Inhibitors of epoxide hydrolases for the treatment of hypertension

Abstract

Biologically stable inhibitors of soluble epoxide hydrolases are provided. The inhibitors can be used, for example, to selectively inhibit epoxide hydrolase in therapeutic applications such as treating inflammation, for use in affinity separations of the epoxide hydrolases, and in agricultural applications. A preferred class of compounds for practicing the invention have the structure shown by Formula 1 wherein X and Y is each independently nitrogen, oxygen, or sulfur, and X can further be carbon, at least one of R 1 -R 4 is hydrogen, R 2 is hydrogen when X is nitrogen but is not present when X is sulfur or oxygen, R 4 is hydrogen when Y is nitrogen but is not present when Y is sulfur or oxygen, R 1 and R 3 are each independently a substituted or unsubstituted alkyl, haloalkyl, cycloalkyl, aryl, acyl, or heterocyclic, or being a metabolite or degradation product thereof.

1 . A method of treating inflammatory disease in a patient, comprising administering to the patient an effective amount of an inhibitor of soluble epoxide hydrolase (“sEH”).  
   
   
       2 . A method of  claim 1 , wherein said inflammatory disease is adult respiratory distress syndrome (“ARDS”).  
   
   
       3 . A method of  claim 1 , wherein said inflammatory disease is systemic inflammatory response syndrome (“SIRS”).  
   
   
       4 . A method of  claim 1 , wherein said inflammatory disease is sepsis.  
   
   
       5 . A method of  claim 1 , wherein said inflammatory disease is pancreatitis.  
   
   
       6 . A method of  claim 1 , wherein said inflammatory disease is multiple trauma.  
   
   
       7 . A method of  claim 1 , wherein said inflammatory disease is brain surgery.  
   
   
       8 . A method of  claim 1 , wherein said inflammatory disease is hemorrhagic shock.  
   
   
       9 . A method of  claim 1 , wherein said inflammatory disease is a severe bum.  
   
   
       10 . A method of  claim 1 , wherein said inflammatory disease is an inflammatory disease of the lung.  
   
   
       11 . A method of  claim 1 , wherein said sEH inhibitor is an inhibitor of Formula 2:  
     
       
         
         
             
             
         
       
     
     wherein Z is oxygen, nitrogen, or sulfur, W is carbon, phosphorous, or sulfur, X and Y is each independently nitrogen, oxygen, or sulfur, and X can further be carbon, R 1 -R 4  is hydrogen, R 2  is hydrogen when X is nitrogen but is not present when X is sulfur or oxygen, R 4  is hydrogen when Y is nitrogen but is not present when Y is sulfur or oxygen, R 1  and R 3  is each independently H, C 1-20  substituted or unsubstituted alkyl, cycloalkyl, aryl, acyl, or heterocyclic.  
   
   
       12 . A method of treating an epoxide hydrolase, useful to purify, isolate, or inhibit the epoxide hydrolase, comprising: 
 providing a compound having the structure                          wherein Z is oxygen, nitrogen, or sulfur, W is carbon, phosphorous, or sulfur, X and Y is each independently nitrogen, oxygen, or sulfur, and X can further be carbon, R 1 -R 4  is hydrogen, R 2  is hydrogen when X is nitrogen but is not present when X is sulfur or oxygen, R 4  is hydrogen when Y is nitrogen but is not present when Y is sulfur or oxygen, R 1  and R 3  is each independently H, C 1-20  substituted or unsubstituted alkyl, cycloalkyl, aryl, acyl, or heterocyclic,    the compound provided being in free form or being derivatized so as to be immobilized to a water soluble support; and,    contacting the free form or immobilized compound with an epoxide hydrolase under conditions in which the epoxide hydrolase is enzymatically active, the contacting effective to form a complex between the compound and the epoxide hydrolase, wherein the activity of the epoxide hydrolase so complexed is modified with respect to enzymatically active, uncomplexed epoxide hydrolase.    
   
   
       13 . The method as in  claim 12 , wherein the providing step includes converting a precursor form of the compound before forming the complex.  
   
   
       14 . The method as in  claim 13 , wherein the precursor form of the compound is a carbodiimine or thiourea.  
   
   
       15 . The method as in  claim 12 , where the compound is capable of establishing anionic bond with a carboxylic acid residue of a protein, to stabilize one or more hydrogen bonds or to have a group able to establish a hydrogen bond with a tyrosine residue over the catalytic site.  
   
   
       16 . The method as in  claim 12 , wherein the modified activity of the epoxide hydrolase when in the complex is epoxide hydrolase inhibition.  
   
   
       17 . The method as in  claim 12 , wherein the epoxide hydrolase of the complex is selectively formed with a soluble epoxide hydrolase.  
   
   
       18 . The method as in  claim 12 , wherein the treating is useful for purification or isolation of a microsomal epoxide hydrolase, and the compound is derivatized so as to be immobilized to a water insoluble support.  
   
   
       19 . The method as in  claim 18 , wherein the compound is immobilized through derivation at one of R 1  or R 3 .  
   
   
       20 . The method as in  claim 18 , wherein the contacting includes eluting an aqueous solution through the water insoluble support.  
   
   
       21 . The method as in  claim 12 , wherein the treating is useful for inhibiting a mammalian soluble or microsomal epoxide hydrolase.  
   
   
       22 . The method as in  claim 21 , wherein the compound has an IC 50  of less than about 500 μM.  
   
   
       23 . The method as in  claim 21 , wherein the treating is therapeutically effective to treat an inflammation.  
   
   
       24 . The method as in  claim 23 , wherein the inflammation treated is adult respiratory distress syndrome.  
   
   
       25 . The method as in  claim 21 , wherein the treating is in conjunction with a cancer therapy.  
   
   
       26 . The method as in  claim 21  wherein an effective therapeutic amount of the compound provided is a total daily dose from about 0.001 μM/kg to about 100 mg/kg body weight of the mammal.