GIP-GLP-1 DUAL AGONIST COMPOUNDS AND METHODS

• US 20150299281A1
• Filed: 05/03/2013
• Published: 10/22/2015
• Est. Priority Date: 05/03/2012
• Status: Active Grant

• Current Assignee: Zealand Pharma A/S
• Original Assignee: Zealand Pharma A/S
• Inventors: JUST, Rasmus, RIBER, Ditte, SHELTON, Anne Pernille Tofteng, STERLUND, Torben, HANSEN, Kate, JESSEN, Lene
• Granted Patent: US 10,100,097 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/16 Central respiratory analeptics
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/50 for increasing or potentiating the activity of insulin
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: A61P 9/14 Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: C07K 14/575 Hormones derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin C07K14/665, e.g. corticotropin C07K14/695
• CPC Class Codes: C07K 14/605 Glucagons

Abstract

The present invention relates to truncated GIP analogues which comprise one or more substitutions as compared to wild-type GIP and which may have the property of an altered, preferably increased GLP-1 activity, e.g. as assessed in in vitro efficacy assays. The invention provides GIP-GLP-1 dual agonist compounds and associated methods.

Claims

1. A GIP analogue represented by the general Formula I′

;

2. The GIP analogue of claim 1, wherein the GIP analogue is represented by the general Formula I(b)′

;

8. A GIP analogue of claim 1, wherein the amino acid sequence X1-X29 has no more than 6 amino acid differences from the sequence Y-Aib-EGTFTSDYSIYLDKKAQRAFVEWLLAQ (SEQ ID NO:

70).

9. A GIP analogue of claim 1, wherein the amino acid sequence X1-X29 has no more than 6 amino acid differences from the sequence Y-Aib-EGTFTSDYSIYLEKKAAKEFVEWLLSA (SEQ ID NO:

71).

10. A GIP analogue of claim 1, wherein the amino acid sequence X1-X29 has no more than 5 amino acid differences from sequence Y-Aib-EGTFTSDYSIYLDEKAAKEFIEWLESA (SEQ ID NO:

72).

11. A GIP analogue according to claim 1, wherein X24 is Glu and/or X21 is Ala.

12. A GIP analogue according to claim 1, wherein X7 is Thr and X14 is Leu.

13. A GIP analogue according to claim 1, wherein X7 is Thr, X14 is Leu and X18 is Ala.

14. A GIP analogue according to claim 1, wherein X2 is Aib, X7 is Thr and X14 is Leu.

15. A GIP analogue according to claim 1, wherein X2 is Aib, X7 is Thr, X14 is Leu and X13 and/or X29 is Aib.

16. A GIP analogue according to claim 1, wherein X2 is Aib, X7 is Thr, X14 is Leu and X24 is Glu.

17. A GIP analogue according to claim 1, wherein X2 is Aib, X7 is Thr, X14 is Leu, X24 is Glu and X29 is Gln.

18. A GIP analogue according to claim 1, wherein X2 is Aib, X7 is Thr, X14 is Leu, X21 is Ala, X24 is Glu and X29 is Gln.

19. A GIP analogue according to claim 1, wherein X2 is Aib, X7 is Thr, X14 is Leu, X24 is Glu, X27 is Leu and X28 is Ser.

20. A GIP analogue according to claim 1, wherein X2 is Aib, X7 is Thr, X14 is Leu, X24 is Glu, X27 is Glu and X28 is Ser.

21. A GIP analogue according to claim 1, wherein X2 is Aib, X7 is Thr, X14 is Leu, X20 is His, X24 is Glu, X27 is Leu and X28 is Ser.

22. A GIP analogue according to claim 1 selected from:

23. A GIP analogue according to claim 1 with a lipophilic substituent conjugated to one or more of positions 15, 16, 17, 19, 20, 24, 27, 28 and 30.

25. A pharmaceutical composition comprising a GIP analogue of claim 1, or a salt, solvate or derivative thereof, in admixture with a carrier.

26. The pharmaceutical composition of claim 25, wherein the GIP analogue is a pharmaceutically acceptable acid addition salt.

27. The pharmaceutical composition of claim 25, which is formulated as a liquid suitable for administration by injection or infusion, or which is formulated to cause slow release of said GIP analogue.

44. A method of treating a stomach and/or bowel-related disorder in a patient in need thereof by administering an effective amount a GIP analogue of claim 1.

45. A method of treatment and/or prevention of a metabolic disease or disorder in a patient in need thereof comprising administering to said patient an effective amount of the GIP analogue of claim 1.

46. The method of claim 45, wherein the metabolic disease or disorder is selected from the group consisting of diabetes, a diabetes-related disorder, obesity and an obesity-related disorder.

49. The method of claim 46, wherein the diabetes:

related disorder is selected from the group consisting of insulin resistance, glucose intolerance, increased fasting glucose, pre-diabetes, type 1 diabetes, type 2 diabetes, gestational diabetes hypertension, dyslipidemia, or a combination thereof.

50. The method of claim 46, wherein the diabetes:

related disorder is selected from the group consisting of atherosclerosis, arteriosclerosis, coronary heart disease, peripheral artery disease and stroke;

or is associated with a condition selected from atherogenic dyslipidemia, blood fat disorders, elevated blood pressure, hypertension, a prothrombotic state, and a proinflammatory state, or a combination thereof.

51. The method of claim 50, wherein the blood fat disorder is selected from the group consisting of high triglycerides, low HDL cholesterol, high LDL cholesterol, plaque buildup in artery walls, or a combination thereof.

52. The method of claim 50, wherein the prothrombotic state is selected from the group consisting of high fibrinogen levels in the blood and high plasminogen activator inhibitor-1 levels in the blood.

53. The method of claim 50, wherein the proinflammatory state is an elevated C-reactive protein level in the blood.

54. The method of claim 46, wherein the obesity related disorder is selected from obesity linked inflammation, obesity linked gallbladder disease and obesity induced sleep apnea.

55. A therapeutic kit comprising a GIP analogue according to claim 1, optionally in combination with a pharmaceutically acceptable carrier.

56. A device comprising a GIP analogue according to claim 1, for delivery of the GIP analogue to a subject.

3. A GIP analoaue represented by the general Formula II′

;

4. The GIP analogue of claim 3, wherein the GIP analogue is represented by the general Formula II(a)′

;

5. The GIP analogue of claim 4, wherein the GIP analogue is represented by the general Formula II(b)′

;

6. The GIP analogue of claim 4, wherein the GIP analogue is represented by the general Formula II(c)′

;

7. The GIP analogue of claim 5, wherein the GIP analogue is represented by the general Formula II(d)′

;

24. (canceled)

28-43. -43. (canceled)

47-48. -48. (canceled)

57-67. -67. (canceled)