N-terminus conformationally constrained glp-1 receptor agonist compounds

Abstract

The disclosure provides N-terminus conformationally constrained compounds, which may comprise peptide mimetics and/or amino acid substitutions, which may be used in peptides, such as GLP-1 receptor agonist compounds, to induce β-turn secondary structure at the N-terminus. The N-terminus conformationally constrained compounds may be used for research purposes; to produce GLP-1 receptor agonist compounds having improved GLP-1 receptor binding activity, enzymatic stability, or in vivo glucose lowering activity; and to develop GLP-1 receptor agonist compounds which have fewer amino acid residues. The disclosure also provides GLP-1 receptor agonist compounds, such as exendins, exendin analogs, GLP-1(7-37), GLP-1(7-37) analogs, comprising the N-terminus conformationally constrained compounds. The compounds are useful for treating various diseases, such as diabetes and obesity. The disclosure also provides methods for chemically synthesizing the N-terminus conformationally constrained compounds.

1 - 130 . (canceled) 
     
     
         131 . A polypeptide comprising the amino acid sequence as set forth in Formula (C): 
       
         
           
                 
               
                   (SEQ ID NO: 2) 
                 
                   Xaa 1 Xaa 2 Xaa 3 Xaa 4 TFTSDLSKQXaa 14 EEEAVRLFIEXaa 25 LK-R 10 -Z; 
                 
             
                
                
               
            
           
         
         wherein: 
         Xaa 1  is His; or a compound of Formula (1); 
         Xaa 2  is Gly, dAla, Aib, Ala, Val, NMeAla, a compound of Formula (3), or a compound of Formula (4); and Xaa 2  is absent when Xaa 3  is: 
       
       
         
           
           
               
               
           
         
         Xaa 3  is Pro; a compound of Formula (2); a compound of Formula (3); a Compound of Formula (4); 
       
       
         
           
           
               
               
           
         
         Xaa 4  is Gly, dAla, or Aib; 
         Xaa 14  is Leu or Met; 
         Xaa 25  is Phe or Trp; 
         R 10  is QGGPSKEIIS (SEQ ID NO:22); NG; NGG; NGGP (SEQ ID NO:24); NGGPS (SEQ ID NO:25); NGGPSS (SEQ ID NO:26); NGGPSSG (SEQ ID NO:27); NGGPSSGA (SEQ ID NO:28); NGGPSSGAP (SEQ ID NO:29); NGGPSSGAPP (SEQ ID NO:30); NGGPSSGAPPP (SEQ ID NO:31); QGGPSSGAPPPS (SEQ ID NO:32); NGGPSSGAPPS (SEQ ID NO:33); NGGPSSGAPPSK (SEQ ID NO:34); NGGPSSGAPPS(K) 2-5  (SEQ ID NO:35); NGGPSSGAPPPSK (SEQ ID NO:36); or NK; and 
         Z is OH or NH 2 ; 
         wherein the compound of Formula (1) is: 
       
       
         
           
           
               
               
           
         
         
           wherein R 20  and R 21  are each independently a single bond or a carbon atom; R 23 , R 24 , R 25  and R 26  are each independently absent, hydrogen, hydroxyl, C 1-6  alkyl, carboxyl, amino, or C 1-6  alkoxy; - - - - - - is a single bond or a double bond; and R 21  is a chiral or achiral carbon atom; 
         
         wherein the compound of Formula (2) is: 
       
       
         
           
           
               
               
           
         
         
           wherein Y 1  and Z 1  are each independently a single bond, a carbon, or a sulfur; and W 1 , W 2  and W 3  are each independently selected from hydrogen, C 1-6  alkyl, C 1-6  alkoxy, hydroxyl, and amino; and when one Y 1  or Z 1  is sulfur, the sulfur may be bonded to two oxygen atoms to form a sulfonyl group; and - - - - - - is   or  ; 
         
         wherein the compound of Formula (3) is: 
       
       
         
           
           
               
               
           
         
         
           wherein Y 1  and Z 1  are each independently a single bond, a carbon, or a sulfur; and W 1 , W 2  and W 3  are each independently selected from hydrogen, C 1-6  alkyl, C 1-6  alkoxy, hydroxyl, and amino; and when one Y 1  or Z 1  is sulfur, the sulfur may be bonded to two oxygen atoms to form a sulfonyl group; and - - - - - - is   or  ; and 
         
         wherein the compound of Formula (4) is: 
       
       
         
           
           
               
               
           
         
         
           wherein R 30 , R 31 , and R 32  are each independently hydrogen or a C 1-6  alkyl; or R 30  and R 31 , together with the nitrogen 1  and the carbon 2 , form a 5-membered or 6-membered heterocyclic ring; or R 31  and R 32 , together with the carbon 2 , form a 3-, 4-, or 5-membered carbocyclic ring. 
         
       
     
     
         132 . The polypeptide of  claim 131 , wherein Xaa 3  is Pro. 
     
     
         133 . The polypeptide of  claim 132 , wherein the polypeptide comprises the sequence set forth as: Pro 3 -exendin-4 (SEQ ID NO:40); Pro 3 ,Leu 14 -exendin-4 (SEQ ID NO:41); Pro 3 ,Leu 14 ,Phe 25 -exendin-4 (SEQ ID NO:42); Pro 3 -exendin-4(1-28) (SEQ ID NO:43); Pro 3 ,Leu 14 -exendin-4(1-28) (SEQ ID NO:44); Pro 3 ,Leu 14 ,Phe 25 -exendin-4(1-28) (SEQ ID NO:45); Pro 3 -exendin-4(1-29) (SEQ ID NO:51); Pro 3 ,Leu 14 -exendin-4(1-29) (SEQ ID NO:75); Pro 3 ,Leu 14 ,Phe 25 -exendin-4(1-29) (SEQ ID NO:52); Pro 3 -exendin-4(1-30) (SEQ ID NO:53); Pro 3 ,Leu 14 -exendin-4(1-30) (SEQ ID NO:76); Pro 3 ,Leu 14 ,Phe 25 -exendin-4(1-30) (SEQ ID NO:54); Pro 3 -exendin-4(1-31) (SEQ ID NO:55); Pro 3 ,Leu 14 -exendin-4(1-31) (SEQ ID NO:77); Pro 3 ,Leu 14 ,Phe 25 -exendin-4(1-31) (SEQ ID NO:56); Pro 3 -exendin-4(1-32) (SEQ ID NO:57); Pro 3 ,Leu 14 -exendin-4(1-32) (SEQ ID NO:78); Pro 3 ,Leu 14 ,Phe 25 -exendin-4(1-32) (SEQ ID NO:58); Pro 3 -exendin-4(1-33) (SEQ ID NO:59); Pro 3 ,Leu 14 -exendin-4(1-33) (SEQ ID NO:79); Pro 3 ,Leu 14 ,Phe 25 -exendin-4(1-33) (SEQ ID NO:60); Pro 3 -exendin-4(1-34) (SEQ ID NO:61); Pro 3 ,Leu 14 -exendin-4(1-34) (SEQ ID NO:80); Pro 3 ,Leu 14 ,Phe 25 -exendin-4(1-34) (SEQ ID NO:62); Pro 3 -exendin-4(1-35) (SEQ ID NO:63); Pro 3 ,Leu 14 -exendin-4(1-35) (SEQ ID NO:81); Pro 3 ,Leu 14 ,Phe 25 -exendin-4(1-35) (SEQ ID NO:64); Pro 3 -exendin-4(1-36) (SEQ ID NO:46); Pro 3 ,Leu 14 -exendin-4(1-36) (SEQ ID NO:47); Pro 3 ,Leu 14 ,Phe 25 -exendin-4(1-36) (SEQ ID NO:48); Pro 3 -exendin-4(1-37) (SEQ ID NO:65); Pro 3 ,Leu 14 -exendin-4(1-37) (SEQ ID NO:82); Pro 3 ,Leu 14 ,Phe 25 -exendin-4(1-37) (SEQ ID NO:66); Pro 3 -exendin-4(1-38) (SEQ ID NO:67); Pro 3 ,Leu 14 -exendin-4(1-38) (SEQ ID NO:83); Pro 3 ,Leu 14 ,Phe 25 -exendin-4(1-38) (SEQ ID NO:68); Pro 3 -exendin-3 (SEQ ID NO:50); or HGPGTFTSDLSKQLEEEAVRLFIEWLKQGGPSKEIIS (SEQ ID NO:49). 
     
     
         134 . A method for treating diabetes, treating insulin resistance, treating postprandial hyperglycemia, lowering blood glucose levels, lowering HbA1c levels, stimulating insulin release, reducing gastric motility, delaying gastric emptying, reducing food intake, reducing appetite, reducing weight, treating overweight, or treating obesity in a patient in need thereof, the method comprising:
 administering to the patient a therapeutically effective amount of the peptide of  claim 131  to treat diabetes, treat insulin resistance, treat postprandial hyperglycemia, lower blood glucose levels, lower HbA1c levels, stimulate insulin release, reduce gastric motility, delay gastric emptying, reduce food intake, reduce appetite, reduce weight, treat overweight, or treat obesity in the patient.