US 2014/0155315 A1 · SYNTHETIC LINEAR APELIN MIMETICS FOR THE TREATMENT OF HEART FAILURE

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.

Claims28

Dependent claims

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.

30 more elements

Dependencies are inferred from the claim text.

Synthetic linear apelin mimetics for the treatment of heart failure

Life of this patent

Synthetic linear apelin mimetics for the treatment of heart failure

Life of this patent

Abstract

Claims28