Llp2a-bisphosphonate conjugates for osteoporosis treatment

Abstract

The present invention provides compounds and pharmaceutical compositions of a peptidomimetic ligand, e.g. LLP2A, conjugated with a bisphosphonate drug, e.g. Alendronate. The compounds and pharmaceutical compositions of the present invention are useful in the treatment of osteoporosis and for the promotion of bone growth due to their specificity for the α 4 β 1 integrin on mesenchymal stem cells and for the surface of bone.

1 . A pharmaceutical composition comprising a compound of Formula I: 
       
         
           
           
               
               
           
         
         or a salt or isomer thereof, and a pharmaceutically acceptable excipient, 
       
       wherein
 each R 1  and R 2  is independently selected from the group consisting of H, halogen, C 1-6  alkyl, C 1-6  alkoxy, and C 1-6  haloalkyl; 
 R 3  is selected from the group consisting of H, C 1-6  alkyl and C 3-8  cycloalkyl; 
 X is selected from the group consisting of O, S and NH; 
 Y is selected from the group consisting of O and NH; 
 alternatively, R 1  or R 2  is combined with Y and the atoms to which they are attached to form a 5-membered heteroaryl ring; 
 Z is a peptide having 3-20 independently selected amino acids, wherein at least one amino acid is selected from the group consisting of an unnatural amino acid and a D-amino acid; 
 L is a linker; 
 D has the formula: 
 
       
         
           
           
               
               
           
         
       
       wherein
 R 4  is selected from the group consisting of H, OH and halogen; 
 R 5  is selected from the group consisting of H and C 1-6  alkyl; and 
 subscripts m, n and q are each independently from 0 to 2; and 
 subscript t is from 1 to 6. 
 
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the portion of the compound bonded to Z has a formula selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         3 . The pharmaceutical composition of  claim 1 , wherein the portion of the compound bonded to Z has a formula selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         4 . The pharmaceutical composition of  claim 1 , wherein the portion of the compound bonded to Z has a formula selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         5 . The pharmaceutical composition of  claim 1 , wherein the portion of the compound bonded to Z has a formula selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         6 . The pharmaceutical composition of  claim 1 , wherein the portion of the compound bonded to Z is a formula selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         7 . The pharmaceutical composition of  claim 1 , wherein the portion of the compound bonded to Z has the formula: 
       
         
           
           
               
               
           
         
       
     
     
         8 . The pharmaceutical composition of  claim 1 , wherein peptide Z has the formula:
   —X AA1 —X AA2 —X AA3 —(X AA4 ) p —
   
       wherein
 X AA1  is selected from the group consisting of a hydrophobic amino acid and derivatives of lysine, homolysine (Hly), ornithine (Orn) and α,γ-diaminobutyric acid (Dbu); 
 X AA2  is a negatively charged amino acid; 
 X AA3  is a hydrophobic amino acid; 
 X AA4  is selected from the group consisting of a naturally-occurring amino acid, an unnatural amino acid, and a D-amino acid; and 
 subscript p is 0 or 1. 
 
     
     
         9 . The pharmaceutical composition of  claim 8 , wherein
 X AA1  is lysine-A38 (Lys38);   X AA2  is α-aminohexanedioic acid (Aad);   X AA3  is a D-amino acid; and   subscript p is 0.   
     
     
         10 . The pharmaceutical composition of  claim 1 , wherein peptide Z is selected from the group consisting of -Lys38-Aad-D-Phe, -Lys38-Aad-Ach, -Lys38-Aad-D-Nal-2, -Lys38-Aad-Ile, -Lys38-Aad-Val, and -Lys38-Aad-Leu. 
     
     
         11 . The pharmaceutical composition of  claim 1 , wherein peptide Z is -Lys38-Aad-Ach. 
     
     
         12 . The pharmaceutical composition of  claim 1 , wherein linker L comprises at least one of N-(8-amino-3,6-dioxa-octyl)succinamic acid (EBES) and polyethylene glycol (PEG). 
     
     
         13 . The pharmaceutical composition of  claim 1 , wherein linker L is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein k is from 0 to 6. 
       
     
     
         14 . (canceled) 
     
     
         15 . The pharmaceutical composition of  claim 1 , wherein D has the formula selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         16 . The pharmaceutical composition of  claim 1 , having the compound has a formula selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         17 . (canceled) 
     
     
         18 . A method of treating osteoporosis or low bone mass, comprising administering to a subject in need thereof, a therapeutically effective amount of a pharmaceutical composition of  claim 1 . 
     
     
         19 . A method of promoting bone growth, comprising administering to a subject in need thereof, a therapeutically effective amount of a pharmaceutical composition of  claim 1 . 
     
     
         20 . (canceled)