Synthetic linear apelin mimetics for the treatment of heart failure

1. A polypeptide having the following formula (SEQ ID NO: 1):

X1-X2-X3-R—X5-X6-X7-X8-X9-X10-X11-X12-X13  I

wherein:

X1 is the N-terminus of the polypeptide and is either absent or pE;

X2 is R or r;

X3 is P or 4-PhP;

X5 is L, Cha, D-L, F, Y, Y(Bzl), 3,4-Cl2-F or Nal;

X6 is a D-amino acid, S or A;

X7 is a D-amino acid, L, H or Aib; and at least one of X6 and X7 is D-amino acid or Aib;

X8 is K, k, Q or E;

X9 is G or D;

X10 is P or pipecolic acid;

X11 is D-Nle, Nle, f or D-Nva;

X12 is absent, P or a D-amino acid;

X13 is the C-terminus and is absent, F or a D-amino acid; and at least one of X11, X12 and X13 is a D-amino acid;

wherein:

Nle is L-norleucine;

D-Nle is D-norleucine;

Nal is L-naphthyl)alanine;

D-Nva is D-norvaline;

Aib is α-aminoisobutyric acid;

Cha is (S)-β-cyclohexylalanine;

D-Tic is D-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid;

pE is L-pyroglutamic acid;

3,4-Cl2-F is (S)-3,4-dichlorophenylalanine;

Y is L-tyrosine; and

Y(Bzl) is L-benzyl-tyrosine;

or an amide, an ester or a salt of the polypeptide.

2. The polypeptide of claim 1 having sequence of (SEQ ID NO: 3) wherein X6 and X12 are D-amino acids; or a salt thereof.

3. The polypeptide of claim 2 having the sequence of (SEQ ID NO: 4) wherein X13 is D-amino acid; or a salt thereof.

4. The polypeptide of claim 3 having sequence of (SEQ ID NO: 5) wherein X11 is D-amino acid; of a salt thereof.

5. The polypeptide of claim 1 having sequence of (SEQ ID NO: 6) wherein X6 and X13 are D-amino acids; or a salt thereof.

6. A polypeptide according to claim 1 having the following formula (SEQ ID NO: 9):

X1-R—P—R—X5- a -X7-X8-G-P—X11-X12-X13  II

or a salt of the polypeptide.

7. The polypeptide according to claim 1 having Formula III (SEQ ID NO: 10):

X1-R—P—R—X5-X6-X7-K-G-P—X11- a - f   III;

or a salt of the polypeptide.

8. The polypeptide according to claim 1 having Formula IV (SEQ ID NO: 11):

X1-R—P—R—X5-S—X7-K-G-P—X11-X12-X13  IV;

or a salt of the polypeptide.

9. The polypeptide according to claim 1 having sequence of (SEQ ID NO: 12) wherein X6 is a D-amino acid selected from a, D-Leu, k, s, d, nva, abu, f, h, v and D-Cys(tBu); or a salt thereof.

10. The polypeptide of claim 1 having sequence of (SEQ ID NO: 14) wherein X12 is absent or a D-amino acid selected from a, f, p, e, r, abu, nva, and D-Leu; or a salt thereof.

11. The polypeptide of claim 1 having sequence of (SEQ ID NO: 15) wherein X13 is absent or is a D-amino acid selected from f, y, d, and D-Tic, or a salt thereof.

12. The polypeptide according to claim 11 having sequence of (SEQ ID NO: 16) wherein X13 is absent or f; or a salt of the polypeptide.

13. The polypeptide according to claim 1 having sequence of (SEQ ID NO: 17) wherein X1 is pE; or a salt of the polypeptide.

14. The polypeptide according to claim 1 having sequence of (SEQ ID NO: 18) wherein X5 is L; or a salt of the polypeptide.

15. The polypeptide according to claim 1 having sequence of (SEQ ID NO: 19) wherein X8 is K; or a salt of the polypeptide.

16. The polypeptide according to claim 1 selected from:

(SEQ ID NO: 22)

p E-R-P-R-L-a-H-K-G-Pip-nle-a-f- OH

(SEQ ID NO: 23)

p E-R-P-R-(D-Leu)-S-a-K-G-P-nle-a-f- OH

(SEQ ID NO: 24)

p E-r-P-R-L-a-H-K-G-P-nle-a-f- OH

(SEQ ID NO: 25)

p E-R-P-R-(D-Leu)-S-Aib-K-G-P-nle-a-f- OH

(SEQ ID NO: 26)

p E-R-P-R-L-S-Aib-k-G-P-nle-a-f- OH

(SEQ ID NO: 27)

p E-R-P-R-L-a-H-K-G-P-nle-f- OH

(SEQ ID NO: 28)

p E-R-P-R-L-c(tBu)-H-K-G-P-nle-a-f- OH

(SEQ ID NO: 29)

p E-R-P-R-L-d-H-K-G-P-nle-a-f- OH

(SEQ ID NO: 30)

p E-R-(trans-4-PhP)-R-L-a-H-K-G-P-nle-a-f- OH

(SEQ ID NO: 31)

p E-R-P-R-L-(D-Leu)-H-K-G-P-nle-a-f- OH

(SEQ ID NO: 32)

p E-R-P-R-L-k-H-K-G-P-nle-a-f- OH

(SEQ ID NO: 33)

p E-R-P-R-L-s-H-K-G-P-nle-a-f- OH

(SEQ ID NO: 34)

p E-R-P-R-L-a-H-K-G-P-nle-p-f- OH

(SEQ ID NO: 35)

p E-R-P-R-L-a-H-K-G-P-nle-(D-Leu)-f- OH

(SEQ ID NO: 36)

p E-R-P-R-L-a-Aib-K-G-P-nle-a-f- OH

(SEQ ID NO: 37)

p E-R-P-R-L-a-h-K-G-P-nle-a-f- OH

(SEQ ID NO: 38)

p E-R-P-R-L-a-F-K-G-P-nle-a-f- OH

(SEQ ID NO: 39)

p E-R-P-R-L-a-H-K-G-P-nle-F- OH

(SEQ ID NO: 40)

p E-R-P-R-L-a-H-K-G-P-nle-e-f- OH

(SEQ ID NO: 41)

p E-R-P-R-L-a-H-K-G-P-nle-r-f- OH

(SEQ ID NO: 42)

p E-R-P-R-L-a-H-K-G-P-nle-a-y- OH

(SEQ ID NO: 43)

p E-R-P-R-L-a-H-K-G-P-nle-a-d- OH

(SEQ ID NO: 44)

p E-R-P-R-Cha-a-H-K-G-P-nle-a-f- OH

(SEQ ID NO: 45)

p E-R-P-R-(3,4-Cl2-F)-a-H-K-G-P-nle-a-f- OH

(SEQ ID NO: 46)

p E-R-P-R-(2-Nal)-a-H-K-G-P-nle-a-f- OH

(SEQ ID NO: 47)

p E-R-P-R-L-a-H-K-G-P-nle-a-tic- OH

(SEQ ID NO: 48)

p E-R-P-R-Y(Bzl)-a-H-K-G-P-nle-a-f- OH

(SEQ ID NO: 49)

p E-R-P-R-Y-a-H-K-G-P-nle-a-f- OH

(SEQ ID NO: 50)

p E-R-P-R-L-a-H-K-G-P-nle-a-f- OH

(SEQ ID NO: 51)

p E-R-P-R-L-a-H-K-G-P-Nle-a-f- OH

(SEQ ID NO: 52)

p E-R-P-R-L-a-H-k-G-P-Nle-a-f- OH

(SEQ ID NO: 53)

p E-R-P-R-L-a-H-K-G-P-nle-NH(Phenethyl)

(SEQ ID NO: 54)

p E-R-P-R-L-a-H-K-G-P-nle-a-f-NH2

(SEQ ID NO: 55)

p E-R-P-R-L-a-H-K-G-P-Nle-P-f- OH

(SEQ ID NO: 56)

p E-R-P-R-L-a-H-K-G-P-Nle-f- OH

(SEQ ID NO: 57)

p E-R-P-R-L-a-H-K-G-P-nle-a-NH(Phenethyl)

(SEQ ID NO: 58)

p E-R-P-R-L-S-Aib-K-G-P-nle-a-F- OH

(SEQ ID NO: 59)

p E-R-P-R-L-S-Aib-K-G-P-Nle-a-f- OH

(SEQ ID NO: 60)

p E-R-P-R-L-a-H-K-G-P-Nle-a-F- OH

(SEQ ID NO: 61)

p E-R-P-R-L-S-Aib-K-G-P-nle-a-f- OH

(SEQ ID NO: 62)

p E-R-P-R-L-S-Aib-K-G-P-Nle-P-f- OH

(SEQ ID NO: 63)

p E-R-P-R-L-S-Aib-K-G-P-Nle-a-F- OH

(SEQ ID NO: 64)

p E-R-P-R-L-a-H-K-G-P-nle-(4-Phenoxypiperidin-1-yl)

(SEQ ID NO: 65)

p E-R-P-R-L-abu-H-K-G-P-nle-a-f- OH

(SEQ ID NO: 66)

p E-R-P-R-L-a-H-K-G-P-nle-abu-f- OH

(SEQ ID NO: 67)

p E-R-P-R-L-a-f-K-G-P-nle-a-f- OH

(SEQ ID NO: 68)

p E-R-P-R-L-a-L-K-G-P-nle-a-f- OH

(SEQ ID NO: 69)

p E-R-P-R-L-a-a-K-G-P-nle-a-f- OH

(SEQ ID NO: 70)

p E-R-a-R-L-a-H-K-G-P-nle-a-f- OH

(SEQ ID NO: 71)

H -R-P-R-L-a-H-K-G-P-nle-f- OH

(SEQ ID NO: 72)

p E-R-P-R-L-S-a-K-G-P-nle-a-f- OH

(SEQ ID NO: 73)

p E-R-P-R-L-nva-H-K-G-P-nle-a-f- OH

(SEQ ID NO: 74)

p E-R-P-R-L-a-H-K-G-P-nya-a-f- OH

(SEQ ID NO: 75)

p E-R-P-R-L-a-H-K-G-P-nle-nva-f- OH

(SEQ ID NO: 76)

p E-R-P-R-L-S-f-K-G-P-nle-a-f- OH

(SEQ ID NO: 77)

p E-R-P-R-L-S-h-K-G-P-nle-a-f- OH

(SEQ ID NO: 78)

p E-R-P-R-L-a-H-K-G-P-f-a-f- OH

(SEQ ID NO: 79)

p E-R-P-R-L-A-h-K-G-P-nle-a-f- OH

(SEQ ID NO: 80)

p E-R-P-R-L-a-H-Q-G-P-nle-a-f- OH

(SEQ ID NO: 81)

p E-R-P-R-L-a-H-E-G-P-nle-a-f- OH

(SEQ ID NO: 82)

p E-R-P-R-L-v-H-K-G-P-nle-a-f- OH

(SEQ ID NO: 83)

p E-R-P-R-L-a-H-K-D-P-nle-a-f- OH ;

(SEQ ID NO: 84)

p E-R-P-R-Cha-nva-H-K-G-P-nle-a-f- OH

or an amide, an ester or a salt of the polypeptide.

17. The polypeptide of claim 16 selected from:

(SEQ ID NO: 50)

p E-R-P-R-L-a-H-K-G-P-nle-a-f- OH

(SEQ ID NO: 22)

p E-R-P-R-L-a-H-K-G-Pip-n le-a-f- OH

(SEQ ID NO: 25)

p E-R-P-R-(D-Leu)-S-Aib-K-G-P-nle-a-f- OH

(SEQ ID NO: 51)

p E-R-P-R-L-a-H-K-G-P-Nle-a-f- OH

(SEQ ID NO: 27)

p E-R-P-R-L-a-H-K-G-P-nle-f- OH

(SEQ ID NO: 29)

p E-R-P-R-L-d-H-K-G-P-nle-a-f- OH

(SEQ ID NO: 35)

p E-R-P-R-L-a-H-K-G-P-nle-(D-Leu)-f- OH

(SEQ ID NO: 36)

p E-R-P-R-L-a-Aib-K-G-P-nle-a-f- OH

(SEQ ID NO: 37)

p E-R-P-R-L-a-h-K-G-P-nle-a-f- OH

(SEQ ID NO: 38)

p E-R-P-R-L-a-F-K-G-P-nle-a-f- OH ;

(SEQ ID NO: 78)

p E-R-P-R-L-a-H-K-G-P-f-a-f- OH ;

or an amide, an ester or a salt of the polypeptide.

18. The polypeptide according to claim 1 wherein the polypeptide has a plasma stability of at least 100 minutes and an IC50 of less than 10 nM.

19. A method of treating or preventing a disease or disorder responsive to the agonism of the APJ receptor, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the polypeptide according to claim 1 or an amide, an ester or a salt thereof.

20. The method of claim 19 wherein the disease or disorder is selected from acute decompensated heart failure (ADHF), chronic heart failure, pulmonary hypertension, atrial fibrillation, Brugada syndrome, ventricular tachycardia, atherosclerosis, hypertension, restenosis, ischemic cardiovascular diseases, cardiomyopathy, cardiac fibrosis, arrhythmia, water retention, diabetes, gestational diabetes, obesity, peripheral arterial disease, cerebrovascular accidents, transient ischemic attacks, traumatic brain injuries, amyotrophic lateral sclerosis, burn injuries, sunburn and preeclampsia.

21. A combination comprising a therapeutically effective amount of the polypeptide according to claim 1 or an amide, an ester or a salt thereof, and one or more therapeutically active co-agent.

22. A combination according to claim 21 wherein the co-agent is selected from inotropes, beta adrenergic receptor blockers, HMG-Co-A reductase inhibitors, angiotensin II receptor antagonists, angiotensin converting enzyme (ACE) Inhibitors, calcium channel blockers (CCB), endothelin antagonists, renin inhibitors, diuretics, ApoA-I mimics, anti-diabetic agents, obesity-reducing agents, aldosterone receptor blockers, endothelin receptor blockers, aldosterone synthase inhibitors (ASI), a CETP inhibitor, anti-coagulants, relaxin, BNP (nesiritide) and/or a NEP inhibitor.

23. A pharmaceutical composition comprising a therapeutically effective amount of the polypeptide according to claim 1 or an amide, an ester or a salt thereof, and one or more pharmaceutically acceptable carriers.

24. A pharmaceutical composition comprising a therapeutically effective amount of the polypeptide according to claim 17 , or an amide, an ester or a salt thereof, and one or more pharmaceutically acceptable carriers.