GIP-GLP-1 dual agonist compounds and methods

• US 10,093,713 B2
• Filed: 11/06/2014
• Issued: 10/09/2018
• Est. Priority Date: 11/06/2013
• Status: Active Grant

• Current Assignee: Zealand Pharma A/S
• Original Assignee: Zealand Pharma A/S
• Inventors: Shelton, Anne Pernille Tofteng, Norregaard, Pia, Fog, Jacob Ulrik, Knudsen, Carsten Boye
• Primary Examiner(s): Cordero Garcia, Marcela M
• Application Number:
  US15/034,778
• Publication Number:
  US 20160280754A1
• Time in Patent Office: 1,433 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 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• 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 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
• CPC Class Codes: C07K 14/645 Secretins

Abstract

The present invention relates to acylated GIP analogs which have dual GIP and GLP-1 activity, and their use in the treatment of metabolic disorders.

Claims

1. A GIP analogue having the general Formula I:

R¹-Tyr-X2-Glu-Gly-Thr-Phe-Thr-Ser-Asp-X10-Ser-Ile-X13-Leu-X15-X16-Ψ

-Ala-X19-X20-X21-Phe-X23-X24-Trp-Leu-X27-X28-X29-X30-R² 

 

(SEQ ID NO;

     56) (I)

wherein

R¹ is H, C_1-4 alkyl, acetyl, formyl, benzoyl, trifluoroacetyl or pGlu;

X2 is selected from Aib and D-Ala;

X10 is selected from Tyr and Leu;

X13 is selected from Ala, Tyr and Aib;

X15 is selected from Asp and Glu;

X16 is selected from Glu and Lys;

X19 is selected from Gln and Ala;

X20 is selected from Lys and Arg;

X21 is selected from Ala and Glu;

X23 is selected from Val and Ile;

X24 is selected from Asn and Glu;

X27 is selected from Leu, Glu and Val;

X28 is selected from Ala, Ser and Arg;

X29 is selected from Aib, Ala, and Gln;

X30 is selected from Lys, Gly and Y1, or is absent;

Y1 (when present) is selected from Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO;

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

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

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

     60) and Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO;

     61);

Ψ

is a residue of Lys, Arg, Orn or Cys in which the side chain is conjugated to a substituent having the formula —

Z²-Z¹, wherein Z²-Z¹ is;

4. A GIP analogue of claim 1, comprising one of the following residues or combinations of residues:

Gln19, Arg20, Ala21;

Aib2, Gln19, Arg20, Ala21;

Aib2, Ala13, Gln19, Arg20, Ala21;

Asp15, Gln19, Arg20, Ala21;

Lys16, Gln19, Arg20, Ala21;

Aib2, Ala13, Asp15, Gln19, Arg20, Ala21;

Aib2, Asp15, Gln19, Arg20, Ala21;

Aib2, Lys16, Gln19, Arg20, Ala21;

Aib2, Asp15, Lys16, Gln19, Arg20, Ala21;

Leu27, Ala28, Gln29;

Glu24, Leu27, Ala28, Gln29;

Gln19, Arg20, Ala21;

Leu27, Ala28, Gln29;

Gln19, Arg20, Ala21;

Glu24, Leu27, Ala28, Gln29;

Asp15, Gln19, Arg20, Ala21;

Glu15, Gln19, Arg20, Ala21;

Aib2, Glu15, Gln19, Arg20, Ala21;

Aib2, Glu15, Lys16, Gln19, Arg20, Ala21;

Glu15, Leu27, Ala28, Gln29;

Glu15, Gln19, Arg20, Ala21;

Leu27, Ala28, Gln29;

Glu15, Gln19, Arg20, Ala21, Glu24;

Aib2, Glu15, Gln19, Arg20, Ala21, Glu24;

Aib2, Ala13, Asp15, Gln19, Arg20, Ala21, Glu24;

Aib2, Ala13, Asp15, Gln19, Arg20, Ile23, Glu24;

Aib2, Glu15, Lys16, Gln19, Arg20, Ala21, Glu24;

Aib2, Ala13, Gln19, Arg20, Ala21, Glu24;

Asp15, Ile23, Gln29 Glu15, Glu24, Leu27, Ala28, Gln29;

Glu15, Gln19, Arg20, Ala21;

Glu24, Leu27, Ala28, Gln29;

Ala19, Lys20, Glu21;

Ala13, Ala19, Lys20, Glu21;

Ala19, Lys20, Glu21, Ser28;

Ala19, Lys20, Glu21, Ala29;

Ala19, Lys20, Glu21, Ser28, Ala29;

Glu15, Ala19, Lys20, Glu21;

Ala13, Asp15, Ala19, Lys20, Glu21;

Glu15, Ala19, Lys20, Glu21, Ser28;

Glu15, Ala19, Lys20, Glu21, Ala29;

Ala13, Asp15, Ala19, Lys20, Glu21, Ala29;

Glu15, Ala19, Lys20, Glu21, Ser28, Ala29;

Glu16, Ala19, Lys20, Glu21;

Ala13, Asp15, Glu24, Gln29

Glu16, Ala19, Lys20, Glu21, Ser28;

Glu16, Ala19, Lys20, Glu21, Ala29;

Glu16, Ala19, Lys20, Glu21, Ser28, Ala29;

Ala13, Asp15, Ile23;

Glu27, Ser28, Ala29;

Glu16, Glu27, Ser28, Ala29;

Ala19, Lys20, Glu21, Glu27, Ser28, Ala29;

Glu16, Ala19, Lys20, Glu21, Glu27, Ser28, Ala29;

Val27, Aib29;

Asn24, Val27 Aib29;

Asn24, Aib29;

Ala13, Asp15, Glu27;

Glu15, Glu24;

Glu15, Glu24; and

Leu10, or any of the above in combination with Leu10.

5. A GIP analogue according to claim 1 wherein positions 1 to 29 of the GIP analogue have a maximum of 8 changes compared to the sequence:

6. A GIP analogue according to claim 5 wherein:

(a) if positions 1 to 29 of the GIP analogue have 6 or more changes compared to that sequence, the analogue possesses all of Ala20, Lys21 and Glu22 and optionally one or both of Ser28 and Ala29;

or

(b) if the analogue does not possess Ala19, Lys20 and Glu21, then positions 1 to 29 have 4 or fewer changes compared to that sequence.

7. A GIP analogue according to claim 1 wherein positions 1 to 29 of the GIP analogue have a maximum of 6 changes compared to the sequence

8. A GIP analogue according to claim 7 wherein the analogue possesses one, two, or all of Ala19, Lys20 and Glu21.

9. A GIP analogue according to claim 8, wherein the analogue additionally possesses one or more of the following:

Glu15 and/or Glu16;

Ser28 and/or Ala29;

Val27 and/or Aib29;

Asn24, Val27 and/or Aib29;

Asn24 and/or Aib29;

Glu15 and/or Glu27;

Ala13, Glu15 and/or Glu16;

Ala13, Ser28 and/or Ala29;

Ala13, Val27 and/or Aib29;

Ala13, Asn24, Val27 and/or Aib29;

Ala13, Asn24 and/or Aib29;

Ala13, Glu15 and/or Glu27;

Asp15 and/or Glu16;

Asp15, Ser28 and/or Ala29;

Asp15, Val27 and/or Aib29;

Asp15, Asn24, Val27 and/or Aib29;

Asp15, Asn24, Aib29;

Asp15, Glu27;

Glu15 or Glu16 or Ile23;

Ile23, Ser28 and/or Ala29;

Ile23, Val27 and/or, Aib29;

Ile23, Asn24, Val27 and/or Aib29;

Ile23, Asn24 and/or Aib29;

Glu15, Ile23 and/or Glu27;

Aib2 and/or Ala13;

Aib2 and/or Tyr13;

Asp15 and/or Glu16;

Ile23 and/or Glu24;

DAla, Ser28 and/or Ala29;

Asn24 and/or Arg20;

Asn24 and/or Ala29.

10. A GIP analogue according to claim 1 possessing one of the following combinations of residues at the variable positions between 1 and 29:

Aib2, Tyr10, Tyr13, Asp15, Lys16, Gln19, Arg20, Ala21, Val23, Glu24, Leu27, Ala28, Gln29;

D-Ala2, Tyr10, Tyr13, Asp15, Lys16, Gln19, Arg20, Ala21, Val23, Glu24, Leu27, Ala28, Gln29;

Aib2, Tyr10, Tyr13, Glu15, Lys16, Ala19, Lys20, Glu21, Val23, Glu24, Leu27, Ser28, Ala29;

Aib2, Tyr10, Aib13, Asp15, Lys16, Gln19, Arg20, Ala21, Val23, Glu24, Leu27, Ala28, Gln29;

Aib2, Tyr10, Tyr13, Asp15, Lys16, Gln19, Arg20, Ala21, Val23, Asn24, Leu27, Ala28, Aib29;

Aib2, Tyr10, Tyr13, Asp15, Glu16, Ala19, Lys20, Glu21, Ile23, Glu24, Glu27, Ser28, Ala29;

Aib2, Tyr10, Ala13, Asp15, Lys16, Gln19, Arg20, Ala21, Val23, Asn24, Val27, Ala28, Aib29;

Aib2, Tyr10, Ala13, Glu15, Lys16, Gln19, Arg20, Ala21, Val23, Glu24, Leu27, Ala28, Gln29;

Aib2, Leu10, Ala13, Glu15, Lys16, Gln19, Arg20, Ala21, Val23, Glu24, Leu27, Ala28, Gln29;

Aib2, Tyr10, Tyr13, Glu15, Lys16, Gln19, Arg20, Ala21, Val23, Glu24, Leu27, Arg28, Ala29;

Aib2, Leu10, Ala13, Asp15, Lys16, Gln19, Arg20, Ala21, Val23, Asn24, Val27, Ala28 Aib29;

Aib2, Tyr10, Ala13, Asp15, Lys16, Gln19, Arg20, Ala21, Val23, Glu24, Val27, Ala28, Aib29;

Aib2, Tyr10, Ala13, Glu15, Lys16, Gln19, Arg20, Ala21, Val23, Glu24, Glu27, Ala28, Gln29;

Aib2, Tyr10, Ala13, Glu15, Lys16, Gln19, Arg20, Ala21, Val23, Glu24, Glu27, Ala28, Gln29;

Aib2, Leu10, Ala13, Glu15, Lys16, Gln19, Arg 20, Ala21, Val23, Glu24, Glu27, Ala28, Gln29;

Aib2, Tyr10, Ala13, Asp15, Lys16, Gln19, Arg20, Ala21, Val23, Glu24, Leu27, Ala28, Gln29;

D-Ala2, Tyr10, Ala13, Asp15, Lys16, Gln19, Arg20, Ala21, Val23, Glu24, Leu27, Ala28, Gln29;

Aib2, Tyr10, Ala13, Glu15, Lys16, Ala19, Lys20, Glu21, Val23, Glu24, Leu27, Ser28, Ala29;

Aib2, Tyr10, Ala13, Asp15, Lys16, Gln19, Arg20, Ala21, Val23, Glu24, Leu27, Ala28, Gln29;

Aib2, Tyr10, Ala13, Asp15, Lys16, Gln19, Arg20, Ala21, Val23, Asn24, Leu27, Ala28, Aib29;

Aib2, Tyr10, Ala13, Asp15, Glu16, Ala19, Lys20, Glu21, Ile23, Glu24, Glu27, Ser28, Ala29;

Aib2, Tyr10, Ala13, Glu15, Lys16, Gln19, Arg20, Ala21, Val23, Glu24, Leu27, Arg28, Ala29;

Aib2, Tyr10, Tyr13, Asp15, Lys16, Gln19, Arg20, Ala21, Ile23, Glu24, Leu27, Ala28, Gln29;

D-Ala2, Tyr10, Tyr13, Asp15, Lys16, Gln19, Arg20, Ala21, Ile23, Glu24, Leu27, Ala28, Gln29;

Aib2, Tyr10, Tyr13, Glu15, Lys16, Ala19, Lys20, Glu21, Ile23, Glu24, Leu27, Ser28, Ala29;

Aib2, Tyr10, Aib13, Asp15, Lys16, Gln19, Arg20, Ala21, Ile23, Glu24, Leu27, Ala28, Gln29;

Aib2, Tyr10, Tyr13, Asp15, Lys16, Gln19, Arg20, Ala21, Ile23, Asn24, Leu27, Ala28, Aib29;

Aib2, Tyr10, Ala13, Asp15, Lys16, Gln19, Arg20, Ala21, Ile23, Asn24, Val27, Ala28, Aib29;

Aib2, Tyr10, Ala13, Glu15, Lys16, Gln19, Arg20, Ala21, Ile23, Glu24, Leu27, Ala28, Gln29;

Aib2, Leu10, Ala13, Glu15, Lys16, Gln19, Arg20, Ala21, Ile23, Glu24, Leu27, Ala28, Gln29;

Aib2, Tyr10, Tyr13, Glu15, Lys16, Gln19, Arg20, Ala21, Ile23, Glu24, Leu27, Arg28, Ala29;

Aib2, Leu10, Ala13, Asp15, Lys16, Gln19, Arg20, Ala21, Ile23, Asn24, Val27, Ala28 Aib29;

Aib2, Tyr10, Ala13, Asp15, Lys16, Gln19, Arg20, Ala21, Ile23, Glu24, Val27, Ala28, Aib29;

Aib2, Tyr10, Ala13, Glu15, Lys16, Gln19, Arg20, Ala21, Ile23, Glu24, Glu27, Ala28, Gln29;

Aib2, Tyr10, Ala13, Glu15, Lys16, Gln19, Arg20, Ala21, Ile23, Glu24, Glu27, Ala28, Gln29;

Aib2, Leu10, Ala13, Glu15, Lys16, Gln19, Arg 20, Ala21, Ile23, Glu24, Glu27, Ala28, Gln29.

11. A GIP analogue according to claim 1 residues 1-29 of Formula I have the sequence:

12. A GIP analogue according to claim 1 wherein Ψ

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

Z²-Z¹.

13. A GIP analogue according to claim 1 wherein:

(a) residues 1-29 of Formula I have the sequence;

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

15. 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 in need thereof a GIP analogue according to claim 1, or a pharmaceutically acceptable salt thereof.

16. The method according to claim 15, wherein:

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

or

(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;

or

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

17. The method according to claim 16, wherein the bone related disorder is osteoporosis.

18. The method according to claim 16, wherein 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.

2. A GIP analogue having the general Formula Ib:

3. The GIP analogue according to claim 2, having the general Formula II:

19. A GIP analog according to the following formula:

R¹—

Y-Aib-EGTFTSDYSIYLDK-K([19-carboxy-nonadecanoyl]-Peg3-Peg3)-AQRAFVEWLLAQGPSSGAPPPS-R² 

 

(SEQ ID NO;

     34);

R¹—

Y-Aib-EGTFTSDYSIYLDK-K([19-carboxy-nonadecanoyl]-IsoGlu)-AQRAFVEWLLAQGPSSGAPPPS 

 

(SEQ ID NO;

     35)-R²;

R¹—

Y-Aib-EGTFTSDYSIYLDK-K([19-carboxy-nonadecanoyl]-Dapa-Peg3-Peg3)-AQRAFVEWLLAQGPSSGAPPPS-R² 

 

(SEQ ID NO;

     36);

R¹—

Y-Aib-EGTFTSDYSIYLDK-K([19-carboxy-nonadecanoyl]-Peg3-Peg3)-AQRAFVEWLLAQ-R² 

 

(SEQ ID NO;

     156);

R¹—

Y-Aib-EGTFTSDYSIYLDK-K([19-carboxy-nonadecanoyl]-IsoGlu)-AQRAFVEWLLAQ-R² 

 

(SEQ ID NO;

     157);

or

R¹—

Y-Aib-EGTFTSDYSIYLDK-K([19-carboxy-nonadecanoyl]-Dapa-Peg3-Peg3)-AQRAFVEWLLAQ-R² 

 

(SEQ ID NO;

     158)

wherein R¹ is H, C_1-4 alkyl, acetyl, formyl, benzoyl, trifluoroacetyl or pGlu; and

R² is —

NH₂ or —

OH,

or a pharmaceutically acceptable salt thereof.