Cyclic polypeptides for the treatment of heart failure

Abstract

The invention provides a cyclic polypeptide of Formula I (SEQ ID NO: 1): X1-R-X3-X4-L-S-X7-X8-X9-X10-X11-X12-X13  I or an amide, an ester or a salt thereof, or a bioconjugate thereof, wherein X1, X3, X4, 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 or bioconjugates thereof, and their 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.

What is claimed is: 
     
         1 . A cyclic polypeptide having the following formula I (SEQ ID NO: 1):
   X1-R-X3-X4-L-S-X7-X8-X9-X10-X11-X12-X13  I
   wherein:   X1 is the N-terminus of the polypeptide and is either absent, Q, A or pE or X1 is selected from C, c, hC, D-hC; wherein the side chain of C, c, hC or D-hC form a disulfide bond with the side chain of X7;   X3 is P or X3 is selected from C, c, hC and D-hC; wherein the side chain of C, c, hC or D-hC forms a disulfide bond with the side chain of X7;   X4 is R;   wherein only one of X1 and X3 is a sulfur contain amino-acid selected from C, c, hC and D-hC;   X7 is C, c, hC or D-hC; and the side chain of X7 forms a disulfide bond with the side chain of C, c, hC or D-hC of either X1 or X3;   X8 is K or F;   X9 is G, A, a or absent;   X10 is P or absent;   X11 is D-Nle, Nle, M or f; and   X12 is absent or P, f, a, D-Nva or D-Abu;   X13 is the C-terminus and is absent or is selected from (N-Me)F, F, f, a, y and Nal; wherein:   Nle is L-norleucine;   D-Nle is D-norleucine;   D-hC is D-homocysteine   hC is L-homocysteine;   Nal is L-naphathaline;   D-Nva is D-norvaline;   D-Abu is D-2-aminobutyric acid;   pE is L-pyroglutamic acid;   or an amide, an ester or a salt of the polypeptide; or a polypeptide substantially equivalent thereto.   
     
     
         2 . (canceled) 
     
     
         3 . The polypeptide of  claim 1  having Formula III (SEQ ID NO: 4): 
       
         
           
           
               
               
           
         
         Wherein 
         X1 is the N-terminus of the polypeptide and is selected from C, c, hC and D-hC; 
         X7 is C, c, hC or D-hC; wherein the side chain of X7 forms a disulfide bond with the side chain of X1; 
         X8 is K or F; 
         X9 is G, A, a or absent; 
         X10 is P or absent; 
         X11 is D-Nle, Nle, M or f; and 
         X12 is absent or is selected from P, f, a, D-Nva and D-Abu; 
         X13 is the C-terminus and is absent or is selected from (N-Me)F, F, f, a, y and Nal; 
         or an amide, an ester or a salt of the polypeptide. 
       
     
     
         4 . The polypeptide of  claim 1  having Formula IV (SEQ ID NO: 5): 
       
         
           
           
               
               
           
         
         wherein: 
         X1 is the N-terminus of the polypeptide and is either absent, Q, A or pE; 
         X3 is C, c, hC or D-hC; wherein the side chain of C, c, hC or D-hC; 
         X7 is C, c, hC or D-hC; and the side chain of X7 form a disulfide bond with the side chain of C, c, hC or D-hC of X3; 
         X8 is K or F; 
         X9 is G, A, a or absent; 
         X10 is P or absent; 
         X11 is D-Nle, Nle, M or f; and 
         X12 is absent or is selected from P, f, a, D-Nva and D-Abu; 
         X13 is the C-terminus and is absent or is selected from (N-Me)F, F, f, a, y and Nal; or an amide, an ester or a salt of the polypeptide. 
       
     
     
         5 . The polypeptide according  claim 1  wherein X1 is pE; or an amide, an ester or a salt of the polypeptide. 
     
     
         6 . The polypeptide according to  claim 1  wherein X1 is absent; or an amide, an ester or a salt of the polypeptide. 
     
     
         7 . The polypeptide according to  claim 1  wherein the N-terminus is an amide; or a salt of the polypeptide. 
     
     
         8 . The polypeptide according to  claim 7  wherein the N-terminus is an amide of Formula —NHR and R is Acetyl, benzoyl, phenacyl, succinyl, octanoyl, 4-phenylbutanoyl, 4-Cl-Ph-(CH 2 ) 3 C(O)—, or Ph-CH 2 CH 2 NHC(O)—; or a salt of the polypeptide. 
     
     
         9 . The polypeptide according to  claim 1  wherein X13 is F or f; or an amide, an ester or a salt of the polypeptide. 
     
     
         10 . The polypeptide according to  claim 1  wherein X13 is absent; or an amide, an ester or a salt of the polypeptide. 
     
     
         11 . The polypeptide according to  claim 1  wherein X12 is absent; or an amide, and ester or a salt of the polypeptide. 
     
     
         12 . The polypeptide according to  claim 1  wherein the C-terminus is an amide; or a salt of the polypeptide. 
     
     
         13 . The polypeptide according to  claim 12  wherein the C-terminus is an amide of Formula —C(O)—R2 and R2 is —NH 2 , —NH-Me, —NH—NHBn, or —NH—(CH 2 ) 2 -Ph; or a salt of the polypeptide. 
     
     
         14 . The polypeptide according to  claim 1  wherein X8 is K; or an amide, an ester or a salt of the polypeptide. 
     
     
         15 . The polypeptide according to  claim 1  wherein X9 is G; or an amide, an ester or a salt of the polypeptide. 
     
     
         16 . The polypeptide according to  claim 1  wherein X10 is P; or an amide, an ester or a salt of the polypeptide. 
     
     
         17 . The polypeptide according to  claim 1  wherein X11 is Nle or D-Nle; or an amide, an ester or a salt of the polypeptide. 
     
     
         18 . The polypeptide according to  claim 1  selected from (SEQ ID Nos 19-45, respectively, in order of appearance): 
       
         
           
                 
                 
               
                     
                   Ac-C*-R-P-R-L-S-C*-K-G-P-Nle-P-F- OH   
                 
                     
                     
                 
                     
                   Ac-C*-R-P-R-L-S-C*-K-G-P-Nle-P- NH ( Phenethyl ) 
                 
                     
                     
                 
                     
                   Ac-C*-R-P-R-L-S-C*-K-G-P-Nle-P-(N-Me)F- OH   
                 
                     
                     
                 
                     
                   Ac-C*-R-P-R-L-S-C*-K-G-P-Nle-P- NH   2   
                 
                     
                     
                 
                     
                   Ac-C*-R-P-R-L-S-C*-K-G-P-Nle-P-Nal- OH   
                 
                     
                     
                 
                     
                   Ac-C*-R-P-R-L-S-hC*-K-G-P-Nle-P-F- OH   
                 
                     
                     
                 
                     
                   Ac-hC*-R-P-R-L-S-hC*-K-G-P-Nle-P-F- OH   
                 
                     
                     
                 
                     
                   Ac-C*-R-P-R-L-S-C*-K-G-P-Nle-P-a- OH   
                 
                     
                     
                 
                     
                   Ac-C*-R-P-R-L-S-C*-K-G-P-Nle-P- NMe ( Phenethyl ) 
                 
                     
                     
                 
                     
                   Ac-C*-R-P-R-L-S-C*-K-G-P-Nle-P-f- OH   
                 
                     
                     
                 
                     
                   Ac-C*-R-P-R-L-S-C*-K-G-P-Nle- NH ( Phenethyl ) 
                 
                     
                     
                 
                     
                   Ac-c*-R-P-R-L-S-C*-K-G-P-Nle-P-F- OH   
                 
                     
                     
                 
                     
                   Ac-c*-R-P-R-L-S-hC*-K-G-P-Nle-P-F- OH   
                 
                     
                     
                 
                     
                   Ac-c*-R-P-R-L-S-c*-K-G-P-Nle-P-F- OH   
                 
                     
                     
                 
                     
                   Ac-C*-R-P-R-L-S-c*-K-G-P-Nle-P-F- OH   
                 
                     
                     
                 
                     
                   Ac-(D-hC)*-R-P-R-L-S-hC*-K-G-P-Nle-P-F- OH   
                 
                     
                     
                 
                     
                   Ac-(D-hC)*-R-P-R-L-S-(D-hC)*-K-G-P-Nle-P-F- OH   
                 
                     
                     
                 
                     
                   Ac-(D-hC)*-R-P-R-L-S-(hC)*-K-G-P-f-a-f- OH   
                 
                     
                     
                 
                     
                   Ac-c-R-P-R-L-S-(hC)-K-G-P-(D-Nle)-a-f- OH   
                 
                     
                     
                 
                     
                     p E-R-C*-R-L-S-C*-K-G-P-Nle-P-F- OH   
                 
                     
                     
                 
                     
                     p E-R-C*-R-L-S-C*-K-G-P-(D-Nle)-a-f- OH   
                 
                     
                     
                 
                     
                     p E-R-C*-R-L-S-C*-F-G-P-(D-Nle)-a-f- OH   
                 
                     
                     
                 
                     
                     p E-R-C*-R-L-S-C*-K-a-P-(D-Nle)-a-f- OH   
                 
                     
                     
                 
                     
                     p E-R-C*-R-L-S-C*-K-A-P-(D-Nle)-a-f- OH   
                 
                     
                     
                 
                     
                     p E-R-C*-R-L-S-C*-K-G-P-(D-Nle)- NH   2   
                 
                     
                     
                 
                     
                     p E-R-C*-R-L-S-(D-hC)*-K-G-P-f-a-f- OH   
                 
                     
                     
                 
                     
                     p E-R-c*-R-L-S-C*-K-G-P-(D-Nle)-(D-abu)-f- OH   
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
         wherein the two amino acids labeled with “*” represent the amino acids forming a disulfide; or an amide, an ester or a salt of the polypeptide. 
       
     
     
         19 . A bioconjugate or multimer thereof comprising:
 a. a peptide or polypeptide according to  claim 1 , or an amide, an ester or a salt thereof, and   b. a half-life extending moiety;   
       wherein said peptide or polypeptide and half-life extending moiety are covalently linked or fused, optionally via a linker. 
     
     
         20 . The bioconjugate or a multimer thereof, according to  claim 19 , wherein the half-life extending moiety is an IgG constant domain or fragment thereof or a human Serum Albumin. 
     
     
         21 - 27 . (canceled) 
     
     
         28 . The bioconjugate according to  claim 19  wherein the half-life extending moiety is a fatty acid. 
     
     
         29 - 30 . (canceled) 
     
     
         31 . 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 or an amide, an ester or a salt thereof, according to  claim 1 . 
     
     
         32 . The method of  claim 31  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. 
     
     
         33 - 35 . (canceled) 
     
     
         36 . A Combination comprising a therapeutically effective amount of a polypeptide, an amide, an ester of a salt thereof, according to  claim 1 , and one or more therapeutically active co-agent. 
     
     
         37 . A combination according to  claim 36  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. 
     
     
         38 . A pharmaceutical composition comprising a therapeutically effective amount of a polypeptide, an amide, an ester of a salt thereof, according to  claim 1 , and one or more pharmaceutically acceptable carriers. 
     
     
         39 . A pharmaceutical composition comprising a therapeutically effective amount of a bioconjugate according to  claim 19 , and one or more pharmaceutically acceptable carriers. 
     
     
         40 . 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 bioconjugate according to  claim 19 .