Compounds having affinity for the granulocyte-colony stimulating factor receptor (G-CSFR) and associated uses

Abstract

Novel compounds are provided that bind to G-CSFR. The novel compounds have a peptide chain approximately 6 to 40 amino acids in length that binds to G-CSFR. The compounds are useful as probes for affinity screening. In addition, the compounds have demonstrated agonist or antagonist activity for the G-CSFR, and are therefore useful in treatment of diseases including patients who suffer from a low white blood cell titer. Pharmaceutical compositions and methods of use are provided as well.

1 - 161 . (CANCELED)  
     
     
         162 . A compound comprising a peptide chain approximately 12 to 40 amino acids in length that binds to G-CSFR and contains a sequence of amino acids of formula (V) (V) CX IV   1 X IV   2 X IV   3 X IV   4 X IV   5 X IV   6 X IV   7 X IV   8 X IV   9 X IV   10 C (SEQ ID NO: 5) wherein each amino acid is indicated by standard one-letter abbreviation, and wherein 
 X IV   1  is E, G, P, N, R, T, W, S, L, H, A, Q or Y;    X IV   2  is S, T, E, A, D, G, W, P, L, N, V, Y, R or M;    X IV   3  is R, Y, V, Q, E, T, L, P, S, K, M, A or W;    X IV   4  is L, M, G, F, W, R, S, V, P, A, D, C or T;    X IV   5  is V, T, A, R, S, L, W, C, I, E, P, H, F, D or Q;    X IV   6  is E, Y, G, T, Q, M, S, N, A or P;    X IV   7  is C, V, D, G, L, W, E, V, I, S, M or A;    X IV   8  is S, Y, A, W, P, V, L, Q, G, K, F, I, E or D;    X IV   9  is R, W, M, D, H, V, G, A, Q, L, S, E or Y;    X IV   10  is M, L, I, S, V, P, W, F, T, Y, R, or Q;    and wherein said compound does not comprise sequence LLDICELKLQECARRCN (SEQ ID NO: 208).    
     
     
         163 . The compound of  claim 162 , wherein 
 X IV   1  is E, X IV   2  is S or A, X IV   3  is R, X IV   4  is L, X IV   5  is V or S, X IV   6  is E,    X IV   7  is C, X IV   8  is S, X IV   9  is R, and X IV   10  is L.    
     
     
         164 . The compound of  claim 162 , wherein the sequence of amino acids is selected from the group consisting of: 
 GGGLLDICELKLQECARRCN (SEQ ID NO: 209);    GRTGGLLDICELKLQECARRCN (SEQ ID NO: 210);    LGIEGRTGGGLLDICELKLQECARRCN (SEQ ID NO: 211);    LLDICEELKLQEAARRCN (SEQ ID NO: 212); and    KLLDICELKLQEAARRCN (SEQ ID NO: 213).    
     
     
         165 . The compound of  claim 162 , comprising a dimer having the structure of formula (VIII)  
       
         
           
           
               
               
           
         
       
       wherein R 1  and R 2  are independently selected from the sequences of amino acids of formula (V); βA is a β-alanine residue; n1, n2, n3, n4, x and y are independently zero or one with the proviso that the sum of x and y is either one or two; and Lk is a terminal linking moiety selected from the group consisting of a disulfide bond, a carbonyl moiety, a C1-12 linking moiety optionally terminated with one or two-NH-linkages and optionally substituted at one or more available carbon atoms with a lower alkyl substituent, a lysine residue or a lysine amide.  
     
     
         166 . The compound of  claim 162 , containing a disulfide bond.  
     
     
         167 . The compound of claims  162  wherein the N terminus of the peptide is coupled to a polyethylene glycol molecule.  
     
     
         168 . The compound of  claim 162  wherein the N terminus of the peptide is acetylated.  
     
     
         169 . The compound of  claim 162 , wherein the C terminus of the peptide is amidated.  
     
     
         170 . A pharmaceutical composition comprising a therapeutically effective amount of the compound of any  claim 162 , in combination with a pharmaceutically acceptable carrier.  
     
     
         171 . A method for treating a patient who would benefit from administration of a GCSF modulator, comprising administering to the patient a therapeutically effective amount of the compound of  claim 162 .  
     
     
         172 . The method of  claim 171 , wherein the G-CSF modulator is an agonist for the GCSFR.  
     
     
         173 . The method of  claim 171 , wherein the patient suffers from a depressed neutrophil count.  
     
     
         174 . The method of  claim 173 , wherein the depressed neutrophil count is associated with a condition selected from the group consisting of chemotherapy-induced neutropenia, AIDSinduced neutropenia and community-acquired pneumonia-induced neutropenia.