Dipeptide mimetics of ngf and bdnf neurotrophins

Abstract

The invention relates to compounds having either agonist or antagonist activities for the neurotrophins NGF and BDNF and represented by monomeric or dimeric substituted dipeptides that are analogs of the exposed portions of loop 1 or loop 4 regions of these neurotrophins near or at a beta-turn of the respective loop. N-acylated substituents of these dipeptides are biostereoisomers of the amino acid residues preceding these dipeptide sequences in the neurotrophin primary structure. The dimeric structure is produced advantageously by using hexamethylenediamine to which dipeptides are attached via their carboxyl groups. The claimed compounds displayed neuroprotective and differentiation-inducing activities in cellular models and enhanced the amount of phosphorylated tyrosine kinase A and the heat shock proteins Hsp32 and Hsp70 in the concentration range of 10 −9 to 10 −5 M. They also displayed neuroprotective, anti-parkinsonian, anti-stroke, anti-ischemic, anti-depressant and anti-amnestic activities in animal models and were active in experimental models of Alzheimer's disease. These in vivo effects of the claimed compounds are displayed in the dose range of 0.01 to 10 mg/kg when administered intraperitoneally.

1 . A compound of general formula (R—CH 2 —CO-A-B—NH—R′) n  (I), which is a substituted linear dipeptide having a sequence that corresponds to the sequence of a solvent-exposed portion of the loop 1 or loop 4 region of a neurotrophic factor, wherein at least one amino acid residue or its biostereoisomer forms part of a beta-turn of the respective loop, having a full or partial agonist or antagonist activity. 
     
     
         2 . The compound according to  claim 1 , wherein said neurotrophic factor is nerve growth factor (NGF) or brain-derived neurotrophic factor (BDNF). 
     
     
         3 . The compound according to  claim 1 , wherein in the formula I:
 A and B are amino acid residues of a dipeptide sequence AB;   R is a side chain radical of the amino acid residue preceding the dipeptide fragment AB in the neurotrophin sequence or H or a bivalent radical —R—, in particular —(CH 2 ) m —;   R′ is a side chain radical of the amino acid residue following the dipeptide fragment AB in the neurotrophin sequence or H or a bivalent radical —R′—, in particular —(CH 2 ) m —;   n=1 or 2.   In the presence of a bivalent radical —R′— or —R— n=2 and the compound is a dimer having the monomeric dipeptides linked by a C-terminal spacer —R—R— or an N-terminal spacer —R′—R′—. In other cases n=1 and the compound is a substituted monomeric dipeptide.   
     
     
         4 . The compound according to  claim 3 , wherein R is HO(O)C—CH 2 —; A is Glu; B is Lys; R′ is H; and n=1. 
     
     
         5 . The compound according to  claim 3 , wherein R is HO(O)C—CH 2 —; A is Glu; B is Lys; R′ is —(CH 2 ) m —; m=1 or 1.5 or 2 or 2.5 or 3; and n=2. 
     
     
         6 . The compound according to  claim 3 , wherein R is HO(O)C—CH 2 —; A is Glu; B is Lys; R′ is —(CH 2 ) 5 —NH—C(O)—(CH 2 ) 3/2 —; and n=2. 
     
     
         7 . The compound according to  claim 3 , wherein R is H; A is Lys; B is Glu; R′ is H; and n=1. 
     
     
         8 . The compound according to  claim 3 , wherein R is H; A is Lys; B is Glu; R′ is —(CH 2 ) 3 —; and n=2. 
     
     
         9 . The compound according to  claim 3 , wherein R is NH 2 —(CH 2 ) 4 —; A is Lys; B is Glu; R′ is H; and n=1. 
     
     
         10 . The compound according to  claim 3 , wherein R is NH 2 —(CH 2 ) 4 —; A is Lys; B is Glu; R′ is —(CH 2 ) 3 —; and n=2. 
     
     
         11 . The compound according to  claim 3 , wherein R is H; A is Gly; B is Lys; R′ is —(CH 2 ) 3 —COOH; and n=1. 
     
     
         12 . The compound according to  claim 3 , wherein R is —(CH 2 ) 2 —; A is Gly; B is Lys; R′ is —(CH 2 ) 3 —COOH; and n=2. 
     
     
         13 . The compound according to  claim 3 , wherein R is HO(O)C—CH 2 —; A is Ser; B is Lys; R′ is H; and n=1. 
     
     
         14 . The compound according to  claim 3 , wherein R is HO(O)C—CH 2 —; A is Ser; B is Lys; R′ is —(CH 2 ) 3 —; and n=2. 
     
     
         15 . The compound according to  claim 3 , wherein R is HO(O)C—CH 2 —; A is Lys; B is Lys; R′ is —(CH 2 ) 3 —; and n=2. 
     
     
         16 . The compound according to  claim 3 , wherein R is H; A is Asp; B is Ser; R′ is H; and n=1. 
     
     
         17 . The compound according to  claim 3 , wherein R is HO(O)C—CH 2 —; A is Met; B is Ser; R′ is H; and n=1. 
     
     
         18 . The compound according to  claim 3 , wherein R is HO(O)C—CH 2 —; A is Met; B is Ser; R′ is —(CH 2 ) 7/2 —; and n=2. 
     
     
         19 . (canceled) 
     
     
         20 . A method for the treatment of acute neurodegenerative disease such as stroke or a chronic neurodegenerative disease such as Alzheimer's disease or Parkinson's disease by administering an effective amount of the compound according to  claim 5 , wherein m=3. 
     
     
         21 . (canceled) 
     
     
         22 . A method for the treatment of a mental disorder such as depression by administering an effective amount of the compound according to  claim 14 . 
     
     
         23 . (canceled)