# US 2014/0155315 A1 · Synthetic linear apelin mimetics for the treatment of heart failure

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 2014/0155315 A1
- Document ID: US20140155315A1
- Status: Published application
- Kind: A1
- Application number: 14/082,771
- Filed: 2013-11-18
- Published: 2014-06-05
- Earliest claimed: 2012-11-20
- Assignees: Novartis AG
- Inventors: Frédéric Zecri; Kayo Yasoshima; Philipp Grosche; Jun Yuan; Hongjuan Zhao
- Web page: https://patentgrep.com/patent/US20140155315A1

## CPC

- C07K 7/08: having 12 to 20 amino acids (gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68)
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- C07K 14/47: from mammals
- 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)
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## Abstract

The invention provides a synthetic polypeptide of Formula I′ (SEQ ID NO: 1): X1-X2-X3-R—X5-X6-X7-X8-X9-X10-X11-X12-X13 I or an amide, an ester or a salt thereof, wherein X1, X2, X3, X5, X6, X7, X8, X9, X10, X11, X12 and X13 are defined herein. The polypeptides are agonist of the APJ receptor. The invention also relates to a method for manufacturing the polypeptides of the invention, and its therapeutic uses such as treatment or prevention of 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 (including gestational diabetes), obesity, peripheral arterial disease, cerebrovascular accidents, transient ischemic attacks, traumatic brain injuries, amyotrophic lateral sclerosis, burn injuries (including sunburn) and preeclampsia. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical composition.

## Claims

### Claim 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; or a polypeptide substantially equivalent thereto.

### Claim 2 (depends on 1)

The polypeptide of claim 1 wherein X6 and X12 are D-amino acids (SEQ ID NO: 3); or an amide, an ester or a salt thereof.

### Claim 3 (depends on 2)

The polypeptide of claim 2 wherein X13 is D-amino acid (SEQ ID NO: 4); or an amide, an ester or a salt thereof.

### Claim 4 (depends on 3)

The polypeptide of claim 3 wherein X11 is D-amino acid (SEQ ID NO: 5); or an amide, an ester of a salt thereof.

### Claim 5 (depends on 1)

The polypeptide of claim 1 wherein X6 and X13 are D-amino acids (SEQ ID NO: 6); or an amide, an ester or a salt thereof.

### Claim at position 6

6-7. (canceled)

### Claim 8 (depends on 1)

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

### Claim 9 (depends on 1)

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

### Claim 10 (depends on 1)

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

### Claim 11 (depends on 1)

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

### Claim 12

(canceled)

### Claim 13 (depends on 1)

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

### Claim 14 (depends on 1)

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

### Claim 15 (depends on 14)

The polypeptide according to claim 14 wherein X13 is absent or f (SEQ ID NO: 16); or an amide, an ester or a salt of the polypeptide.

### Claim 16 (depends on 1)

The polypeptide according to claim 1 wherein X1 is pE (SEQ ID NO: 17); or an amide, an ester or a salt of the polypeptide.

### Claim 17 (depends on 1)

The polypeptide according to claim 1 wherein X5 is L (SEQ ID NO: 18); or an amide, an ester or a salt of the polypeptide.

### Claim 18 (depends on 1)

The polypeptide according to claim 1 wherein X8 is K (SEQ ID NO: 19); or an amide, an ester or a salt of the polypeptide.

### Claim at position 18

19-21. (canceled)

### Claim 22 (depends on 1)

The polypeptide according to claim 1 selected from:
(SEQ ID NO: 22)
pE-R-P-R-L-a-H-K-G-Pip-nle-a-f-OH
(SEQ ID NO: 23)
pE-R-P-R-(D-Leu)-S-a-K-G-P-nle-a-f-OH
(SEQ ID NO: 24)
pE-r-P-R-L-a-H-K-G-P-nle-a-f-OH
(SEQ ID NO: 25)
pE-R-P-R-(D-Leu)-S-Aib-K-G-P-nle-a-f-OH
(SEQ ID NO: 26)
pE-R-P-R-L-S-Aib-k-G-P-nle-a-f-OH
(SEQ ID NO: 27)
pE-R-P-R-L-a-H-K-G-P-nle-f-OH
(SEQ ID NO: 28)
pE-R-P-R-L-c(tBu)-H-K-G-P-nle-a-f-OH
(SEQ ID NO: 29)
pE-R-P-R-L-d-H-K-G-P-nle-a-f-OH
(SEQ ID NO: 30)
pE-R-(trans-4-PhP)-R-L-a-H-K-G-P-nle-a-f-OH
(SEQ ID NO: 31)
pE-R-P-R-L-(D-Leu)-H-K-G-P-nle-a-f-OH
(SEQ ID NO: 32)
pE-R-P-R-L-k-H-K-G-P-nle-a-f-OH
(SEQ ID NO: 33)
pE-R-P-R-L-s-H-K-G-P-nle-a-f-OH
(SEQ ID NO: 34)
pE-R-P-R-L-a-H-K-G-P-nle-p-f-OH
(SEQ ID NO: 35)
pE-R-P-R-L-a-H-K-G-P-nle-(D-Leu)-f-OH
(SEQ ID NO: 36)
pE-R-P-R-L-a-Aib-K-G-P-nle-a-f-OH
(SEQ ID NO: 37)
pE-R-P-R-L-a-h-K-G-P-nle-a-f-OH
(SEQ ID NO: 38)
pE-R-P-R-L-a-F-K-G-P-nle-a-f-OH
(SEQ ID NO: 39)
pE-R-P-R-L-a-H-K-G-P-nle-F-OH
(SEQ ID NO: 40)
pE-R-P-R-L-a-H-K-G-P-nle-e-f-OH
(SEQ ID NO: 41)
pE-R-P-R-L-a-H-K-G-P-nle-r-f-OH
(SEQ ID NO: 42)
pE-R-P-R-L-a-H-K-G-P-nle-a-y-OH
(SEQ ID NO: 43)
pE-R-P-R-L-a-H-K-G-P-nle-a-d-OH
(SEQ ID NO: 44)
pE-R-P-R-Cha-a-H-K-G-P-nle-a-f-OH
(SEQ ID NO: 45)
pE-R-P-R-(3,4-Cl2-F)-a-H-K-G-P-nle-a-f-OH
(SEQ ID NO: 46)
pE-R-P-R-(2-Nal)-a-H-K-G-P-nle-a-f-OH
(SEQ ID NO: 47)
pE-R-P-R-L-a-H-K-G-P-nle-a-tic-OH
(SEQ ID NO: 48)
pE-R-P-R-Y(Bzl)-a-H-K-G-P-nle-a-f-OH
(SEQ ID NO: 49)
pE-R-P-R-Y-a-H-K-G-P-nle-a-f-OH
(SEQ ID NO: 50)
pE-R-P-R-L-a-H-K-G-P-nle-a-f-OH
(SEQ ID NO: 51)
pE-R-P-R-L-a-H-K-G-P-Nle-a-f-OH
(SEQ ID NO: 52)
pE-R-P-R-L-a-H-k-G-P-Nle-a-f-OH
(SEQ ID NO: 53)
pE-R-P-R-L-a-H-K-G-P-nle-NH(Phenethyl)
(SEQ ID NO: 54)
pE-R-P-R-L-a-H-K-G-P-nle-a-f-NH2
(SEQ ID NO: 55)
pE-R-P-R-L-a-H-K-G-P-Nle-P-f-OH
(SEQ ID NO: 56)
pE-R-P-R-L-a-H-K-G-P-Nle-f-OH
(SEQ ID NO: 57)
pE-R-P-R-L-a-H-K-G-P-nle-a-NH(Phenethyl)
(SEQ ID NO: 58)
pE-R-P-R-L-S-Aib-K-G-P-nle-a-F-OH
(SEQ ID NO: 59)
pE-R-P-R-L-S-Aib-K-G-P-Nle-a-f-OH
(SEQ ID NO: 60)
pE-R-P-R-L-a-H-K-G-P-Nle-a-F-OH
(SEQ ID NO: 61)
pE-R-P-R-L-S-Aib-K-G-P-nle-a-f-OH
(SEQ ID NO: 62)
pE-R-P-R-L-S-Aib-K-G-P-Nle-P-f-OH
(SEQ ID NO: 63)
pE-R-P-R-L-S-Aib-K-G-P-Nle-a-F-OH
(SEQ ID NO: 64)
pE-R-P-R-L-a-H-K-G-P-nle-(4-Phenoxypiperidin-1-yl)
(SEQ ID NO: 65)
pE-R-P-R-L-abu-H-K-G-P-nle-a-f-OH
(SEQ ID NO: 66)
pE-R-P-R-L-a-H-K-G-P-nle-abu-f-OH
(SEQ ID NO: 67)
pE-R-P-R-L-a-f-K-G-P-nle-a-f-OH
(SEQ ID NO: 68)
pE-R-P-R-L-a-L-K-G-P-nle-a-f-OH
(SEQ ID NO: 69)
pE-R-P-R-L-a-a-K-G-P-nle-a-f-OH
(SEQ ID NO: 70)
pE-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)
pE-R-P-R-L-S-a-K-G-P-nle-a-f-OH
(SEQ ID NO: 73)
pE-R-P-R-L-nva-H-K-G-P-nle-a-f-OH
(SEQ ID NO: 74)
pE-R-P-R-L-a-H-K-G-P-nya-a-f-OH
(SEQ ID NO: 75)
pE-R-P-R-L-a-H-K-G-P-nle-nva-f-OH
(SEQ ID NO: 76)
pE-R-P-R-L-S-f-K-G-P-nle-a-f-OH
(SEQ ID NO: 77)
pE-R-P-R-L-S-h-K-G-P-nle-a-f-OH
(SEQ ID NO: 78)
pE-R-P-R-L-a-H-K-G-P-f-a-f-OH
(SEQ ID NO: 79)
pE-R-P-R-L-A-h-K-G-P-nle-a-f-OH
(SEQ ID NO: 80)
pE-R-P-R-L-a-H-Q-G-P-nle-a-f-OH
(SEQ ID NO: 81)
pE-R-P-R-L-a-H-E-G-P-nle-a-f-OH
(SEQ ID NO: 82)
pE-R-P-R-L-v-H-K-G-P-nle-a-f-OH
(SEQ ID NO: 83)
pE-R-P-R-L-a-H-K-D-P-nle-a-f-OH;
(SEQ ID NO: 84)
pE-R-P-R-Cha-nva-H-K-G-P-nle-a-f-OH
or an amide, an ester or a salt of the polypeptide.

### Claim 23 (depends on 22)

The polypeptide of claim 22 selected from:
(SEQ ID NO: 50)
pE-R-P-R-L-a-H-K-G-P-nle-a-f-OH
(SEQ ID NO: 22)
pE-R-P-R-L-a-H-K-G-Pip-n le-a-f-OH
(SEQ ID NO: 25)
pE-R-P-R-(D-Leu)-S-Aib-K-G-P-nle-a-f-OH
(SEQ ID NO: 51)
pE-R-P-R-L-a-H-K-G-P-Nle-a-f-OH
(SEQ ID NO: 27)
pE-R-P-R-L-a-H-K-G-P-nle-f-OH
(SEQ ID NO: 29)
pE-R-P-R-L-d-H-K-G-P-nle-a-f-OH
(SEQ ID NO: 35)
pE-R-P-R-L-a-H-K-G-P-nle-(D-Leu)-f-OH
(SEQ ID NO: 36)
pE-R-P-R-L-a-Aib-K-G-P-nle-a-f-OH
(SEQ ID NO: 37)
pE-R-P-R-L-a-h-K-G-P-nle-a-f-OH
(SEQ ID NO: 38)
pE-R-P-R-L-a-F-K-G-P-nle-a-f-OH;
(SEQ ID NO: 78)
pE-R-P-R-L-a-H-K-G-P-f-a-f-OH;
or an amide, an ester or a salt of the polypeptide.

### Claim 24 (depends on 1)

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.

### Claim 25 (depends on 1)

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 a polypeptide according to claim 1 or an amide, an ester or a salt thereof.

### Claim 26 (depends on 25)

The method of claim 25 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 (including gestational diabetes), obesity, peripheral arterial disease, cerebrovascular accidents, transient ischemic attacks, traumatic brain injuries, amyotrophic lateral sclerosis, burn injuries (including sunburn) and preeclampsia.

### Claim at position 24

27-29. (canceled)

### Claim 30 (depends on 1)

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

### Claim 31 (depends on 30)

A combination according to claim 30 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.

### Claim 32 (depends on 1)

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

### Claim 33 (depends on 23)

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