Acylated active agents and methods of their use for the treatment of autoimmune disorders

Abstract

Disclosed herein are acylated active agents and methods of their use, e.g., for modulating an autoimmunity marker or for treating an autoimmune disorder.

What is claimed is: 
     
         1 . A method of modulating an autoimmunity marker or treating an autoimmune disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of an acylated active agent selected from the group consisting of an acylated catechin polyphenol, acylated carotenoid, acylated mesalamine, acylated sugar, acylated shikimic acid, acylated ellagic acid, acylated ellagic acid analogue, and acylated hydroxy benzoic acid. 
     
     
         2 . The method of  claim 1 , wherein the autoimmunity marker is for ulcerative colitis or Crohn's disease. 
     
     
         3 . The method of  claim 1 , wherein the autoimmune disorder is ulcerative colitis or Crohn's disease. 
     
     
         4 . The method of  claim 1 , wherein a CYP1A1 mRNA level, intestinal motility, CD4 + CD25 +  Treg cell count, short chain fatty acids level, mucus secretion is increased following the administration of the acylated active agent to the subject; or
 wherein abdominal pain, gastrointestinal inflammation, gastrointestinal permeability, gastrointestinal bleeding, intestinal motility, or frequency of bowel movements is reduced following the administration of the acylated active agent to the subject; or 
 wherein an interleukin-8 (IL-8) level, macrophage inflammatory protein 1α (MIP-1α) level, macrophage inflammatory protein 1β (MIP-1p) level, NFκB level, inducible nitric oxide synthase (iNOS) level, matrix metallopeptidase 9 (MMP9) level, interferon γ (IFNγ) level, interleukin-17 (IL17) level, intercellular adhesion molecule (ICAM) level, CXCL13 level, 8-iso-prostaglandin F 2α  (8-iso-PGF2α) level IgA level, calprotectin level, lipocalin-2 level, or indoxyl sulfate level is reduced following the administration of the acylated active agent to the subject; or 
 wherein the T h 1 cell count is modulated following the administration of the acylated active agent to the subject. 
 
     
     
         5 . The method of  claim 1 , wherein the acylated active agent is selected from the group consisting of an acylated catechin polyphenol, acylated mesalamine, acylated sugar, acylated shikimic acid, and acylated hydroxybenzoic acid. 
     
     
         6 . The method of  claim 1 , wherein the method comprises administering the acylated active agent to the subject orally. 
     
     
         7 . The method of  claim 1 , wherein the acylated active agent is cleaved to release at least one fatty acid, at least one ketone body, at least one pre-ketone body, or at least one amino acid metabolite. 
     
     
         8 . The method of  claim 1 , wherein the acylated active agent comprises a group containing a fatty acid, and wherein the group containing a fatty acid is a monosaccharide, sugar alcohol, or sugar acid having one or more hydroxyl groups substituted with a fatty acid acyl. 
     
     
         9 . The method of  claim 1 , wherein the acylated active agent comprises a group containing a fatty acid. 
     
     
         10 . The method of  claim 9 , wherein the fatty acid is a short chain fatty acid. 
     
     
         11 . The method of  claim 10 , wherein the short chain fatty acid is acetyl, propionyl, or butyryl. 
     
     
         12 . The method of  claim 1 , wherein the acylated active agent comprises a group containing an amino acid metabolite. 
     
     
         13 . The method of  claim 1 , wherein the acylated active agent is an acylated mesalamine. 
     
     
         14 . The method of  claim 1 , wherein the acylated active agent is an acylated catechin polyphenol, acylated sugar, acylated shikimic acid, acylated hydroxybenzoic acid, acylated ellagic acid, or acylated ellagic acid analogue. 
     
     
         15 . The method of  claim 1 , wherein the acylated active agent comprises at least one ketone body acyl or at least one amino acid metabolite acyl. 
     
     
         16 . An acylated mesalamine of formula (II): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, 
       wherein
 R 1  is H, alkyl, acyl, a group containing a fatty acid, a group containing a ketone body or pre-ketone body, or a group containing an amino acid metabolite; 
 R 2  is H, alkyl, a group containing a fatty acid, a group containing a ketone body or pre-ketone body, or a group containing an amino acid metabolite; and 
 each R 3  is independently H, alkyl, acyl, a group containing a fatty acid, a group containing a ketone body or pre-ketone body, or a group containing an amino acid metabolite; or both R 2  groups combine to form: 
 
       
         
           
           
               
               
           
         
         provided that the acylated mesalamine comprises at least one group containing a fatty acid, at least one group containing a ketone body or pre-ketone body, or at least one group containing an amino acid metabolite. 
       
     
     
         17 . The acylated mesalamine of  claim 16 , wherein R 1  is a group containing a fatty acid. 
     
     
         18 . The acylated mesalamine of  claim 17 , wherein the group containing a fatty acid is bonded through a glycosidic bond. 
     
     
         19 . The acylated mesalamine of  claim 16 , wherein the group containing a fatty acid is a monosaccharide, sugar alcohol, or sugar acid having one or more hydroxyl groups substituted with a fatty acid acyl. 
     
     
         20 . The acylated mesalamine of  claim 16 , wherein the fatty acid is a short chain fatty acid. 
     
     
         21 . The acylated mesalamine of  claim 20 , wherein the short chain fatty acid is butyryl. 
     
     
         22 . The acylated mesalamine of  claim 16 , wherein R 2  is H. 
     
     
         23 . The acylated mesalamine of  claim 16 , wherein each R 3  is H. 
     
     
         24 . The acylated mesalamine of  claim 16 , wherein the acylated mesalamine is a compound of the following structure: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         25 . The acylated mesalamine of  claim 24 , wherein the compound is of the following structure: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         26 . The acylated mesalamine of  claim 24 , wherein the compound is of the following structure: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         27 . The acylated mesalamine of  claim 24 , wherein the compound is of the following structure: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         28 . A composition comprising an excipient and the acylated mesalamine of  claim 16 . 
     
     
         29 . An acylated shikimic acid of the following structure: 
       
         
           
           
               
               
           
         
       
       or a salt thereof,
 where 
 each R 1  is independently H, acyl, alkyl, a group containing a fatty acid, a group containing a ketone body or pre-ketone body, or a group containing an amino acid metabolite; and 
 R 2  is H, alkyl, a group containing a fatty acid, a group containing a ketone body or pre-ketone body, or a group containing an amino acid metabolite; 
 provided that the compound includes at least one group containing a fatty acid, group containing a ketone body or pre-ketone body, or group containing an amino acid metabolite. 
 
     
     
         30 . An acylated catechin polyphenol of formula (I): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, 
       wherein
    is a single carbon-carbon bond or double carbon-carbon bond; 
 Q is —CH 2 — or —C(O)—; 
 each R 1  and each R 3  is independently H, halogen, —OR A , phosphate, or sulfate; 
 R 2  is H or —OR A ; 
 each R A  is independently H, optionally substituted alkyl, a monosaccharide, a sugar acid, a group containing a fatty acid, a group containing a ketone body or pre-ketone body, a group containing an amino acid metabolite, or benzoyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of H, hydroxy, halogen, a group containing a fatty acid, a group containing a ketone body or pre-ketone body, a group containing an amino acid metabolite, an optionally substituted alkyl, an optionally substituted alkoxy, a monosaccharide, a sugar acid, phosphate, and sulfate; 
 each of n and m is independently 0, 1, 2, 3, or 4; 
 provided that the compound of formula (I) comprises at least one group containing a fatty acid, group containing a ketone body or pre-ketone body, or group containing an amino acid metabolite; and 
 provided that at least one group containing a fatty acid, when present, is a monosaccharide having one, two, three, or four hydroxyls substituted with fatty acid acyls.