GIP agonist compounds and methods

• US 10,253,078 B2
• Filed: 10/29/2015
• Issued: 04/09/2019
• Est. Priority Date: 10/29/2014
• Status: Active Grant

• Current Assignee: Zealand Pharma A/S
• Original Assignee: Zealand Pharma A/S
• Inventors: Shelton, Anne Pernille Tofteng, Norregaard, Pia, Deryabina, Maria Alexandrovna, Larsen, Bjarne Due, Fog, Jacob Ulrik
• Primary Examiner(s): Heard, Thomas S
• Application Number:
  US15/521,631
• Publication Number:
  US 20170240609A1
• Time in Patent Office: 1,258 Days
• Field of Search: None
• 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: A61K 38/22 Hormones derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin A61K38/33, e.g. corticotropin A61K38/35
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 19/10 for osteoporosis
• 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 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• 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 14/575 Hormones derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin C07K14/665, e.g. corticotropin C07K14/695

Abstract

The present invention relates to acylated GIP analogs which have GIP agonist activity, and their use in the treatment of metabolic disorders.

Claims

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

R¹-Tyr-X2-Glu-Gly-Thr-Phe-Ile-Ser-Asp-X10-X11-X12-Glu-Leu-X15-X16-X17-X18-X19-X20-X21-Phe-X23-X24-X25-Leu-X27-X28-X29-Y1-Y2-R² 

 

(I) (SEQ ID NO;

     42)

wherein

R¹ is H—

, Ac or pGlu;

X2 is Aib or D-Ala;

X10 is Tyr;

X11 is Ser;

X12 is Ψ

or Ile;

X15 is Asp or Glu;

X16 is Lys or Ψ

;

X17 is Ile or Ψ

;

X18 is His or Ala;

X19 is Gln or Ala;

X20 is Gln, Lys, or Arg;

X21 is Ala, Asp or Glu;

X23 is Val or Ile;

X24 is Asn or Glu;

X25 is Tyr or Trp;

X27 is Leu;

X28 is Ala;

X29 is Ala, Gln, Thr, Ser or Lys or is absent;

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

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

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

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

     46), or absent;

Y2 is Ψ

or is absent;

R² is —

NH₂ or —

OH;

wherein Ψ

is a Lys residue and wherein the side chain of said Lys residue is conjugated to a lipophilic substituent;

wherein the GIP analogue contains one and only one residue Ψ

;

and wherein the GIP analogue has agonist activity at the GIP receptor;

or a pharmaceutically acceptable salt thereof.

2. A GIP analogue according to claim 1 comprising one of the following residues or combinations of residues:

Aib2, Asp15, Lys20;

Aib2, Asp15, Arg20;

Aib2, Asp15, Arg20, Ile23;

Aib2, Ile12, Asp15, Arg20, Ile23, Glu24;

Ile12, Asp15, Ile23;

Ile12, Asp15, Ile23 Glu24;

Ile12, Asp15, Ala21, Ile23;

Aib2, Ala21, Ile23, Glu24;

Aib2, Asp15, Ile23;

Aib2, Asp15, Arg20, Ile23, Gln29;

DAla2, Asp15, Ile23;

Aib2, Asp15, Ile17, Lys20, Ala28;

Asp15, Ile23, Glu24.

3. A GIP analogue according to claim 1 represented by the general Formula III:

R¹-Tyr-Aib-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Glu-Leu-X15-X16-X17-X18-X19-X20-X21-Phe-Val-X24-X25-Leu-Leu-Ala-X29-Y1-Y2-R² 

 

(III) (SEQ ID NO;

     50)

wherein

R¹ is H—

, Ac or pGlu;

X15 is Asp or Glu;

X16 is Lys or Ψ

;

X17 is Ile or Ψ

;

X18 is His or Ala X19 is Gln or Ala;

X20 is Gln, Lys or Arg;

X21 is Ala, Asp or Glu;

X24 is Asn or Glu;

X25 is Tyr or Trp

X29 is Gln or is absent;

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

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

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

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

     46), or absent;

Y2 is Ψ

or is absent;

R² is —

NH₂ or —

OH;

wherein Ψ

is a Lys residue and wherein the side chain of said Lys residue is conjugated to a lipophilic substituent;

and wherein the GIP analogue contains one and only one residue Ψ

;

and wherein the GIP analogue has agonist activity at the GIP receptor;

or a pharmaceutically acceptable salt thereof.

4. A GIP analogue according to claim 3 comprising one of the following residues or combinations of residues:

Asp15, Lys20;

Asp15, Arg20;

Asp15, Arg20, Glu24;

Asp15, Lys16;

Asp15, Lys16, Glu24;

Asp15, Ψ

16, Ala21;

Ala21, Glu24;

Asp15, Arg20, Gln29;

Asp15, Arg20, Gly29;

Asp15, Ile17, Arg20, Gly29;

Asp15, Ile17, Lys20, Gly29;

Asp15, Ala28;

Asp15, Ile17, Lys20, Ala28;

Asp15, Ile23, Glu24;

Asp15, Ψ

17, Lys20;

Asp15, Ψ

17, Arg20;

Asp15 , Ψ

17, Arg20

Asp15, Ψ

17, Arg20, Glu24;

Asp15, Lys 16, Ψ

17;

Asp15, Lys 16, Ψ

17, Glu24;

Asp15 , Ψ

17, Ala21;

Ala21, Ψ

17, Glu24;

Asp15, Asp15 , Ψ

17, Arg20, Gln29;

Asp15 , Ψ

17, Arg20, Gly29;

Asp15, Ile17, Arg20, Gly29;

Asp15, Ile17, Lys20, Gly29;

Asp15;

Ψ

17;

Asp15, Ψ

17, Ala28;

Asp15, Ile17, Lys20, Ala28;

Asp15 , Ψ

17, Ile23, Glu24.

5. A GIP analogue according to claim 1, wherein Ψ

is a Lys in which the side chain is conjugated to a substituent having the formula —

Z¹ or —

Z²—

Z¹.

6. A GIP analogue according to claim 5, 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.

7. A GIP analogue according to claim 6 wherein Z¹ is a group of formula:

A-B-Alk-X—

wherein A is hydrogen or a carboxylic acid, a carboxylic acid bioisostere, a phosphonic acid, or a sulfonic acid group;

B is a bond or a linker;

X is a bond, acyl (—

CO—

), sulfinyl (—

SO—

), or sulfonyl (—

SO₂—

);

and Alk is a fatty chain that may be optionally substituted with one or more substituents.

8. A GIP analogue according to claim 7, wherein Z¹ is:

A-B—

C_16-20 alkylene-(CO)—

wherein A is H or —

COOH and B is

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)—

.

9. A GIP analogue according to claim 5, wherein Z² is a spacer bound at one terminus by Y, which is a nitrogen, oxygen or sulfur atom, and at the other terminus by X, which is a bond or an acyl (—

CO—

), sulfinyl (—

SO—

), sulfonyl (—

SO₂—

) or absent.

10. A GIP analogue according to claim 5, wherein —

Z¹-Z² is;

11. A GIP analogue according to claim 1 having the sequence

12. A GIP analogue according to claim 1 having the sequence

13. A GIP analogue according to claim 1 which is:

14. A pharmaceutical composition comprising a GIP analogue according to claim 1, or a pharmaceutically acceptable salt thereof, in admixture with a carrier.

15. A method of treating a metabolic disorder in an individual in need thereof, comprising administering to said individual a GIP analogue according to claim 1, or a pharmaceutically acceptable salt thereof.

16. The method according to claim 15 wherein the metabolic disorder is diabetes, a diabetes related disorder, obesity, or an obesity related disorder.

17. The method according to claim 16 wherein the diabetes related disorder is selected from the group consisting of insulin resistance, glucose intolerance, increased fasting glucose, hypoglycemia (for example induced by insulin treatment), pre-diabetes, type 1 diabetes, type 2 diabetes, gestational diabetes hypertension and dyslipidemia.

18. The method according to claim 16 wherein the obesity related disorder is selected from the group consisting of obesity linked inflammation, obesity linked gallbladder disease, obesity induced sleep apnea, atherogenic dyslipidemia, blood fat disorders, elevated blood pressure, hypertension, a prothrombotic state, a proinflammatory state, and combinations thereof.