GIP-GLP-1 dual agonist compounds and methods

• US 10,100,097 B2
• Filed: 05/03/2013
• Issued: 10/16/2018
• 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, Osterlund, Torben, Hansen, Kate, Jessen, Lene
• Primary Examiner(s): Steele, Amber D
• Application Number:
  US14/398,260
• Publication Number:
  US 20150299281A1
• Time in Patent Office: 1,992 Days
• 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 analogs 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.

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

25. The pharmaceutical composition of claim 24, wherein the GIP analogue is a pharmaceutically acceptable acid addition salt.

26. The pharmaceutical composition of claim 24, 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.

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

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

3. A GIP analogue 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 4, wherein the GIP analogue is represented by the general Formula II(d)′

;