Inhibitors of macrophage migration inhibitory factor and methods for identifying the same

Abstract

Inhibitors of MIF are provided which have utility in the treatment of a variety of disorders, including the treatment of pathological conditions associated with MIF activity. The inhibitors of MIF have the following structures: including stereoisomers, prodrugs and pharmaceutically acceptable salts thereof, wherein n, R 1 , R 2 , R 3 , R 4 , X, and Z are as defined herein. Compositions containing an inhibitor of MIF in combination with a pharmaceutically acceptable carrier are also provided, as well as methods for use of the same.

1 . A method for treating inflammatory bowel disease, the method comprising administering a drug for treating inflammatory bowel disease that has no measurable macrophage migration inhibitory factor inhibiting activity, and further administering a macrophage migration inhibitory factor inhibiting compound having a structure selected from the group consisting of  
       
         
           
           
               
               
           
         
         or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein:  
         X is oxygen or sulfur;  
         Z is —CH 2 — or —C(═O)—;  
         R 1  is selected from the group consisting of C 1-10  alkyl and aryl C 1-10  alkyl, wherein R 1  is unsubstituted or substituted with at least one substituent selected from the group consisting of halogen, alkoxy, alkylamino, dialkylamino, and keto;  
         R 2  and R 3  are independently selected from the group consisting of halogen, hydrogen, and C 1-6  alkyl; and  
         R 7  is selected from the group consisting of cyclopentyl, phenyl, pyrazolyl, thiadiazolyl, isoxazolyl, imidazolyl, pyrrolyl, indolyl, isoquinolinyl, pyridinyl, tetrahydrothiophenyl, thienyl, furyl, tetrahydrofuranyl, thiazolidinyl, pyrazinyl, pyrrolidinyl, and piperidinyl, wherein R 7  is unsubstituted or substituted with at least one substituent selected from the group consisting of halogen, alkoxy, nitro, and alkylamino.  
       
     
     
         2 . The method of  claim 1 , wherein the drug is azathioprine.  
     
     
         3 . The method of  claim 1 , wherein the drug is a corticosteroid.  
     
     
         4 . The method of  claim 3 , wherein the corticosteroid is selected from the group consisting of cortisone, hydrocortisone, methylprednisolone, prednisone, prednisolone, betamethesone, beclomethasone dipropionate, budesonide, dexamethasone sodium phosphate, flunisolide, fluticasone propionate, triamcinolone acetonide, betamethasone, fluocinolone, fluocinonide, betamethasone dipropionate, betamethasone valerate, desonide, desoximetasone, fluocinolone, triamcinolone, triamcinolone acetonide, clobetasol propionate, dexamethasone, and rofecoxib.  
     
     
         5 . The method of  claim 1 , wherein the compound has a structure:  
       
         
           
           
               
               
           
         
         or a stereoisomer or a pharmaceutically acceptable salt thereof.  
       
     
     
         6 . A method for treating acute respiratory distress syndrome, the method comprising administering a drug for treating acute respiratory distress syndrome that has no measurable macrophage migration inhibitory factor inhibiting activity, and further administering a macrophage migration inhibitory factor inhibiting compound having a structure selected from the group consisting of:  
       
         
           
           
               
               
           
         
         or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein:  
         X is oxygen or sulfur;  
         Z is —CH 2 — or —C(═O)—;  
         R 1  is selected from the group consisting of C 1-10  alkyl and aryl C 1-10  alkyl, wherein R 1  is unsubstituted or substituted with at least one substituent selected from the group consisting of halogen, alkoxy, alkylamino, dialkylamino, and keto;  
         R 2  and R 3  are independently selected from the group consisting of halogen, hydrogen, and C 1-6  alkyl; and  
         R 7  is selected from the group consisting of cyclopentyl, phenyl, pyrazolyl, thiadiazolyl, isoxazolyl, imidazolyl, pyrrolyl, indolyl, isoquinolinyl, pyridinyl, tetrahydrothiophenyl, thienyl, furyl, tetrahydrofuranyl, thiazolidinyl, pyrazinyl, pyrrolidinyl, and piperidinyl, wherein R 7  is unsubstituted or substituted with at least one substituent selected from the group consisting of halogen, alkoxy, nitro, and alkylamino.  
       
     
     
         7 . The method of  claim 6 , wherein the drug is selected from the group consisting of a beta stimulant, an inhalation corticosteroid, an antihistamine, and a hormone.  
     
     
         8 . The method of  claim 6 , wherein the drug is a bronchodilator.  
     
     
         9 . The method of  claim 6 , wherein the drug is an inhalation corticosteroid selected from the group consisting of beclomethasone, fluticasone, triamcinolone, mometasone, prednisone, prednisolone, and methylprednisolone.  
     
     
         10 . The method of  claim 6 , wherein the drug is an antihistamine selected from the group consisting of azatadine, carbinoxamine/pseudoephedrine, cetirizine, cyproheptadine, dexchlorpheniramine, fexofenadine, loratadine, promethazine, tripelennamine, brompheniramine, cholopheniramine, clemastine, and diphenhydramine.  
     
     
         11 . The method of  claim 6 , wherein the drug is epinephrine.  
     
     
         12 . The method of  claim 6 , wherein the compound has a structure:  
       
         
           
           
               
               
           
         
         or a stereoisomer or a pharmaceutically acceptable salt thereof.