Beta-Arrestin Effectors And Compositions And Methods Of Use Thereof

Abstract

This application describes a family of compounds acting as β-arrestin effectors. Such compounds may provide significant therapeutic benefit in the treatment of chronic and acute cardiovascular diseases.

What is claimed is: 
     
         1 . A method of treating a cardiovascular disorder in a subject, the method comprising administering to the subject a pharmaceutical composition comprising a peptide, or a pharmaceutically acceptable salt thereof, comprising the sequence of: 
       
         
           
                 
                 
               
                     
                   Xx-Yy-Val-Ww-Zz-Aa-Bb-Cc, 
                 
             
                
               
            
           
         
         wherein Xx is selected from the group consisting of sarcosine, N-methyl-L-alanine, N-methyl-D-alanine, N,N-dimethylglycine, L-aspartic acid, D-aspartic acid, L-glutamic acid, D-glutamic acid, N-methyl-L-aspartic acid, N-methyl-L-glutamic acid, pyrrolid-1-ylacetic acid, and morpholin-4-ylacetic acid; 
         Yy is selected from the group consisting of L-arginine, and L-lysine; 
         Ww is selected from the group consisting of L-isoleucine, glycine, L-tyrosine, O-methyl-L-tyrosine, L-valine, L-phenylalanine, 3-hydroxy-L-tyrosine, 2,6-dimethyl-L-tyrosine, 3-fluoro-L-tyrosine, 4-fluorophenyl-L-analine, 2,6-difluoro-L-tyrosine, 3-nitro-L-tyrosine, 3,5-dinitro-L-tyrosine, 3,5-dibromo-L-tyrosine, 3-chloro-L-tyrosine, O-allyl-L-tyrosine, and 3,5-diiodo-L-tyrosine; 
         Zz is selected from the group consisting of L-isoleucine, L-valine, L-tyrosine, L-glutamic acid, L-phenylalanine, L-histidine, L-lysine, L-arginine, O-methyl-L-threonine, D-alanine, and L-norvaline; 
         Aa is selected from the group consisting of L-histidine, L-histidine-amide, and L-lysine; 
         Bb is selected from the group consisting of L-proline, L-proline-amide, D-proline, and D-proline-amide; and 
         Cc is selected from the group consisting of null, L-isoleucine, L-isoleucine-amide, glycine, glycine-amide, L-alanine, L-alanine-amide, D-alanine, D-phenylalanine, L-norvaline; 
         provided that when Xx is L-Aspartic acid, Cc is not L-phenylalanine; when Xx is sarcosine, Cc is not L-isoleucine; when Ww is glycine, Cc is not glycine; when Xx is sarcosine, and Zz is L-valine, Cc is not L-alanine; and when Xx is sarcosine, Ww is a L-tyrosine, and Zz is L-isoleucine, Cc is not L-alanine. 
       
     
     
         2 . A method of treating a cardiovascular disorder in a subject, the method comprising administering to the subject a pharmaceutical composition comprising a peptide, or a pharmaceutically acceptable salt thereof, comprising the sequence of: 
       
         
           
                 
                 
               
                     
                   Xx-Arg-Val-Ww-Zz-His-Pro-Cc, 
                 
             
                
               
            
           
         
         wherein Xx is selected from the group consisting of sarcosine, N-methyl-L-alanine, N-methyl-D-alanine, N,N-dimethylglycine, L-aspartic acid, D-aspartic acid, L-glutamic acid, D-glutamic acid, N-methyl-L-aspartic acid, N-methyl-L-glutamic acid, pyrrolid-1-ylacetic acid, and morpholin-4-ylacetic acid; 
         Ww is selected from the group consisting of L-isoleucine, glycine, L-tyrosine, O-methyl-L-tyrosine, L-valine, L-phenylalanine, 3-hydroxy-L-tyrosine, 2,6-dimethyl-L-tyrosine, 3-fluoro-L-tyrosine, 4-fluorophenyl-L-analine, 2,6-difluoro-L-tyrosine, 3-nitro-L-tyrosine, 3,5-dinitro-L-tyrosine, 3,5-dibromo-L-tyrosine, 3-chloro-L-tyrosine, O-allyl-L-tyrosine, and 3,5-diiodo-L-tyrosine; 
         Zz is selected from the group consisting of L-isoleucine, L-valine, L-tyrosine, L-glutamic acid, L-phenylalanine, L-histidine, L-lysine, L-arginine, O-methyl-L-threonine, D-alanine, and L-norvaline; and 
         Cc is selected from the group consisting of L-isoleucine, L-isoleucine-amide, glycine, glycine-amide, L-alanine, L-alanine-amide, D-alanine, D-phenylalanine, and L-norvaline; 
         provided that when Xx is L-Aspartic acid, Cc is not L-phenylalanine; when Xx is sarcosine, Cc is not L-isoleucine; when Ww is glycine, Cc is not glycine; when Xx is sarcosine, and Zz is L-valine, Cc is not L-alanine; and when Xx is sarcosine, Ww is a L-tyrosine, and Zz is L-isoleucine, Cc is not L-alanine. 
       
     
     
         3 . A method of treating a cardiovascular disorder in a subject, the method comprising administering to the subject a pharmaceutical composition comprising a peptide, or a pharmaceutically acceptable salt thereof, comprising the sequence of: a) Sar-Arg-Val-Ww-OMTh-His-Pro-Cc,
 wherein Ww is selected from the group consisting of L-tyrosine, 3-hydroxy-L-tyrosine; 3-fluoro-L-tyrosine, and 3-chloro-L-tyrosine; and   Cc is selected from the group consisting of D-alanine and L-alanine;   b) Sar-Arg-Val-Ww-Tyr-His-Pro-NH 2 ,   wherein Ww is selected from the group consisting of L-tyrosine, 3-hydroxy-L-tyrosine, 3-fluoro-L-tyrosine, 2,6-difluoro-L-tyrosine, 3-nitro-L-tyrosine, 3,5-dinitro-L-tyrosine, and 3-chloro-L-tyrosine; or   c) NMAla-Arg-Val-Ww-Zz-His-Pro-Cc,   wherein Ww is selected from the group consisting of L-tyrosine, 3-hydroxy-L-tyrosine, 3-fluoro-L-tyrosine, 2,6-difluoro-L-tyrosine, 3-nitro-L-tyrosine, 3,5-dinitro-L-tyrosine, and 3-chloro-L-tyrosine;   Zz is selected from the group consisting of L-isoleucine, L-lysine, and O-methyl-L-threonine;   and Cc is selected from the group consisting of D-alanine, and L-alanine.   
     
     
         4 . The method of  claim 3 , wherein the peptide of formula of Sar-Arg-Val-Ww-OMTh-His-Pro-Cc, wherein Ww is selected from the group consisting of 3-hydroxy-L-tyrosine; 3-fluoro-L-tyrosine, and 3-chloro-L-tyrosine; and Cc is L-alanine. 
     
     
         5 . The method of  claim 4 , wherein the peptide comprises the sequence of SEQ ID NO:77, SEQ ID NO:78, or SEQ ID NO:79. 
     
     
         6 . The method of  claim 3 , wherein the peptide comprises the sequence of SEQ ID NO:26. 
     
     
         7 . The method of  claim 3 , wherein the peptide is of formula:
 NMAla-Arg-Val-Ww-Zz-His-Pro-Cc, wherein Ww is L-tyrosine;   NMAla-Arg-Val-Ww-Zz-His-Pro-Cc, wherein Zz is L-isoleucine; or   NMAla-Arg-Val-Ww-Zz-His-Pro-Cc, wherein Cc is L-alanine.   
     
     
         8 . The method of  claim 3 , wherein the peptide comprises the sequence of SEQ ID NO:34. 
     
     
         9 . The method of  claim 1 , wherein the peptide is cyclic, dimerized or trimerized. 
     
     
         10 . The method of  claim 1 , wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier. 
     
     
         11 . The method of  claim 1 , wherein the pharmaceutical composition comprises sterile water, phosphate buffered saline, or an aqueous glucose solution. 
     
     
         12 . The method of  claim 1 , wherein the cardiovascular disorder is acute heart failure. 
     
     
         13 . The method of  claim 1 , wherein the cardiovascular disorder is heart failure. 
     
     
         14 . The method of  claim 1 , wherein the cardiovascular disorder is selected from the group consisting of acute decompensated heart failure, chronic hypertension, hypertensive crisis, acute congestive heart failure, angina, acute myocardial infarction, left ventricular failure, cerebrovascular insufficiency, intracranial hemorrhage, essential hypertension, post-operative hypertension, hypertensive heart disease, hypertensive renal disease, renovascular hypertension, malignant hypertension, post-renal transplant patient stabilization, dilated cardiomyopathy, myocarditis, post-cardiac transplant patient stabilization, disorders associated with post-stent management, neurogenic hypertension, preeclampsia, and abdominal aortic aneurysm. 
     
     
         15 . The method of  claim 1 , wherein the subject is a subject in need thereof. 
     
     
         16 . The method of  claim 1 , wherein the pharmaceutical composition is administered intravenously. 
     
     
         17 . The method of  claim 1 , wherein the administration of the pharmaceutical composition maintains glomerular filtration rate in the subject. 
     
     
         18 . The method of  claim 1 , wherein the administration of the pharmaceutical composition decreases vascular resistance in the subject. 
     
     
         19 . A method of decreasing renal vascular resistance and/or maintaining glomerular filtration rate in a subject in need thereof, the method comprising administering to the subject in need thereof a pharmaceutical composition comprising a peptide, or a pharmaceutically acceptable salt thereof, comprising peptide of  claim 1 . 
     
     
         20 . A method of decreasing renal vascular resistance and/or maintaining glomerular filtration rate in a subject in need thereof, the method comprising administering to the subject in need thereof a pharmaceutical composition comprising a peptide, or a pharmaceutically acceptable salt thereof, comprising peptide of  claim 3 .