Lipid-amino acid conjugates and methods of use

Abstract

N-fatty acid-amino acid conjugates and J 2 prostanoid-amino acid conjugates are disclosed along with methods for making such conjugates and methods of using these conjugates in the treatment of conditions that involve dysfunctional lipid metabolism, insulin sensitivity, glucose homeostasis, and/or inflammation.

1 . A compound having the following general formula (Formula I) 
     
       
         
         
             
             
         
       
       wherein R 1  is a hydrocarbon chain of a fatty acid selected from the group consisting of myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, eicosatrienoic acid, arachidonic acid, eicosapentenoic acid, and docosatetraenoic acid; and wherein 
       (a) R 4  is a hydrogen, and R 2  and R 3  together form a cyclic side chain of an amino acid analog selected from the group consisting of 1-amino-cyclopropane carboxylic acid, 1-amino-cyclopentane carboxylic acid, and 1-amino-cyclohexane carboxylic acid; 
       (b) R 4  is a hydrogen, and R 2  and R 3  are two methyl groups of 2-aminoisobutyric acid; 
       (c) R 3  and R 4  are hydrogens, and R 2  is a side chain of a phenyl-glycine or a phenyl-glycine derivative; 
       (d) R 3  and R 4  are hydrogens, and R 2  is a side chain of a phenyl-alanine derivative; 
       (e) R 3  is a hydrogen, and R 2  and R 4 , together, form a side chain of a proline derivative; 
       (f) R 3  and R 4  are hydrogens, and R 2  is a side chain of an amino acid selected from the group consisting of serine, threonine, methionine, phenylalanine, tyrosine, lysine, aspartic acid, and glutamic acid, and the Cα has the same stereochemistry as a D amino acid; or 
       (g) R 3  is a hydrogen, and R 2  and R 4 , together, form D-proline. 
     
   
   
       2 . The compound of  claim 1 , wherein the fatty acid is arachidonic acid. 
   
   
       3 . A compound having the following general formula (Formula I): 
     
       
         
         
             
             
         
       
       wherein R 1  is a hydrocarbon chain of a non-mammalian fatty acid or J 2  prostanoid selected from the group consisting of pentadecanoic acid; heptadecanoic acid; nonadecanoic acid; heneicosanoic acid; 9-trans-tetradecanoic acid, 14:1T; 10-trans-pentadecanoic acid, 15:1T; 9-trans-hexadecenoic acid, 16:1T; 10-heptadecenoic acid, 17:1; 10-trans-heptadecenoic acid, 17:1T; 7-trans-nonadecenoic acid, 19:1T; 10,13-nonadecadienoic acid, 19:2; 11-trans-eicosenoic acid, 20:1T; 12-heneicosenoic acid, 21:1; prostaglandin J 2 ; 15-deoxy-Δ 12,14 -prostaglandin J 2 ; Δ 12 -prostaglandin J 2 ; and 9,10-dihydro-15-deoxy-Δ 12,14 -prostaglandin J 2 ; and wherein 
       (a) R 4  is a hydrogen, and R 2  and R 3  together form a cyclic side chain of an amino acid analog selected from the group consisting of 1-amino-cyclopropane carboxylic acid, 1-amino-cyclopentane carboxylic acid, and 1-amino-cyclohexane carboxylic acid; 
       (b) R 4  is a hydrogen, and R 2  and R 3  are two methyl groups of 2-aminoisobutyric acid 
       (c) R 3  and R 4  are hydrogens, and R 2  is a side chain of a phenyl-glycine or a phenyl-glycine derivative; 
       (d) R 3  and R 4  are hydrogens, and R 2  is a side chain of a phenyl-alanine derivative; 
       (e) R 3  is a hydrogen, and R 2  and R 4  together form a side chain of a proline or a proline derivative; or 
       (f) R 3  and R 4  are hydrogens, and R 2  is a side chain of an amino acid selected from the group consisting of glycine, alanine, valine, leucine, isoleucine, serine, threonine, methionine, phenylalanine, tyrosine, lysine, aspartic acid, glutamic acid, asparagine, and glutamine. 
     
   
   
       4 . (canceled) 
   
   
       5 . A pharmaceutical composition comprising the compound of  claim 1 . 
   
   
       6 . A pharmaceutical composition comprising the compound of  claim 2 . 
   
   
       7 . A pharmaceutical composition comprising the compound of  claim 3 . 
   
   
       8 . (canceled) 
   
   
       9 . A method of treating inflammation of bodily tissue of a subject, the method comprising administering to the subject an anti-inflammatory amount of the pharmaceutical composition of  claim 5 . 
   
   
       10 . A method of treating inflammation of bodily tissue of a subject, the method comprising administering to the subject an anti-inflammatory amount of the pharmaceutical composition of  claim 6 . 
   
   
       11 . A method of treating inflammation of bodily tissue of a subject, the method comprising administering to the subject an anti-inflammatory amount of the pharmaceutical composition of  claim 7 . 
   
   
       12 . (canceled) 
   
   
       13 . A method of treating a subject in need of treatment for type II diabetes, the method comprising administering to the subject a therapeutic amount of a pharmaceutical composition comprising an N-fatty acid-amino acid conjugate or J 2  prostanoid-amino acid conjugate. 
   
   
       14 . The method of  claim 13 , wherein the pharmaceutical composition comprises a compound having the following general formula (Formula I) 
     
       
         
         
             
             
         
       
       wherein: 
       (a) R 1  is a non-carboxyl portion of a fatty acid or J 2  prostanoid selected from the group consisting of myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, eicosatrienoic acid, arachidonic acid, eicosapentenoic acid, docosatetraenoic acid, prostaglandin J 2 , 15-deoxy-Δ 12,14 -prostaglandin J 2 , Δ 12 -prostaglandin J 2 , and 9,10-dihydro-15-deoxy-Δ 12,14 -prostaglandin J 2 ; and R 3  and R 4  are hydrogens, and R 2  is a side chain of an amino acid selected from the group consisting of glycine, alanine, valine, leucine, isoleucine, asparagine, and glutamine; or 
       (b) R 1  is a hydrocarbon chain of arachidonic acid; and R 3  and R 4  are hydrogens, and R 2  is the side chain of an amino acid selected from the group consisting of glycine, alanine, valine, leucine, isoleucine, asparagine, and glutamine. 
     
   
   
       15 . A method of treating a subject in need of treatment for type II diabetes, the method comprising administering to the subject a therapeutic amount of the pharmaceutical composition of  claim 5 . 
   
   
       16 . A method of treating a subject in need of treatment for type II diabetes, the method comprising administering to the subject a therapeutic amount of the pharmaceutical composition of  claim 6 . 
   
   
       17 . A method of treating a subject in need of treatment for type II diabetes, the method comprising administering to the subject a therapeutic amount of the pharmaceutical composition of  claim 7 . 
   
   
       18 . (canceled) 
   
   
       19 . A method of treating a subject in need of treatment for HIV virus infection, the method comprising:
 (i) administering to the subject an effective amount of treatment with an HIV protease inhibitor cocktail; and   (ii) co-administering to the subject a therapeutic amount of the pharmaceutical composition of  claim 5 .   
   
   
       20 . (canceled) 
   
   
       21 . A method of treating psoriasis or rheumatoid arthritis in a subject, the method comprising administering to the subject an anti-inflammatory amount of the pharmaceutical composition of  claim 5 . 
   
   
       22 . A method of treating psoriasis or rheumatoid arthritis in a subject, the method comprising administering to the subject an anti-inflammatory amount of the pharmaceutical composition of  claim 6 . 
   
   
       23 . A method of treating psoriasis or rheumatoid arthritis in a subject, the method comprising administering to the subject an anti-inflammatory amount of the pharmaceutical composition of  claim 7 . 
   
   
       24 . (canceled)