Glucagon-GLP-1-GIP triple agonist compounds

• US 10,131,702 B2
• Filed: 11/06/2014
• Issued: 11/20/2018
• Est. Priority Date: 11/06/2013
• 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): Cordero Garcia, Marcela M
• Application Number:
  US15/034,784
• Publication Number:
  US 20160257729A1
• Time in Patent Office: 1,475 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 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 19/10 for osteoporosis
• 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 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 5/48 of the pancreatic hormones
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• 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: C07K 14/605 Glucagons

Abstract

The present invention relates to compounds which have agonist activity at the glucagon, GIP and GLP-1 receptors, and to their use in the treatment of metabolic disorders.

Claims

1. A glucagon-GLP-1-GIP triple agonist compound having the general formula I:

R¹-Tyr-X2-Gln-Gly-Thr-Phe-Thr-Ser-Asp-X10-Ser-X12-X13-Leu-X15-X16-X17-Ala-X19-X20-X21-Phe-X23-X24-Trp-Leu-X27-X28-X29-X30-Y1-R² (SEQ ID NO;

     52) 

 

(I)

wherein

R¹ is H—

, C_1-4 alkyl, acetyl, formyl, benzoyl, trifluoroacetyl or pGlu;

X2 is Aib, Gly, Ala, D-Ala, Ser, N-Me-Ser, Ac3c, Ac4c or Ac5c;

X10 is Tyr or Leu;

X12 is Lys, Ile or ψ

;

X13 is Ala, Tyr or Aib;

X15 is Asp or Glu;

X16 is Ser, Glu, Lys or ψ

;

X17 is Lys or ψ

;

X19 is Gln or Ala;

X20 is Lys, His, Arg or ψ

;

X21 is Ala, Asp or Glu;

X23 is Val or Ile;

X24 is Asn, Glu or ψ

;

X27 is Leu, Glu or Val;

X28 is Ala, Ser, Arg or ψ

;

X29 is Aib, Ala, Gln or Lys;

X30 is Lys, Gly, or is absent;

Y1 is Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO;

     53), Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO;

     54), Lys-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO;

     55), Lys-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO;

     56), Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO;

     57) or Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO;

     58), or is absent;

ψ

is a residue of Lys, Arg, Orn or Cys in which the side chain is conjugated to a lipophilic substituent;

and

R² is —

NH₂ or —

OH;

or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 wherein ψ

is present at one of positions X12, X16 or X17.

3. The compound according to claim 1 wherein the compound contains only one residue ψ

.

4. The compound according to claim 1 wherein the compound possesses one or more of the following sets of residues:

K12 and Y13;

I12 and Y13;

K12 and A13;

I12 and A13;

or ψ

12 and Y13;

D15 and S16;

D15 and E16;

E15 and K16;

D15 and ψ

16;

E15 and S16;

or E15 and ψ

16;

A19, H20, and D21;

A19, K20, and D21;

A19, R20, and D21;

Q19, K20, and E21;

A19, K20, and E21;

or Q19, R20, and A21;

I23 and E24;

V23 and E24;

or V23 and N24;

L27, R28, and A29;

L27, S28, and A29;

L27, A28, and Q29;

E27, S28, and A29;

or V27, A28, and Aib29;

E15 and K17;

E15 and ψ

17;

E15, ψ

17, and Q19;

Q19 and E24;

E16, ψ

17, and Q19;

or

K16, ψ

17, and Q19.

5. The compound according to claim 1 wherein positions 1 to 29 have the sequence:

6. The compound according to claim 1 which differs at up to 4 positions from any of the sequences:

7. The compound according to claim 1 wherein the peptide backbone of Formula I has the sequence:

8. The compound according to claim 1 wherein the peptide backbone of Formula I has a sequence which differs at up to 5 positions from one of the sequences:

9. The compound according to claim 1 wherein ψ

is a residue of Lys in which the side chain is conjugated to a lipophilic substituent.

10. The compound according to claim 1 wherein the lipophilic substituent has the formula —

Z¹ or —

Z²—

Z¹ wherein;

—

Z¹ is a fatty chain having at a terminus a connection —

X—

to ψ

or to Z²;

wherein

—

X—

is a bond, —

CO—

, —

SO—

, or —

SO₂—

;

and, optionally, Z¹ has a polar group at the end of the chain distal from connection —

X—

, said polar group comprising a carboxylic acid or a carboxylic acid bioisostere, a phosphonic acid, or a sulfonic acid group;

and wherein —

Z²—

, if present, is a spacer of formula;

11. The compound according to claim 10 wherein the lipophilic substituent has the formula —

Z²—

Z¹.

12. The compound according to claim 9 wherein Z¹ is A-B-alkylene-CO—

wherein A is H or —

COOH and B is a bond.

13. The compound according to claim 12 wherein Z¹ is A-B—

C_16-20alkylene-(CO)—

.

14. The compound according to claim 10 wherein Z¹ is:

hexadecanoyl;

17-carboxy-heptadecanoyl [HOOC—

(CH₂)₁₆—

(CO)—

];

19-carboxy-nonadecanoyl [HOOC—

(CH₂)₁₈—

(CO)—

];

Octadecanoyl [H₃C—

(CH₂)₁₆—

(CO)—

];

or

Eicosanoyl [H₃C—

(CH₂)₁₈—

(CO)—

].

15. The compound according to claim 10 wherein Z² comprises a residue selected from isoGlu or Dapa.

16. The compound according to claim 10 wherein —

Z¹ or —

Z²—

Z¹ is;

(i) [17-carboxy-heptadecanoyl]-isoGlu-Peg3-Peg3

17. The compound according to claim 1 wherein:

(a) positions 1 to 29 have the sequence;

18. A pharmaceutical composition comprising the triple agonist compound according to claim 1, or a pharmaceutically acceptable salt thereof, in admixture with a carrier, wherein the pharmaceutical composition is formulated as a liquid suitable for administration by injection or infusion, or formulated to cause slow release of said triple agonist compound.

19. A method of treatment and/or prevention of diabetes or a diabetes related disorder, or obesity or an obesity related disorder, comprising administering to a subject the triple agonist compound according to claim 1, or a pharmaceutically acceptable salt thereof.

20. The method according to claim 19 wherein:

(a) the diabetes related disorder is insulin resistance, glucose intolerance, increased fasting glucose, pre-diabetes, type 1 diabetes, type 2 diabetes, gestational diabetes hypertension, dyslipidemia, bone related disorder or a combination thereof;

(b) the diabetes related disorder is atherosclerosis, arteriosclerosis, coronary heart disease, peripheral artery disease, stroke, or a condition associated with atherogenic dyslipidemia, a blood fat disorder, elevated blood pressure, hypertension, a prothrombotic state, or a proinflammatory state, wherein optionally the condition associated with a blood fat disorder is high triglycerides, low HDL cholesterol, high LDL cholesterol, plaque buildup in artery walls, or a combination thereof;

or

(c) the obesity related disorder is obesity linked inflammation, obesity linked gallbladder disease, obesity induced sleep apnea, or associated with a condition selected from atherogenic dyslipidemia, blood fat disorders, elevated blood pressure, hypertension, a prothrombotic state, a proinflammatory state, or a combination thereof.

21. The compound according to claim 4, further comprising:

Aib2, Ser2 or Ac4c2;

or

Tyr10;

or

Leu10.

22. The compound according to claim 6 which differs at up to 4 positions from one of the sequences:

23. The compound according to claim 1, wherein the peptide backbone of Formula (I) has the sequence:

24. The method according to claim 20, wherein the bone related disorder is osteoporosis.