Anti-inflammatory compositions and methods

Abstract

The disclosed invention includes pharmaceutical compositions and methods for treating inflammatory conditions, particularly those that are characterized by increased binding of alpha-9 integrin to one or more of its ligands. Also disclosed are methods for selecting compounds for use in such compositions and methods.

1 . A pharmaceutical composition effective in treating an inflammatory condition in mammalian subject, comprising a pharmaceutically effective dosage of alpha-9 integrin antagonist compound and a pharmaceutical excipient.  
   
   
       2 . A pharmaceutical composition of  claim 1 , wherein said inflammatory condition is characterized by increased neutrophil adhesion.  
   
   
       3 . The pharmaceutical composition of  claim 1 , wherein said alpha-9 antagonist compound inhibits binding between alpha-9 integrin and an alpha-9 integrin ligand.  
   
   
       4 . (canceled)  
   
   
       5 . The pharmaceutical composition of  claim 3 , wherein said alpha-9 integrin antagonist compound is effective in inhibiting binding between alpha-9 integrin and an alpha-9 integrin ligand as evidenced by an IC 50  for such inhibition of less than about 100 μM.  
   
   
       6 . The pharmaceutical compositon of  claim 5 , wherein said alpha-9 integrin antagonist compound is selected from a group of compounds which inhibit alpha-4/beta-1 integrin binding to an alpha-4/beta-a integrin ligand.  
   
   
       7 . The pharmaceutical composition of  claim 1 , wherein said compound is selected from the group consisting of compounds having the formula:  
       R 1 —SO 2 —NR 2 —CHR 3 -Q-CHR 5 —CO 2 H  wherein    R 1  is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, heteroaryl and substituted heteroaryl;    R 2  is selected from the group consisting of hydrogen, alkyl, cycloalkyl, substituted sycloalkyl, cycloalkenyl, substituted cylcoalkenyl, heterocyclic, substituted heterocyclic, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and R 1  and R 2  together with the nitrogen atom bound to R 2  and the SO 2  group bound to R 1  can form a heterocyclic or a substituted heterocyclic group;    R 3  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and, when R 2  does not form a heterocyclic group with R 1 , R 2  and R 3  together with the nitrogen atom bound to R 2  and the carbon atom bound to R 3  can form a heterocyclic or a substituted heterocyclic group;    R 5  is —(CH 2 ) x —Ar—R 5′  where R 5  is selected from the group consisting of —O-Z-NR 8 R 8′  and —O-Z-R 12  wherein R 8 R 8  are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, and where R 8  and R 8′  are joined to form a heterocycle or a substituted heterocycle, R 12  is selected from the group consisting of heterocycle and substituted heterocycle, and Z is selected from the group consisting of —C(O)— and —SO 2 —,    Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl,    x is an integer of from 1 to 4;    A is —C(X)NR 7 — wherein R 7  is selected from the group consisting of hydrogen and alkyl; and X is selected from the group consisting of oxygen and sulfur;    and pharmaceutically acceptable salts thereof.    
   
   
       8 - 17 . (canceled)  
   
   
       18 . A method of treating an inflammatory condition in mammalian subject, comprising administering to the subject a pharmaceutically effective dosage of an alpha-9 integrin antagonist compound.  
   
   
       19 . The method of  claim 18 , wherein said inflammatory condition is characterized by increased neutrophil adhesion.  
   
   
       20 . The method of  claim 18 , wherein said alpha-9 integrin antagoinist compound is selected from a group of compounds which inhibit alpha-4/beta-1 integrin binding to an alpha-4/beta-1 integrin ligand.  
   
   
       21 . The method of  claim 18 , wherein said alpha-9 integrin antagoinist compound exhibits a potency in inhibiting binding between alpha-9 integrin and an alpha-9 integrin ligand that is at least 1/1000 as high as an inhibitory potency exhibited by a compound selected from the group consisting of: 
 N-(toluene-4-sulfonyl)-L-prolyl-L-4(4-methylpiperazin-1-ylcarbonyloxy)phenylalanine, N-(toluene-4-sulfonyl)-L-prolyl-L-4(N,N-dimethylcarbamyloxy)phenylalanine,    N-(1-methylpyrazole-4-sulfonyl)-L-prolyl-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,    N-(toluene-4-sulfonyl)-L-(1,1-dioxo-5,5-dimethyl)thiaprolyl-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,    N-(toluene-4-sulfonyl)-N-methyl-L-alaninyl-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,    N-(toluene-4-sulfonyl)-L-[(1,1-dioxo)thiamorpholin-3-carbonyl]-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,    N-(N-p-toluenesulfonyl)prolyl-4-(piperazinoyloxy)phenylalanine,    N-(N-p-toluenesulfonyl)sarcosyl-4-(N,N-dimethylcarbamyloxy)phenylalanine, and    N-(toluene-4-sulfonyl)-L-(5,5-dimethyl)thiaprolyl-L-4-[3-(N,N-dimethyl)propoxy]phenylalanine.    
   
   
       22 . The method of  claim 18 , wherein said compound is selected from the group consisting of carbamyl compounds having the formula:  
       R 1 —SO 2 —NR 2 —CHR 3 -Q-CHR 5 —CO 2 H  wherein    R 1  is selected from the group consisiting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocylic, heteroaryl and substituted heteroaryl;    R 2  is selected from the group consisting of hydrogen, alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and R 1  and R 2  together with the nitrogen atom bound to R 2  and the SO 2  group bound to R 1  can form heterocyclic or a substituted heterocyclic group;    R 3  is selected from the group consisiting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and, when R 2  does not form a heterocyclic group with R 1 , R 2  and R 3  together with the nitrogen atom bound to R 2  and the carbon atom bound to R 3  can form a heterocyclic or a substituted heterocyclic group;    R 5  is —(CH 2 ) x —Ar—R 5′  where R 5′  is selected from the group consisting of —O-Z-NR 8 R 8  and —O-Z-R 12  wherein R 8  and R 8′  are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, and where R 8  and R 8′  are joined to form a heterocycle or a substituted heterocycle, R 12  is selected from the group consisting of heterocycle and substituted heterocycle, and Z is selected from the group consisting of —C(O)— and —SO 2 —,    Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl,    x is an integer of from 1 to 4;    Q is —C(X)NR 7 — wherein R 7  is selected from the group consisting of hydrogen and alkyl; and X is selected from the group consisting of oxygen and sulfur; and pharmaceutically acceptable salts thereof.    
   
   
       23 . The method of  claim 18 , wherein said alpha-9 integrin antagonist is selected from the group consisting of: 
 N-(toluene-4-sulfonyl)-L-prolyl-L-4(4-methylpiperazin-1-ylcarbonyloxy)phenylalanine,    N-(toluene-4-sulfonyl)-L-prolyl-L-4(N,N-dimethylcarbamyloxy)phenylalanine,    N-(1-methylpyrazole-4-sulfonyl)-L-prolyl-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,    N-(toluene-4-sulfonyl)-L-(1,1-dioxo-5,5-dimethyl)thiaprolyl-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,    N-(toluene-4-sulfonyl)-N-methyl-L-alaninyl-L-4-(N,N-dimethylcarbamyloxy)-phenylalanine,    N-(toluene-4-sulfonyl)-L-[(1,1-dioxo)thiamorpholin-3-carbonyl]-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,    N-(N-p-toluenesulfonyl)prolyl-4-(piperazinoyloxy)phenylalanine,    N-(N-p-toluenesulfonyl)sarcosyl-4-(N,N-dimethylcarbamyloxy)phenylalanine, and    N-(toluene-4-sulfonyl)-L-(5,5-dimethyl)thiaprolyl-L-4-[3-(N,N-dimethyl)-propoxy]phenylalanine.