Npy2 receptor agonists

Abstract

The invention relates to PYY analogues having alanine at position 4, lysine at position 7, QRY as the C-terminal end and a half-life extending group. The analogues of the invention are soluble around pH 6 and 7. The invention also relates to pharmaceutical compositions comprising such PYY analogues, and to the medical use of the analogues.

What is claimed is: 
     
         1 . A PYY analogue comprising an amino acid sequence corresponding to the amino acid sequence of hPYY(3-36), wherein the analogue comprises
 i) alanine at the position corresponding to position 4 of hPYY(3-36)   ii) lysine at the position corresponding to position 7 of hPYY(3-36)   iii) the sequence QRY at its C-terminal end,   and wherein a half-life extending group is attached to the epsilon amino group of the lysine at position 7 or of a lysine at positions 6, 10, 11, 14, 17, 21, 22 or 30, or to the carboxylic acid group of the side chain of a aspartate or a glutamate at positions 14 or 30,   or a pharmaceutically acceptable salt thereof.   
     
     
         2 . The PYY analogue according to  claim 1 , wherein the analogue comprises glutamate at the position corresponding to position 9 of hPYY(3-36), and/or tyrosine at the position corresponding to position 20 of hPYY(3-36), and/or arginine at the position corresponding to position 25 of hPYY(3-36) and/or tryptophane at the position corresponding to position 30 of hPYY(3-36), and/or leucine at the position corresponding to position 31 of hPYY(3-36), and/or threonine at the position corresponding to position 32 of hPYY(3-36), and/or arginine or lysine at the position corresponding to position 33 of hPYY(3-36), or a pharmaceutically acceptable salt thereof. 
     
     
         3 . The PYY analogue according to  claim 1 , wherein the PYY analogue is a compound having the formula:
   R 1 —Z—R 2 ,
   wherein R 1  is hydrogen, —C(O)C 1-6  alkyl, —C(O)C 6 H 6 , —C(O)C 3-6  cycloalkyl, —C(O)C 1-6  alkyl-C 3-6  cycloalkyl, or C 1-6  alkyl or C 1-6  alkyl-C 3-6  cycloalkyl:   R 2  is OH or NHR 3 , wherein R 3  is hydrogen or C 1-3  alkyl; and   Z is a peptide comprising an amino acid sequence of formula I (SEQ ID NO: 254):   
       
         
           
                 
               
                   (I) 
                 
                   Ala-X5-X6-Lys-X8-X9-X10-X11-X12-X13-X14-X15-X16- 
                 
                     
                 
                   X17-X18-X19-Tyr-X21-X22-X23-X24-Arg-X26-X27-X28- 
                 
                     
                 
                   X29-X30-X31-X32-Arg-Gln-Arg-Tyr 
                 
             
                
                
                
                
                
                
               
            
           
         
         wherein 
         X5 is selected from the group consisting of Pro and Hyp; 
         X6 is selected from the group consisting of Ala and Glu; 
         X8 is selected from the group consisting of Ala, lie, Pro, Thr, Val and Hyp; 
         X9 is selected from the group consisting of Glu, Gly, Gln and Pro; 
         X10 is selected from the group consisting of Ala and Glu; 
         X11 is selected from the group consisting of Ala, Asp, Glu and Pro; 
         X12 is selected from the group consisting of Ala, Gly, Ser, Thr and Val; 
         X13 is selected from the group consisting of Ala, Glu, Ser, Gln, Thr and Pro; 
         X14 is selected from the group consisting of Ala, Glu, Gly, Pro and Hyp; 
         X15 is selected from the group consisting of Ala, Glu and Ser; 
         X16 is selected from the group consisting of Ala, Glu and Ser; 
         X17 is selected from the group consisting of Ala, lie, Leu, Thr and Val; 
         X18 is selected from the group consisting of Glu and Gln; 
         X19 is selected from the group consisting of Ala, Glu, Arg, Lys and Gln 
         X21 is selected from the group consisting of Ala, Glu, Gln and Tyr; 
         X22 is selected from the group consisting of lie, Ser, Thr and Val; 
         X23 is selected from the group consisting of Ala, Glu, Ser and Thr; 
         X24 is selected from the group consisting of Ala, lie, Leu, Thr and Val; 
         X26 is selected from the group consisting of Ala, His and Lys; 
         X27 is selected from the group consisting of Gln and Tyr; 
         X28 is selected from the group consisting of His, Trp and Tyr; 
         X29 is selected from the group consisting of Asn, Trp and Tyr; 
         X30 is selected from the group consisting of Ala, His, Trp, and Tyr; 
         X31 is selected from the group consisting of Ala, He, Leu and Thr; 
         X32 is selected from the group consisting of Gln, Leu and Thr; 
         wherein one to three amino acids of X5, X6, X8-X19, X21-X24 and X26-X32 may be absent, and 
         wherein a half-life extending group is attached to the epsilon amino group of the lysine at position 7, 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         4 . The PYY analogue according to  claim 1 , wherein the PYY analogue is a compound having the formula:
   R 1 —Z—R 2 ,
   wherein R 1  is hydrogen, —C(O)C 1-6  alkyl, —C(O)C 6 H 6 , —C(O)C 3-6  cycloalkyl, —C(O)C 1-6  alkyl-C 3-6  cycloalkyl, or C 1-6  alkyl or C 1-6  alkyl-C 3-6  cycloalkyl:   R 2  is OH or NHR 3 , wherein R 3  is hydrogen or C 1-3  alkyl; and   Z is an amino acid sequence of formula III (SEQ ID NO: 256):   
       
         
           
                 
               
                   (III) 
                 
                   Ala-Pro-X6-Lys-Pro-X9-X10-X11-X12-X13-X14-X15-X16- 
                 
                     
                 
                   X17-X18-X19-Tyr-X21-Va1-X23-Leu-Arg-His-Tyr-Tyr- 
                 
                     
                 
                   Asn-Trp-Leu-Thr-Arg-Gln-Arg-Tyr 
                 
             
                
                
                
                
                
                
               
            
           
         
         wherein 
         X6 is selected from the group consisting of Ala and Glu; 
         X9 is selected from the group consisting of Glu and Gly; 
         X10 is selected from the group consisting of Ala and Glu; 
         X11 is selected from the group consisting of Ala, Asp, Glu and Pro; 
         X12 is selected from the group consisting of Ala and Ser; 
         X13 is selected from the group consisting of Ala, Glu, Ser, Thr and Pro; 
         X14 is selected from the group consisting of Ala, Glu and Pro; 
         X15 is selected from the group consisting of Ala and Glu, 
         X16 is selected from the group consisting of Ala and Glu; 
         X17 is selected from the group consisting of lie, Leu, Thr and Val; 
         X18 is selected from the group consisting of Glu and Gln; 
         X19 is selected from the group consisting of Ala, Glu, Arg, Lys, and Gln; 
         X21 is selected from the group consisting of Glu and Tyr; 
         X23 is selected from the group consisting of Ala, Glu, Ser and Thr; 
         and wherein a half-life extending group is attached to the epsilon amino group of the lysine at position 7, 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         5 . The PYY analogue according to  claim 1 , wherein the PYY analogue is a compound having the formula:
   R 1 —Z—R 2 ,
   wherein R 1  is hydrogen, —C(O)C 1-6  alkyl, —C(O)C 6 H 6 , —C(O)C 3-6  cycloalkyl or C 1-6  alkyl:   R 2  is OH or NHR 3 , wherein R 3  is hydrogen or C 1-3  alkyl; and   Z is an amino acid sequence selected from any one of SEQ ID Nos. 5 to 248,   or a pharmaceutically acceptable salt thereof.   
     
     
         6 . The PYY analogue according to  claim 3 , wherein at least two amino acids from X6, X10, X11, X13 and X23 are selected from the group consisting of Asp and Glu,
 or a pharmaceutically acceptable salt thereof.   
     
     
         7 . The PYY analogue according to  claim 3 , wherein only one of X6, X10 and X15 is Ala,
 or a pharmaceutically acceptable salt thereof.   
     
     
         8 . The PYY analogue according to  claim 1 , wherein the half-life extending group consists of a lipophilic substituent X and a linker U, wherein the linker U is attached to the amino acid side chain and X is attached to U,
 or a pharmaceutically acceptable salt thereof.   
     
     
         9 . The PYY analogue according to  claim 8 , wherein X is selected from the group consisting of 15-carboxy-pentadecanoyl, 17-carboxy-heptadecanoyl (C18DA) and 19-carboxy-nonadecanoyl, and U consists of one, two or three sub-moieties independently selected from the group consisting of Gly, Glu, γ-Glu, ε-Lys, Ser and OEG,
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         10 . The PYY analogue according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein the PYY analogue is a compound selected from the group consisting of Compound 1 to Compound 244. 
     
     
         11 . The PYY analogue according to  claim 1 , wherein the PYY analogue is in the form of pharmaceutically acceptable salt. 
     
     
         12 . The PYY analogue according to  claim 1 , wherein the PYY analogue is in the form of a non-salt. 
     
     
         13 . The PYY analogue according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein the binding affinity (Ki) towards hNPY2R is below 100 nM. 
     
     
         14 . The PYY analogue according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein the solubility of the PYY analogue is greater than 1.0 mg/ml at pH 6. 
     
     
         15 . A pharmaceutical composition comprising at least one PYY analogue according to  claim 1 , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. 
     
     
         16 . A method for treating a condition or disease related or caused by excess body weight or excess body weight gain, the method comprising administering to a patient in need thereof a pharmaceutically effective amount of a PYY analogue according to  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         17 . A method for treating obesity or an obesity-related condition, the method comprising administering to a patient in need thereof a PYY analogue according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein the obesity-related condition is selected from the group consisting of type 2 diabetes, hypertension, dyslipidemia, sleep apnea and cardiovascular disease. 
     
     
         18 . A method for treating obesity and/or an obesity-related condition, the method comprising administering to a patient in need thereof a therapeutically effective amount of a PYY analogue according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein the obesity-related condition is selected from the group consisting of dyslipidemia, hepatic steatosis, NAFLD, NASH, kidney failure and atherosclerosis. 
     
     
         19 . A method for treating diabetes, obesity, dyslipidemia or hypertension, the method comprising administering to a patient in need thereof a pharmaceutically effective amount of a PYY analogue according to  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         20 . A method for treating diabetes, obesity, or an obesity-related condition, the method comprising administering to a patient in need thereof
 a pharmaceutically effective amount of a PYY analogue according  claim 1 , or a pharmaceutically acceptable salt thereof; and   an agent for the treatment of obesity selected from the group consisting of GIP, a GLP-1 receptor agonist, exendin-4, an exendin-4 analogue, a glucagon-GLP-1 dual agonist, a GLP-1/GIP/glucagon triple agonist, or an amylin receptor agonist.