 2019-04-24 Novo Nordisk A/S Stable formulations of glp-1
US20080125361A1 (en) 2004-11-12 2008-05-29 Novo Nordisk A/S Stable Formulations Of Peptides
US20090011976A1 (en) 2004-11-12 2009-01-08 Novo Nordisk A/S Stable Formulations Of Peptides
CA2589800A1 (en) 2004-12-02 2006-06-08 Domantis Limited Bispecific domain antibodies targeting serum albumin and glp-1 or pyy
PL1824876T3 (pl) 2004-12-13 2016-01-29 Amylin Pharmaceuticals Llc Motywy rodziny polipeptydów trzustkowych, polipeptydy i sposoby je obejmujące
JP5243041B2 (ja) 2004-12-21 2013-07-24 ネクター セラピューティックス 安定化ポリマーチオール試薬
ES2326906T3 (es) 2004-12-22 2009-10-21 Eli Lilly And Company Formulaciones de proteinas de fusion analogas al glp-1.
AU2005323063B2 (en) 2004-12-24 2011-01-27 Amylin Pharmaceuticals, Llc Use of GLP-1 and agonists thereof to prevent cardiac myocyte apoptosis
EP2505207B1 (en) 2005-01-14 2015-04-22 Wuxi Grandchamp Pharmaceutical Technology Co., Ltd. Modified exendins and uses thereof
US8716221B2 (en) 2005-01-14 2014-05-06 Wuxi Grandchamp Pharmaceutical Technology Co., Ltd. Modified exendins and uses thereof
WO2006082588A2 (en) 2005-02-07 2006-08-10 Pharmalight Inc. Method and device for ophthalmic administration of active pharmaceutical ingredients
US8263545B2 (en) 2005-02-11 2012-09-11 Amylin Pharmaceuticals, Inc. GIP analog and hybrid polypeptides with selectable properties
EA011653B1 (ru) 2005-02-11 2009-04-28 Амилин Фармасьютикалз, Инк. Аналоги и гибридные полипептиды gip с избираемыми свойствами
US20090286723A1 (en) 2005-02-11 2009-11-19 Amylin Pharmaceuticals, Inc. Hybrid Polypeptides with Selectable Properties
WO2006097535A2 (en) 2005-03-18 2006-09-21 Novo Nordisk A/S Peptide agonists of the glucagon family with secretin like activity
EP1888103B1 (en) 2005-04-11 2012-03-21 Amylin Pharmaceuticals, Inc. Use of glp-1, exendin and agonists thereof to delay or prevent cardiac remodeling
JP4979686B2 (ja) 2005-04-24 2012-07-18 ノボ・ノルデイスク・エー／エス 注入デバイス
CN101180081B (zh) 2005-05-25 2015-08-26 诺沃-诺迪斯克有限公司 稳定的多肽制剂
EP1883652A2 (en) 2005-05-26 2008-02-06 Bristol-Myers Squibb Company N-terminally modified glp-1 receptor modulators
ES2399645T3 (es) 2005-06-06 2013-04-02 Camurus Ab Formulaciones de análogos de GLP-1
AU2006258841B2 (en) 2005-06-13 2012-05-03 Imperial Innovations Limited Oxyntomodulin analogues and their effects on feeding behaviour
GB0511986D0 (en) 2005-06-13 2005-07-20 Imp College Innovations Ltd Novel compounds and their effects on feeding behaviour
CA2611823C (en) 2005-06-16 2013-07-30 Nektar Therapeutics Al, Corporation Conjugates having a degradable linkage and polymeric reagents useful in preparing such conjugates
WO2007019331A2 (en) 2005-08-04 2007-02-15 Nektar Therapeutics Al, Corporation Conjugates of a g-csf moiety and a polymer
EP1924293A4 (en) 2005-08-06 2008-12-24 Qinghua Wang COMPOSITION AND METHOD FOR THE PREVENTION AND TREATMENT OF DIABETES TYPE I
CN105056211A (zh) 2005-08-19 2015-11-18 安米林药品有限责任公司 治疗糖尿病和降低体重的毒蜥外泌肽
CN102614131A (zh) 2005-09-14 2012-08-01 曼金德公司 以提高结晶微粒表面对活性试剂的亲和力为基础的药物配制方法
JP5072848B2 (ja) 2005-09-20 2012-11-14 ノバルティス アーゲー 低血糖イベントを低減するためのｄｐｐ−ｉｖ阻害剤の使用
WO2007047834A2 (en) 2005-10-18 2007-04-26 Biocon Limited Oral peptide conjugates for metabolic diseases
WO2007047922A2 (en) 2005-10-19 2007-04-26 Smartcells, Inc. Polymer-drug conjugates
CA2628241C (en) 2005-11-07 2016-02-02 Indiana University Research And Technology Corporation Glucagon analogs exhibiting physiological solubility and stability
WO2007053946A1 (en) 2005-11-09 2007-05-18 Conjuchem Biotechnologies Inc. Method of treating diabetes and/or obesity with reduced nausea side effects using an insulinotropic peptide conjugated to albumin
CA2632903C (en) 2005-12-02 2015-11-24 Vianova Labs, Inc. Treatment of cancer and other diseases
WO2007067964A2 (en) 2005-12-08 2007-06-14 Nastech Pharmaceutical Company Inc. Mucosal delivery of stabilized formulations of exendin
ES2390286T3 (es) 2005-12-16 2012-11-08 Nektar Therapeutics Conjugados poliméricos de GLP-1
US20130172274A1 (en) 2005-12-20 2013-07-04 Duke University Methods and compositions for delivering active agents with enhanced pharmacological properties
ES2779992T3 (es) 2005-12-20 2020-08-21 Univ Duke Métodos y composiciones para suministrar agentes activos con propiedades farmacológicas potenciadas
US8841255B2 (en) 2005-12-20 2014-09-23 Duke University Therapeutic agents comprising fusions of vasoactive intestinal peptide and elastic peptides
MX2008009125A (es) 2006-01-18 2008-10-23 Qps Llc Composiciones farmaceuticas con estabilidad mejorada.
JP2009525986A (ja) 2006-02-03 2009-07-16 メディミューン，エルエルシー タンパク質製剤
US7704953B2 (en) 2006-02-17 2010-04-27 Mdrna, Inc. Phage displayed cell binding peptides
US20090186817A1 (en) 2006-03-21 2009-07-23 Amylin Pharmaceuticals, Inc. Peptide-peptidase inhibitor conjugates and methods of using same
WO2007120899A2 (en) 2006-04-13 2007-10-25 Societe De Conseils De Recherches Et D'applications Scientifiques, S.A.S. Pharmaceutical compositions of hglp-1, exendin-4 and analogs thereof
MX2008013216A (es) 2006-04-14 2008-10-27 Mannkind Corp Formulaciones farmaceuticas de peptido-1 tipo glucagon (glp-1).
PE20080251A1 (es) 2006-05-04 2008-04-25 Boehringer Ingelheim Int Usos de inhibidores de dpp iv
US8299024B2 (en) 2006-05-12 2012-10-30 Amylin Pharmaceuticals, Llc Methods to restore glycemic control
WO2007139589A1 (en) 2006-05-26 2007-12-06 Bristol-Myers Squibb Company Sustained release glp-1 receptor modulators
CA2652907A1 (en) 2006-05-26 2007-12-06 Amylin Pharmaceuticals, Inc. Compositions and methods for treatment of diabetes
EP2038423B1 (en) 2006-06-21 2012-12-26 Biocon Limited A method of producing biologically active polypeptide having insulinotropic activity
PL2494959T3 (pl) 2006-07-05 2015-06-30 Foamix Pharmaceuticals Ltd Nośnik ze spienialnego kwasu dikarboksylowego oraz kompozycje farmaceutyczne z nośnikiem
JP5102833B2 (ja) 2006-07-24 2012-12-19 バイオレクシス ファーマシューティカル コーポレーション エキセンディン融合タンパク質
US7928186B2 (en) 2006-08-02 2011-04-19 Phoenix Pharmaceuticals, Inc. Cell permeable bioactive peptide conjugates
AU2007281433A1 (en) 2006-08-04 2008-02-07 Nastech Pharmaceutical Company Inc. Compositions for intranasal delivery of human insulin and uses thereof
NZ574524A (en) 2006-08-09 2011-07-29 Intarcia Therapeutics Inc Piston assembly for positioning lumen of a reservoir for an osmotic delivery having a columnar body and a spring
AU2007284365A1 (en) 2006-08-17 2008-02-21 Amylin Pharmaceuticals, Inc. DPP-IV resistant GIP hybrid polypeptides with selectable properties
US8497240B2 (en) 2006-08-17 2013-07-30 Amylin Pharmaceuticals, Llc DPP-IV resistant GIP hybrid polypeptides with selectable properties
WO2008023050A1 (en) * 2006-08-25 2008-02-28 Novo Nordisk A/S Acylated exendin-4 compounds
CN101125207B (zh) 2006-11-14 2012-09-05 上海华谊生物技术有限公司 带有聚乙二醇基团的艾塞丁或其类似物及其制剂和用途
WO2008073448A2 (en) 2006-12-12 2008-06-19 Amylin Pharmaceuticals, Inc. Pharmaceutical formulations and methods for making the same
TWI428346B (zh) 2006-12-13 2014-03-01 Imp Innovations Ltd 新穎化合物及其等對進食行為影響
US20090098130A1 (en) 2007-01-05 2009-04-16 Bradshaw Curt W Glucagon-like protein-1 receptor (glp-1r) agonist compounds
EP2124974B1 (en) 2007-01-05 2017-03-15 Indiana University Research and Technology Corporation Glucagon analogs exhibiting enhanced solubility in physiological ph buffers
CN101663317A (zh) * 2007-01-05 2010-03-03 CovX科技爱尔兰有限公司 胰高血糖素样蛋白-1受体glp-1r激动剂化合物
RU2432361C2 (ru) 2007-01-05 2011-10-27 КовЭкс Текнолоджиз Айэлэнд Лимитед Соединения агонисты рецептора глюкагоноподобного белка-1 (glp-1r)
WO2008098212A2 (en) 2007-02-08 2008-08-14 Diobex, Inc. Extended release formulations of glucagon and other peptides and proteins
EP2487184A1 (en) 2007-02-15 2012-08-15 Indiana University Research and Technology Corporation Glucagon/GLP-1 receptor co-agonists
US8420598B2 (en) 2007-04-20 2013-04-16 B & L Delipharm Corp. Mono modified exendin with polyethylene glycol or its derivatives and uses thereof
HRP20130259T1 (hr) 2007-04-23 2013-04-30 Intarcia Therapeutics, Inc. Suspenzijske formulacije inzulinotropnih peptida i njihove uporabe
US8236760B2 (en) 2007-04-27 2012-08-07 Cedars-Sinsai Medical Center Use of GLP-1 receptor agonists for the treatment of short bowel syndrome
US7829664B2 (en) 2007-06-01 2010-11-09 Boehringer Ingelheim International Gmbh Modified nucleotide sequence encoding glucagon-like peptide-1 (GLP-1), nucleic acid construct comprising same for production of glucagon-like peptide-1 (GLP-1), human cells comprising said construct and insulin-producing constructs, and methods of use thereof
WO2008148839A2 (en) 2007-06-08 2008-12-11 Ascendis Pharma As Long-acting polymeric prodrugs of exendin
JP5385266B2 (ja) 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 グルカゴン類似体
US20100196405A1 (en) 2007-07-10 2010-08-05 Kingman Ng GLP-1 Fc FUSION PROTEIN FORMULATION
EP2185178B1 (en) 2007-08-03 2017-08-23 Eli Lilly And Company Use of an fgf-21 compound and a glp-1 compound for the treatment of obesity
CN101366692A (zh) 2007-08-15 2009-02-18 江苏豪森药业股份有限公司 一种稳定的艾塞那肽制剂
KR20100080519A (ko) 2007-08-30 2010-07-08 큐어디엠 인코포레이티드 프로섬 펩타이드 및 이의 유사체의 조성물 및 이의 이용 방법
CN101842109B (zh) 2007-09-05 2014-01-29 诺沃-诺迪斯克有限公司 用a-b-c-d-衍生的肽和它们的治疗用途
WO2009035540A2 (en) 2007-09-07 2009-03-19 Ipsen Pharma S.A.S. Analogues of exendin-4 and exendin-3
CN101969928B (zh) 2007-10-24 2014-05-07 曼金德公司 活性剂的递送
US8785396B2 (en) 2007-10-24 2014-07-22 Mannkind Corporation Method and composition for treating migraines
EP2211842B1 (en) 2007-10-24 2015-08-12 MannKind Corporation An inhalable dry powder formulation comprising glp-1 for use in the treatment of hyperglycemia and diabetes by pulmonary administration
WO2009058662A2 (en) 2007-10-30 2009-05-07 Indiana University Research And Technology Corporation Glucagon antagonists
WO2009058734A1 (en) 2007-10-30 2009-05-07 Indiana University Research And Technology Corporation Compounds exhibiting glucagon antagonist and glp-1 agonist activity
HUE030383T2 (en) 2007-11-16 2017-05-29 Novo Nordisk As Stable pharmaceutical formulations containing liraglutide and deglates
US8710002B2 (en) 2007-11-23 2014-04-29 Michael Rothkopf Methods of enhancing diabetes resolution
CN101444618B (zh) 2007-11-26 2012-06-13 杭州九源基因工程有限公司 含有艾塞那肽的药物制剂
US20090186819A1 (en) 2007-12-11 2009-07-23 Marieve Carrier Formulation of insulinotropic peptide conjugates
ES2613152T3 (es) 2008-01-09 2017-05-22 Sanofi-Aventis Deutschland Gmbh Nuevos derivados de insulina con perfil tiempo/acción extremadamente retardado
JP2011511778A (ja) 2008-01-30 2011-04-14 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 エステルに基づいたペプチドプロドラッグ
DK2596805T3 (da) 2008-02-01 2021-12-13 Ascendis Pharma As Prodrug omfattende et lægemiddel-linker-konjugat
RU2595380C2 (ru) 2008-02-06 2016-08-27 Байокон Лимитид Ферментационная среда для получения правастатина и способ получения правастатина
WO2009114959A1 (zh) 2008-03-20 2009-09-24 中国人民解放军军事医学科学院毒物药物研究所 可注射用缓释药物制剂及其制备方法
WO2009125423A2 (en) 2008-04-07 2009-10-15 National Institute Of Immunology Compositions useful for the treatment of diabetes and other chronic disorder
TW200950801A (en) 2008-05-07 2009-12-16 Merrion Res Iii Ltd Compositions of peptides and processes of preparation thereof
ES2552646T3 (es) 2008-05-21 2015-12-01 Amylin Pharmaceuticals, Inc. Exendinas para disminuir el colesterol y los triglicéridos
EP2288918A1 (en) 2008-05-23 2011-03-02 Amylin Pharmaceuticals, Inc. Glp-1 receptor agonist bioassays
CN104491962B (zh) 2008-06-13 2018-10-23 曼金德公司 干粉吸入器和用于药物输送的系统
US8485180B2 (en) 2008-06-13 2013-07-16 Mannkind Corporation Dry powder drug delivery system
AU2009260302B2 (en) 2008-06-17 2014-10-23 Indiana University Research And Technology Corporation Glucagon/GLP-1 receptor co-agonists
EP2298801A4 (en) 2008-06-17 2011-08-03 Otsuka Chemical Co Ltd GLYCOSYLATED GLP-1 PEPTIDE
BRPI0915282A2 (pt) 2008-06-17 2017-02-07 Univ Indiana Res & Tech Corp agonistas mistos baseados no gip para o tratamento de distúrbios metabólicos e obesidade
KR20110039230A (ko) 2008-06-17 2011-04-15 인디애나 유니버시티 리서치 앤드 테크놀로지 코퍼레이션 생리학적 ｐＨ 완충액에서 강화된 용해도 및 안정성을 나타내는 글루카곤 유사체
EP3412300A1 (en) 2008-06-27 2018-12-12 Duke University Therapeutic agents comprising elastin-like peptides
US20110129522A1 (en) 2008-07-21 2011-06-02 Transpharma Medical Ltd. Transdermal system for extended delivery of incretins and incretn mimetic peptides
WO2010013012A2 (en) 2008-08-01 2010-02-04 Lund University Bioscience Ab Novel polypeptides and uses thereof
CN101670096B (zh) 2008-09-11 2013-01-16 杭州九源基因工程有限公司 含有艾塞那肽的药物制剂
ES2772731T3 (es) 2008-10-17 2020-07-08 Sanofi Aventis Deutschland Combinación de una insulina y un agonista de GLP-1
SMT201700189T1 (it) 2008-12-10 2017-05-08 Glaxosmithkline Llc Composizioni farmaceutiche di albiglutide
MX2011006315A (es) 2008-12-15 2011-09-22 Zealand Pharma As Analogos de glucagon.
KR20110126592A (ko) 2008-12-15 2011-11-23 질랜드 파마 에이/에스 글루카곤 유사체
KR20110126591A (ko) 2008-12-15 2011-11-23 질랜드 파마 에이/에스 글루카곤 유사체
CA2747109A1 (en) 2008-12-15 2010-06-24 Zealand Pharma A/S Glucagon analogues
SG172291A1 (en) 2008-12-19 2011-07-28 Univ Indiana Res & Tech Corp Amide based glucagon superfamily peptide prodrugs
CN101538323B (zh) 2009-01-13 2012-05-09 深圳翰宇药业股份有限公司 一种纯化艾塞那肽的方法
DE102009006602A1 (de) 2009-01-29 2010-08-05 Bayer Schering Pharma Aktiengesellschaft Alkylamino-substituierte Dicyanopyridine und deren Aminosäureester-Prodrugs
WO2010096052A1 (en) 2009-02-19 2010-08-26 Merck Sharp & Dohme Corp. Oxyntomodulin analogs
MX2011009251A (es) 2009-03-04 2011-11-18 Mannkind Corp Sistema mejorado de suministro de farmaco en polvo seco.
AU2010220255B2 (en) 2009-03-05 2014-09-04 Sanofi-Aventis Deutschland Gmbh Drug delivery device with retractable needle
EP2413955A4 (en) 2009-04-01 2012-12-26 Amylin Pharmaceuticals Inc N-TERMINAL CONFORMATION RESTRICTED GLP-1 RECEPTOR AGONIST COMPOUNDS
WO2010118034A2 (en) 2009-04-06 2010-10-14 Board Of Regents, The University Of Texas System Cyclic peptide analogues for non-invasive imaging of pancreatic beta-cells
JP5727459B2 (ja) 2009-04-22 2015-06-03 アルテオゼン， インクＡｌｔｅｏｇｅｎ， Ｉｎｃ 体内持続性を維持することにより体内半減期が増加したタンパク質またはペプチド融合体
CN101870728A (zh) 2009-04-23 2010-10-27 派格生物医药(苏州)有限公司 新型Exendin变体及其缀合物
CN101559041B (zh) 2009-05-19 2014-01-15 中国科学院过程工程研究所 粒径均一的多肽药物缓释微球或微囊制剂及制备方法
WO2010133676A1 (en) 2009-05-20 2010-11-25 Sanofi-Aventis Deutschland Gmbh A system comprising a drug delivery device and a cartridge provided with a bung and a method of identifying the cartridge
CA2760760A1 (en) 2009-05-20 2010-11-25 Sanofi-Aventis Deutschland Gmbh A bung for drug containing cartridges in drug delivery devices
EP2435061A4 (en) 2009-05-28 2013-03-27 Amylin Pharmaceuticals Inc DAMPING GLP-1 RECEPTOR AGONIST COMPOUNDS
JP2012529463A (ja) 2009-06-11 2012-11-22 ノヴォ ノルディスク アー／エス ２型糖尿病を治療するための、ｇｌｐ−１とｆｇｆ２１との組合せ
BRPI1014508A2 (pt) 2009-06-16 2016-04-05 Univ Indiana Res & Tech Corp análogos de peptídeo de glucagon, dimer de dois peptídeos de glucagon, composição farmacêutica deles derivada e métodos para seu uso"
CA2766537A1 (en) 2009-07-02 2011-01-06 Angiochem Inc. Multimeric peptide conjugates and uses thereof
HUE026255T2 (en) 2009-07-13 2016-06-28 Zealand Pharma As Acylated glucagon analogues
CN101601646B (zh) 2009-07-22 2011-03-23 南京凯瑞尔纳米生物技术有限公司 治疗糖尿病的鼻腔滴剂及其制备方法
WO2011011675A1 (en) 2009-07-23 2011-01-27 Zelos Therapeutics, Inc. Pharmaceutically acceptable formulations/compositions for peptidyl drugs
CA2769340C (en) 2009-07-31 2018-09-11 Harald Rau Prodrugs comprising an insulin linker conjugate
WO2011017835A1 (en) 2009-08-11 2011-02-17 Nanjing University Preparation method of protein or peptide nanoparticles for in vivo drug delivery by unfolding and refolding
CN101993485B (zh) 2009-08-20 2013-04-17 重庆富进生物医药有限公司 促胰岛素分泌肽类似物同源二聚体及其用途
US20120148586A1 (en) 2009-08-27 2012-06-14 Joyce Ching Tsu Chou Glucagon-like protein-1 receptor (glp-1r) agonists for treating autoimmune disorders
WO2011039096A1 (en) 2009-09-30 2011-04-07 Glaxo Group Limited Drug fusions and conjugates with extended half life
EP2490708B1 (en) 2009-10-22 2013-03-27 Biodel Inc. Stabilized glucagon solutions
US20110097386A1 (en) 2009-10-22 2011-04-28 Biodel, Inc. Stabilized glucagon solutions
US9610329B2 (en) 2009-10-22 2017-04-04 Albireo Pharma, Inc. Stabilized glucagon solutions
EP2495255A4 (en) 2009-10-30 2013-05-15 Otsuka Chemical Co Ltd GLYCOSYLATED FORM OF AN ANTIGENIC GLP-1 ANALOG
HRP20150107T1 (xx) 2009-11-02 2015-03-13 Pfizer Inc. Derivati dioksabiciklo[3.2.1]oktan-2,3,4-triola
WO2011056713A2 (en) 2009-11-03 2011-05-12 Amylin Pharmaceuticals, Inc. Glp-1 receptor agonist compounds for obstructive sleep apnea
AR078973A1 (es) 2009-11-13 2011-12-14 Sanofi Aventis Deutschland Composicion farmaceutica que comprende un agonista de glp-1 y metionina
MY180661A (en) 2009-11-13 2020-12-04 Sanofi Aventis Deutschland Pharmaceutical composition comprising a glp-1 agonist, an insulin and methionine
RU2012130011A (ru) 2009-12-15 2014-01-27 МЕТАБОЛИК СОЛЮШНЗ ДЕВЕЛОПМЕНТ КОМПАНИ, ЭлЭлСи Ppar-снижающие тиазолидиндионы и комбинации для лечения сахарного диабета и других нарушений обмена веществ
EP2512475A1 (en) 2009-12-15 2012-10-24 Metabolic Solutions Development Company LLC Ppar-sparing thiazolidinediones and combinations for the treatment of obesity and other metabolic diseases
AU2010331926B2 (en) 2009-12-15 2014-03-27 Cirius Therapeutics, Inc. PPAR-sparing thiazolidinediones and combinations for the treatment of neurodegenerative diseases
KR102029560B1 (ko) 2009-12-15 2019-10-07 씨리우스 테라퓨틱스, 엘엘씨 대사성 질환의 치료를 위한 ｐｐａｒ 절약형 티아졸리딘디온염
CN111560060A (zh) 2009-12-16 2020-08-21 诺沃—诺迪斯克有限公司 双酰化glp-1衍生物
WO2011075623A1 (en) 2009-12-18 2011-06-23 Latitude Pharmaceuticals, Inc. One - phase gel compos ition compri s ing phos pholi pids
US8703701B2 (en) 2009-12-18 2014-04-22 Indiana University Research And Technology Corporation Glucagon/GLP-1 receptor co-agonists
CN101798588B (zh) * 2009-12-21 2015-09-09 上海仁会生物制药股份有限公司 Glp-1受体激动剂生物学活性测定方法
JO2976B1 (en) 2009-12-22 2016-03-15 ايلي ليلي اند كومباني Axentomodulin polypeptide
AR079344A1 (es) 2009-12-22 2012-01-18 Lilly Co Eli Analogo peptidico de oxintomodulina, composicion farmaceutica que lo comprende y uso para preparar un medicamento util para tratar diabetes no insulinodependiente y/u obesidad
BR112012018104A2 (pt) 2010-01-20 2017-10-17 Zeland Pharma As tratamento de doenças cardíacas
CN102834108A (zh) * 2010-01-27 2012-12-19 印第安纳大学研究及科技有限公司 用于治疗代谢紊乱和肥胖症的胰高血糖素拮抗剂-gip激动剂偶联物和组合物
AU2011209472B2 (en) 2010-02-01 2014-07-24 Sanofi-Aventis Deutschland Gmbh Cartridge holder, drug delivery device and method for securing a cartridge in a cartridge holder
WO2011109784A1 (en) 2010-03-05 2011-09-09 Conjuchem, Llc Formulation of insulinotropic peptide conjugates
CN102917748B (zh) 2010-03-24 2015-04-01 施菲姆德控股有限责任公司 血管内组织破坏
AR080592A1 (es) * 2010-03-26 2012-04-18 Lilly Co Eli Peptido con actividad para el gip-r y glp-1-r, formulacion famaceutica que lo comprende, su uso para preparar un medicamento util para el tratamiento de diabetes mellitus y para inducir la perdida de peso
WO2011117415A1 (en) 2010-03-26 2011-09-29 Novo Nordisk A/S Novel glucagon analogues
CN103179976A (zh) 2010-05-13 2013-06-26 印第安纳大学研究及科技有限公司 呈现g蛋白偶联受体活性的胰高血糖素超家族肽
CN103079587B (zh) 2010-05-13 2016-05-11 印第安纳大学研究及科技有限公司 呈现核激素受体活性的胰高血糖素超家族肽
AU2011202239C1 (en) 2010-05-19 2017-03-16 Sanofi Long-acting formulations of insulins
WO2011144751A1 (en) 2010-05-20 2011-11-24 Glaxo Group Limited Improved anti-serum albumin binding variants
WO2011156407A2 (en) 2010-06-09 2011-12-15 Amylin Pharmaceuticals, Inc. Glp-1 receptor agonists to treat pancre-atitis
CN101891823B (zh) 2010-06-11 2012-10-03 北京东方百泰生物科技有限公司 一种Exendin-4及其类似物融合蛋白
US8636711B2 (en) 2010-06-14 2014-01-28 Legacy Emanuel Hospital & Health Center Stabilized glucagon solutions and uses therefor
EP2582421A1 (en) 2010-06-21 2013-04-24 MannKind Corporation Dry powder drug delivery system and methods
AR081975A1 (es) 2010-06-23 2012-10-31 Zealand Pharma As Analogos de glucagon
CN103179979A (zh) 2010-06-24 2013-06-26 印第安纳大学研究及科技有限公司 基于酰胺的胰高血糖素超家族肽前药
US9234023B2 (en) 2010-06-24 2016-01-12 Biousian Biosystems, Inc. Glucagon-like peptide-1 glycopeptides
WO2011163473A1 (en) 2010-06-25 2011-12-29 Indiana University Research And Technology Corporation Glucagon analogs exhibiting enhanced solubility and stability in physiological ph buffers
WO2012012460A1 (en) 2010-07-19 2012-01-26 Xeris Pharmaceuticals, Inc. Stable glucagon formulations for the treatment of hypoglycemia
US20130137645A1 (en) 2010-07-19 2013-05-30 Mary S. Rosendahl Modified peptides and proteins
KR20130101005A (ko) 2010-07-28 2013-09-12 아밀린 파마슈티칼스, 엘엘씨. 안정화된 영역을 갖는 glp-1 수용체 효능제 화합물
CN102397558B (zh) 2010-09-09 2013-08-14 中国人民解放军军事医学科学院毒物药物研究所 Exendin-4类似物的定位聚乙二醇化修饰物及其用途
EP2438930A1 (en) 2010-09-17 2012-04-11 Sanofi-Aventis Deutschland GmbH Prodrugs comprising an exendin linker conjugate
WO2012050923A2 (en) 2010-09-28 2012-04-19 Amylin Pharmaceuticals, Inc. Engineered polypeptides having enhanced duration of action
WO2012059762A1 (en) 2010-11-03 2012-05-10 Arecor Limited Novel composition comprising glucagon
EP2637657B1 (en) 2010-11-09 2019-05-22 MannKind Corporation Composition comprising a serotonin receptor agonist and a diketopiperazine for treating migraines
EP2460552A1 (en) 2010-12-06 2012-06-06 Sanofi-Aventis Deutschland GmbH Drug delivery device with locking arrangement for dose button
CN102552883B (zh) 2010-12-09 2014-02-19 天津药物研究院 一种多肽复合物、药物组合物、其制备方法和应用
RU2600440C3 (ru) 2010-12-16 2021-12-10 Ново Нордиск А/С Твердые композиции, содержащие агонист glp-1 и соль n-(8-(2-гидроксибензоил)амино)каприловой кислоты
JP2014504588A (ja) 2010-12-22 2014-02-24 アミリン・ファーマシューティカルズ，リミテッド・ライアビリティ・カンパニー 膵島細胞移植のためのｇｌｐ−１受容体アゴニスト
EA201390941A1 (ru) 2010-12-22 2013-12-30 Индиана Юниверсити Рисерч Энд Текнолоджи Корпорейшн Аналоги глюкагона, проявляющие активность на рецепторе gip
CN102532301B (zh) 2010-12-31 2014-09-03 上海医药工业研究院 一类新型的Exendin-4类似物及其制备方法
US20120208755A1 (en) 2011-02-16 2012-08-16 Intarcia Therapeutics, Inc. Compositions, Devices and Methods of Use Thereof for the Treatment of Cancers
CN102100906A (zh) 2011-02-18 2011-06-22 深圳翰宇药业股份有限公司 一种艾塞那肽的药用制剂及其制备方法
MX342675B (es) 2011-03-10 2016-10-07 Xeris Pharmaceuticals Inc Formulaciones estables para inyeccion parenteral de farmacos de peptido.
CN102718858B (zh) 2011-03-29 2014-07-02 天津药物研究院 胰高血糖素样肽-1类似物单体、二聚体及其制备方法与应用
CN102718868A (zh) 2011-03-30 2012-10-10 上海华谊生物技术有限公司 定点单取代聚乙二醇化Exendin类似物及其制备方法
EP2694095B1 (en) 2011-04-05 2018-03-07 Longevity Biotech, Inc. Compositions comprising glucagon analogs and methods of making and using the same
EP2696897A2 (en) 2011-04-11 2014-02-19 Yeda Research and Development Co. Ltd. Albumin binding probes and drug conjugates thereof
WO2012150503A2 (en) 2011-05-03 2012-11-08 Zealand Pharma A/S Glu-glp-1 dual agonist signaling-selective compounds
CN102766204B (zh) 2011-05-05 2014-10-15 天津药物研究院 胰高血糖素样肽-1突变体多肽及其制备方法和其应用
KR102255479B1 (ko) 2011-05-18 2021-05-24 메더리스 다이어비티즈, 엘엘씨 인슐린 저항성에 대한 개선된 펩티드 제약
JP2014521594A (ja) 2011-05-25 2014-08-28 アミリン・ファーマシューティカルズ，リミテッド・ライアビリティ・カンパニー 長持続期間デュアルホルモンコンジュゲート
UA113626C2 (xx) 2011-06-02 2017-02-27 Композиція для лікування діабету, що містить кон'югат інсуліну тривалої дії та кон'югат інсулінотропного пептиду тривалої дії
JP5914641B2 (ja) 2011-06-10 2016-05-11 ベイジン・ハンミ・ファーマシューティカル・カンパニー・リミテッドＢｅｉｊｉｎｇ Ｈａｎｍｉ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｃｏ．， Ｌｔｄ． グルコース依存性インスリン分泌刺激ポリペプチドのアナログ、医薬組成物及びその使用
CA2838503C (en) 2011-06-10 2020-02-18 Hanmi Science Co., Ltd. Novel oxyntomodulin derivatives and pharmaceutical composition for treating obesity comprising the same
WO2012174478A2 (en) 2011-06-17 2012-12-20 Halozyme, Inc. Stable formulations of a hyaluronan-degrading enzyme
TR201901402T4 (tr) 2011-06-17 2019-02-21 Hanmi Science Co Ltd Oksintomodulin ve bir immünoglobulin fragmanı içeren bir konjugat ve onun kullanımı.
CN103857408B (zh) 2011-06-22 2017-04-12 印第安那大学科技研究公司 胰高血糖素/glp‑1受体协同激动剂
BR112013032717A2 (pt) 2011-06-22 2017-01-24 Univ Indiana Res & Tech Corp coagonistas do receptor de glucagon/glp-1
EP2723359A4 (en) 2011-06-24 2015-03-11 Amylin Pharmaceuticals Llc METHOD FOR THE TREATMENT OF DIABETES WITH THE HELP OF DELAYED RELEASED FORMULATIONS FROM GLP-1 RECEPTOR AGONISTS
KR101357117B1 (ko) 2011-06-28 2014-02-06 비앤엘델리팜 주식회사 폴리에틸렌글라이콜 또는 이의 유도체로 페길화된 엑센딘-4 유사체, 이의 제조방법 및 이를 유효성분으로 함유하는 당뇨병 예방 또는 치료용 약학적 조성물
US9944687B2 (en) 2011-07-04 2018-04-17 Imperial Innovations Limited Compounds and their effects on feeding behaviour
EP2729481B1 (en) 2011-07-08 2018-10-17 Amylin Pharmaceuticals, LLC Engineered polypeptides having enhanced duration of action with reduced immunogenicity
MX2014001190A (es) 2011-08-10 2014-05-12 Adocia Solucion inyectable de al menos insulina basal.
EP4295858A1 (en) 2011-08-24 2023-12-27 ImmunoForge Co., Ltd. Formulations of active agents for sustained release
CN103189389B (zh) 2011-09-03 2017-08-11 深圳市健元医药科技有限公司 新的glp‑ⅰ类似物及其制备方法和用途
US8541368B2 (en) 2011-09-23 2013-09-24 Novo Nordisk A/S Glucagon analogues
CN107693783A (zh) 2011-10-28 2018-02-16 赛诺菲-安万特德国有限公司 2型糖尿病的治疗方案
CN102363633B (zh) 2011-11-16 2013-11-20 天津拓飞生物科技有限公司 胰高血糖素样肽-1突变体多肽及其制备方法、药物组合物和其应用
ES2672880T3 (es) 2011-11-17 2018-06-18 Indiana University Research And Technology Corporation Péptidos de la superfamilia de glucagón que muestran actividad de receptor de glucocorticoides
AU2012268889B2 (en) 2011-11-29 2013-12-19 Zoetis Services Llc Pharmaceutical compositions
PL2791160T3 (pl) 2011-12-16 2022-06-20 Modernatx, Inc. Kompozycje zmodyfikowanego mrna
ES2623786T3 (es) 2011-12-22 2017-07-12 Pfizer Inc. Procedimiento de purificación de una muestra de anticuerpo H38C2
MX2014007120A (es) 2011-12-23 2015-03-05 Boehringer Ingelheim Int Analogos de glucagon.
EP2797585A4 (en) 2011-12-29 2015-10-07 Latitude Pharmaceuticals Inc STABILIZED GLUCAGONNANOULULSIONS
US9198971B2 (en) 2012-01-09 2015-12-01 Adocia Injectable solution at pH 7 comprising at least one basal insulin the pI of which is between 5.8 and 8.5 and a substituted co-polyamino acid
US20150133373A1 (en) 2012-03-28 2015-05-14 Amylin Pharmaceuticals, Llc Transmucosal delivery of engineered polypeptides
WO2013148871A1 (en) 2012-03-28 2013-10-03 Amylin Pharmaceuticals, Llc Engineered polypeptides
WO2013151665A2 (en) 2012-04-02 2013-10-10 modeRNA Therapeutics Modified polynucleotides for the production of proteins associated with human disease
CN104411338A (zh) 2012-04-02 2015-03-11 现代治疗公司 用于产生与人类疾病相关的生物制剂和蛋白质的修饰多核苷酸
CN102649947A (zh) 2012-04-20 2012-08-29 无锡和邦生物科技有限公司 一种用于测定glp-1及其功能类似物生物活性的细胞株及其应用
WO2013163162A1 (en) 2012-04-24 2013-10-31 Amylin Pharmaceuticals, Llc Site-specific enzymatic modification of exendins and analogs thereof
US20130289241A1 (en) 2012-04-26 2013-10-31 Shanghai Ambiopharm, Inc. Method for preparing exenatide
US8901484B2 (en) 2012-04-27 2014-12-02 Sanofi-Aventis Deutschland Gmbh Quantification of impurities for release testing of peptide products
WO2013182217A1 (en) 2012-04-27 2013-12-12 Sanofi-Aventis Deutschland Gmbh Quantification of impurities for release testing of peptide products
JP6228187B2 (ja) 2012-05-03 2017-11-08 ジーランド ファーマ アクティーゼルスカブ Ｇｉｐ−ｇｌｐ−１デュアルアゴニスト化合物及び方法
CA2872315A1 (en) 2012-05-03 2013-11-07 Zealand Pharma A/S Glucagon-like-peptide-2 (glp-2) analogues
EP2664374A1 (en) 2012-05-15 2013-11-20 F. Hoffmann-La Roche AG Lysin-glutamic acid dipeptide derivatives
CN103421094A (zh) 2012-05-24 2013-12-04 上海医药工业研究院 一种具有epo类似活性的多肽化合物
WO2013177565A1 (en) 2012-05-25 2013-11-28 Amylin Pharmaceuticals, Llc Insulin-pramlintide compositions and methods for making and using them
AU2013276610A1 (en) 2012-06-14 2015-01-15 Sanofi Exendin-4 peptide analogues
DK2864350T3 (en) 2012-06-21 2018-05-28 Univ Indiana Res & Tech Corp ANALOGUE OF GLUCAGON EXPRESSING GIP RECEPTOR ACTIVITY
WO2013192129A1 (en) 2012-06-21 2013-12-27 Indiana University Research And Technology Corporation Glucagon analogs exhibiting gip receptor activity
BR112015000529B1 (pt) 2012-07-12 2022-01-11 Mannkind Corporation Inalador de pó seco
MY170671A (en) 2012-07-23 2019-08-26 Zealand Pharma As Glucagon analogues
AR092862A1 (es) 2012-07-25 2015-05-06 Hanmi Pharm Ind Co Ltd Formulacion liquida de insulina de accion prolongada y un peptido insulinotropico y metodo de preparacion
AR094821A1 (es) 2012-07-25 2015-09-02 Hanmi Pharm Ind Co Ltd Formulación líquida de un conjugado de péptido insulinotrópico de acción prolongada
KR101968344B1 (ko) 2012-07-25 2019-04-12 한미약품 주식회사 옥신토모듈린 유도체를 포함하는 고지혈증 치료용 조성물
WO2014027253A1 (en) 2012-08-14 2014-02-20 Wockhardt Limited Pharmaceutical microparticulate compositions of polypeptides
EP2931300A1 (en) 2012-08-14 2015-10-21 Wockhardt Limited Pharmaceutical microparticulate compositions of polypeptides
CN102816244A (zh) 2012-08-23 2012-12-12 无锡和邦生物科技有限公司 一种Exendin-4肽与人血清白蛋白HSA的融合蛋白及其制备方法
CN102827270A (zh) 2012-09-13 2012-12-19 无锡和邦生物科技有限公司 一种聚乙二醇化艾塞那肽衍生物及其用途
EP2895506A1 (en) 2012-09-17 2015-07-22 Imperial Innovations Limited Peptide analogues of glucagon and glp1
TWI608013B (zh) 2012-09-17 2017-12-11 西蘭製藥公司 升糖素類似物
AR092873A1 (es) 2012-09-26 2015-05-06 Cadila Healthcare Ltd Peptidos como agonistas triples de los receptores de gip, glp-1 y glugagon
UA116217C2 (uk) 2012-10-09 2018-02-26 Санофі Пептидна сполука як подвійний агоніст рецепторів glp1-1 та глюкагону
KR101993393B1 (ko) 2012-11-06 2019-10-01 한미약품 주식회사 옥신토모듈린 유도체를 포함하는 당뇨병 또는 비만성 당뇨병 치료용 조성물
EP3610856B1 (en) 2012-11-06 2021-08-18 Hanmi Pharm. Co., Ltd. Liquid formulation of protein conjugate comprising the oxyntomodulin and an immunoglobulin fragment
JP6525456B2 (ja) 2012-11-20 2019-06-05 メデリス ダイアビーティーズ，エルエルシー インスリン抵抗性のための改善されたペプチド製剤
TWI617574B (zh) 2012-12-11 2018-03-11 梅迪繆思有限公司 用於治療肥胖之升糖素與ｇｌｐ－１共促效劑
MX2015008077A (es) 2012-12-21 2015-10-30 Sanofi Sa Derivados de exendina-4 como agonistas dobles de glp1/gip o trigonal de glp1-gip/glucagon.
CN103908657A (zh) 2012-12-31 2014-07-09 复旦大学附属华山医院 胰升糖素样肽-1类似物在制备眼科疾病药物中的用途
JP6538645B2 (ja) 2013-03-14 2019-07-03 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 インスリン‐インクレチン複合物
CA2902352A1 (en) 2013-03-14 2014-09-18 Medimmune Limited Pegylated glucagon and glp-1 co-agonists for the treatment of obesity
JP2016521253A (ja) 2013-03-15 2016-07-21 インディアナ ユニヴァーシティ リサーチ アンド テクノロジー コーポレイション 持続性作用を有するプロドラッグ
AU2014255608B2 (en) 2013-04-18 2018-01-25 Novo Nordisk A/S Stable, protracted GLP-1/glucagon receptor co-agonists for medical use
JP2014227368A (ja) 2013-05-21 2014-12-08 国立大学法人帯広畜産大学 糖尿病および高血糖状態の処置のためのグルカゴンアナログ
CN103304660B (zh) 2013-07-12 2016-08-10 上海昂博生物技术有限公司 一种利拉鲁肽的合成方法
CN103405753B (zh) 2013-08-13 2016-05-11 上海仁会生物制药股份有限公司 稳定的促胰岛素分泌肽水针药物组合物
CA2926314C (en) 2013-10-17 2023-08-29 Zealand Pharma A/S Acylated glucagon analogues
US9988429B2 (en) 2013-10-17 2018-06-05 Zealand Pharma A/S Glucagon analogues
EA035688B1 (ru) 2013-11-06 2020-07-27 Зилэнд Фарма А/С Соединения, которые представляют собой тройные агонисты глюкагона, glp-1 и gip
EP3080151A1 (en) 2013-12-13 2016-10-19 Sanofi Exendin-4 peptide analogues
WO2015086733A1 (en) 2013-12-13 2015-06-18 Sanofi Dual glp-1/glucagon receptor agonists
WO2015086731A1 (en) 2013-12-13 2015-06-18 Sanofi Exendin-4 peptide analogues as dual glp-1/glucagon receptor agonists
WO2015086729A1 (en) 2013-12-13 2015-06-18 Sanofi Dual glp-1/gip receptor agonists
EP3080150B1 (en) 2013-12-13 2018-08-01 Sanofi Exendin-4 peptide analogues as dual glp-1/gip receptor agonists
EP3080152A1 (en) 2013-12-13 2016-10-19 Sanofi Non-acylated exendin-4 peptide analogues
CN103665148B (zh) 2013-12-17 2016-05-11 中国药科大学 一种可口服给药的降糖多肽及其制法和用途
CN103980358B (zh) 2014-01-03 2016-08-31 杭州阿诺生物医药科技股份有限公司 一种制备利拉鲁肽的方法
EP3091965A1 (en) 2014-01-09 2016-11-16 Sanofi Stabilized glycerol free pharmaceutical formulations of insulin analogues and/or insulin derivatives
WO2015104314A1 (en) 2014-01-09 2015-07-16 Sanofi Stabilized pharmaceutical formulations of insulin analogues and/or insulin derivatives
GB201404002D0 (en) 2014-03-06 2014-04-23 Imp Innovations Ltd Novel compounds
TW201625669A (zh) 2014-04-07 2016-07-16 賽諾菲公司 衍生自艾塞那肽－４（Ｅｘｅｎｄｉｎ－４）之肽類雙重ＧＬＰ－１／升糖素受體促效劑
TW201625668A (zh) 2014-04-07 2016-07-16 賽諾菲公司 作為胜肽性雙重ｇｌｐ－１／昇糖素受體激動劑之艾塞那肽－４衍生物
TW201625670A (zh) 2014-04-07 2016-07-16 賽諾菲公司 衍生自ｅｘｅｎｄｉｎ－４之雙重ｇｌｐ－１／升糖素受體促效劑
US9932381B2 (en) 2014-06-18 2018-04-03 Sanofi Exendin-4 derivatives as selective glucagon receptor agonists
CN106519015B (zh) 2014-09-23 2020-04-17 深圳市图微安创科技开发有限公司 胃泌酸调节素类似物
CN107108713A (zh) 2014-10-10 2017-08-29 诺和诺德股份有限公司 稳定的基于glp‑1的glp‑1/胰高血糖素受体共激动剂
WO2016065090A1 (en) 2014-10-24 2016-04-28 Merck Sharp & Dohme Corp. Co-agonists of the glucagon and glp-1 receptors
WO2016198624A1 (en) 2015-06-12 2016-12-15 Sanofi Exendin-4 derivatives as trigonal glp-1/glucagon/gip receptor agonists
WO2016198604A1 (en) 2015-06-12 2016-12-15 Sanofi Exendin-4 derivatives as dual glp-1 /glucagon receptor agonists
AR105284A1 (es) 2015-07-10 2017-09-20 Sanofi Sa Derivados de exendina-4 como agonistas peptídicos duales específicos de los receptores de glp-1 / glucagón

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
Braga et al., "Making Crystals from Crystals: a green route to crystal engineering and polymorphism," Chem. Commun., 2005,pp 3635-3645 *
Seddon, K.R., "Pseudopolymorph: a polemic," Crystal Growth & Design, 2004, 4(6), pp 1087, web release date October 19,2004 *
Vippagunta et al. "Crystalline Solids," Advanced Drug Delivery Reviews, 2001,48, pp 3-26. *

Cited By (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9255154B2 (en) 2012-05-08 2016-02-09 Alderbio Holdings, Llc Anti-PCSK9 antibodies and use thereof
US10259885B2 (en) 2012-05-08 2019-04-16 Alderbio Holdings Llc Anti-PCSK9 antibodies and use thereof
US9365632B2 (en) 2012-10-09 2016-06-14 Sanofi Exendin-4 derivatives as dual GLP1/glucagon agonists
US10758592B2 (en) 2012-10-09 2020-09-01 Sanofi Exendin-4 derivatives as dual GLP1/glucagon agonists
US9745360B2 (en) 2012-12-21 2017-08-29 Sanofi Dual GLP1/GIP or trigonal GLP1/GIP/glucagon agonists
US10253079B2 (en) 2012-12-21 2019-04-09 Sanofi Functionalized Exendin-4 derivatives
US11485753B2 (en) 2012-12-21 2022-11-01 Janssen Pharmaceutica Nv Substituted nucleosides, nucleotides and analogs thereof
US12173025B2 (en) 2012-12-21 2024-12-24 Janssen Pharmaceuticals, Inc. Substituted nucleosides, nucleotides and analogs thereof
US9670261B2 (en) 2012-12-21 2017-06-06 Sanofi Functionalized exendin-4 derivatives
US9750788B2 (en) 2013-12-13 2017-09-05 Sanofi Non-acylated exendin-4 peptide analogues
US9751926B2 (en) 2013-12-13 2017-09-05 Sanofi Dual GLP-1/GIP receptor agonists
US9789165B2 (en) 2013-12-13 2017-10-17 Sanofi Exendin-4 peptide analogues as dual GLP-1/GIP receptor agonists
US9694053B2 (en) 2013-12-13 2017-07-04 Sanofi Dual GLP-1/glucagon receptor agonists
US9771406B2 (en) 2014-04-07 2017-09-26 Sanofi Peptidic dual GLP-1/glucagon receptor agonists derived from exendin-4
US9775904B2 (en) 2014-04-07 2017-10-03 Sanofi Exendin-4 derivatives as peptidic dual GLP-1/glucagon receptor agonists
US9758561B2 (en) 2014-04-07 2017-09-12 Sanofi Dual GLP-1/glucagon receptor agonists derived from exendin-4
US9932381B2 (en) 2014-06-18 2018-04-03 Sanofi Exendin-4 derivatives as selective glucagon receptor agonists
CN114848799A (zh) * 2015-05-28 2022-08-05 免疫新炉有限公司 用于肌肉减少症治疗的包括胰高血糖素样肽-1受体激动剂的药物组合物
US10806797B2 (en) 2015-06-05 2020-10-20 Sanofi Prodrugs comprising an GLP-1/glucagon dual agonist linker hyaluronic acid conjugate
US9982029B2 (en) 2015-07-10 2018-05-29 Sanofi Exendin-4 derivatives as selective peptidic dual GLP-1/glucagon receptor agonists
US10894076B2 (en) 2015-12-29 2021-01-19 Pegbio Co., Ltd. Composition comprising GLP-1 receptor agonist and glucagon receptor agonist and application thereof
US11214606B2 (en) 2019-08-16 2022-01-04 Applied Molecular Transport Inc. Compositions, formulations and interleukin production and purification
US11466067B2 (en) 2019-08-16 2022-10-11 Applied Molecular Transport Inc. Compositions, formulations and interleukin production and purification
US11479593B2 (en) 2019-08-16 2022-10-25 Applied Molecular Transport Inc. Compositions, formulations and interleukin production and purification
US11160869B2 (en) 2019-08-16 2021-11-02 Applied Molecular Transport Inc. Compositions, formulations and interleukin production and purification
US12215133B2 (en) 2021-03-25 2025-02-04 Brightgene Bio-Medical Technology Co., Ltd. GIP and GLP-1 dual receptor agonist, pharmaceutical composition, and use
US12303604B1 (en) 2024-10-16 2025-05-20 Currax Pharmaceuticals Llc Pharmaceutical formulations comprising naltrexone and/or bupropion

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