Fpr1 antagonist derivatives and use thereof

Abstract

A dipeptide derivative as formyl peptide receptor 1 (FPR1) antagonist is provided. The dipeptide derivative is represented by formula (I), wherein: the chiral centers in formula (I) are S and R configurations respectively; each of RK and RT is selected from a group consisting of a hydrogen, a hydroxyl group, a C 1 -C 4 alkyl-substituted hydroxyl group, a C 1 -C 4 alkoxyl group, a carboxylic acid group, a C 1 -C 4 alkyl nitrile-substituted, C 1 -C 4 alkyl-substituted or C 1 -C 4 alkoxyl-substituted amido group, a C 1 -C 4 alkyl-substituted ester group and a benzoyl group having a C 1 -C 4 alkyl-substituted benzene ring; and each of RM and RS is selected from a group consisting of a hydrogen, a hydroxyl group, a phenyl group, a pyridinyl group, a carboxylic acid group, a C 1 -C 4 alkoxyl substituted ester group, and a benzoyl group having a hydroxyl-substituted, a halogen-substituted, a C 1 -C 4 alkoxyl-substituted or a C 1 -C 4 alkyl-substituted benzene ring.

What is claimed is: 
     
         1 . A method for treating neutrophil inflammatory disorders with an antagonist of formyl peptide receptor 1 (FPR1), comprising:
 providing a derivative of N—(N-aroyl-L-tryptophanyl)-D-phenylalanine represented by formula (I), wherein:
 the chiral centers in formula (I) are S and R configurations respectively; 
 each of RK and RT is selected from a group consisting of a hydrogen, a hydroxyl group, a C 1 -C 4  alkyl-hydroxyl substituted (C 1 -C 4  alkyl-OH) group, a C 1 -C 4  alkoxyl group, a carboxylic acid group, a C 1 -C 4  alkyl nitrile-substituted (CONHC 1 -C 4 alkyl-CN) group, or C 1 -C 4  alkyl-substituted (CONHC 1 -C 4  alkyl) or C 1 -C 4  alkoxyl-substituted (CONHC 1 -C 4  alkoxyl) amido group, a C 1 -C 4  alkyl-substituted ester (COOC 1 -C 4  alkyl) group and a benzoyl group having a C 1 -C 4  alkyl-substituted benzene ring; and 
 each of RM and RS is selected from a group consisting of a hydrogen, a hydroxyl group, a phenyl group, a pyridinyl group, a carboxylic acid group, a C 1 -C 4  alkoxyl substituted ester group, and a benzoyl group having a hydroxyl-substituted, a halogen-substituted, a C 1 -C 4  alkoxyl-substituted or a C 1 -C 4  alkyl-substituted benzene ring. 
   
       
         
           
           
               
               
           
         
       
     
     
         2 . The method as claimed in  claim 1 , further comprising providing one selected from a group consisting of a pharmaceutically acceptable salt, solvate and combination thereof for formula (I). 
     
     
         3 . The method as claimed in  claim 1 , wherein the neutrophil inflammatory disorders are selected from a group consisting of lung injury, chronic obstructive pulmonary disease, acute respiratory distress syndrome, asthma, ischemic reperfusing injury, arthritis and septicemia. 
     
     
         4 . A dipeptide derivative represented by formula (I), 
       
         
           
           
               
               
           
         
         wherein: 
         the chiral centers in formula (I) are S and R configurations respectively; 
         each of RK and RT is selected from a group consisting of a hydrogen, a hydroxyl group, a C 1 -C 4  alkyl-substituted hydroxyl group, a C 1 -C 4  alkoxyl group, a carboxylic acid group, a C 1 -C 4  alkyl nitrile-substituted, C 1 -C 4  alkyl-substituted or C 1 -C 4  alkoxyl-substituted amido group, 
         a C 1 -C 4  alkyl-substituted ester group and a benzoyl group having a C 1 -C 4  alkyl-substituted benzene ring; and 
         each of RM and RS is selected from a group consisting of a hydrogen, a hydroxyl group, a phenyl group, a pyridinyl group, a carboxylic acid group, a C 1 -C 4  alkoxyl substituted ester group, and a benzoyl group having a hydroxyl-substituted, a halogen-substituted, a C 1 -C 4  alkoxyl-substituted or a C 1 -C 4  alkyl-substituted benzene ring. 
       
     
     
         5 . The dipeptide derivative as claimed in  claim 4 , wherein the halogen is one selected from a group consisting of fluorine (F), chlorine (Cl), bromine (Br) and iodine (I). 
     
     
         6 . The dipeptide derivative as claimed in  claim 4  inhibits and antagonizes a formyl peptide receptor 1. 
     
     
         7 . A dipeptide derivative represented by formula (II), 
       
         
           
           
               
               
           
         
       
       wherein:
 the chiral centers in formula (II) are S and R configurations respectively; 
 R 1  is selected from one of a hydrogen and a hydroxyl group; 
 R 2  is one selected from a group consisting of non-substituted phenyl group, mono-substituted phenyl group, di-substituted phenyl group, or tri-substituted phenyl group and pyridinyl group; 
 R 3  is one selected from a group consisting of a non-substituted benzoyl group, a mono-substituted benzoyl group, a di-substituted benzoyl group and a tri-substituted benzoyl group; and 
 R 4  is selected from one of C1-C4 alkoxyl group and a glycin-nitrile group. 
 
     
     
         8 . The dipeptide derivative as claimed in  claim 7  inhibits and antagonizes a formyl peptide receptor 1. 
     
     
         9 . The dipeptide derivative as claimed in  claim 8  inhibits at least one selected from a group consisting of FPR1 downstream, calcium, mitogen-activated protein kinases and protein kinase B. 
     
     
         10 . The dipeptide derivative as claimed in  claim 8 , wherein the dipeptide derivative competitively inhibits superoxide anion generation and neutrophil elastase release induced by a FPR1 activator. 
     
     
         11 . The dipeptide derivative as claimed in  claim 10 , wherein the FPR1 activator is derived from neutrophil inflammatory disorders and the neutrophil inflammatory disorder is selected from a group consisting of following diseases or symptoms: lung injury, chronic obstructive pulmonary disease, acute respiratory distress syndrome, asthma, ischemic reperfusing injury, arthritis and septicemia.