Pharmaceutical compositions and methods for metabolic modulation

Abstract

Pharmaceutical compositions include compounds with cytokinin activity to modulate glucose and/or lipid metabolism in a mammal. Especially preferred compounds include those comprising a purine scaffold, and it is further preferred that contemplated compositions are employed to prevent and/or treat various diseases, including pre-diabetes, insulin resistance, type-2 diabetes, Syndrome X, and dyslipidemia In still further preferred aspects, compounds with cytokinin activity are used to activate AMPK and/or Akt. Consequently, various diseases associated with dysregulation of AMPK and/or Akt may be treated using the compounds of the present inventive subject matter.

1 - 33 . (canceled)  
   
   
       34 . A pharmaceutical composition comprising a compound having cytokinin activity and a pharmaceutically acceptable carrier in a dosage form effective to modulate glucose metabolism in a mammal when the composition is administered to the mammal at a concentration effective to modulate glucose metabolism, and wherein the compound is not metformin.  
   
   
       35 . The pharmaceutical composition of  claim 34  wherein the compound having cytokinin activity is selected from the group consisting of N6-benzyladenine, N6-benzyladenine hydrochloride, N6-benzyladenosine, N6-benzyladenine-3-glucoside, N6-benzyladenine-7-glucoside, N6-benzyladenine-9-glucoside, N6-benzyl-9-(2-tetrahydropyranyl)adenine, N6-benzyladenosine-5′-monophosphate, dihydrozeatin, dihydrozeatin riboside, dihydrozeatin-7-β-D-glucoside, dihydrozeatin-9-β-D-glucoside, dihydrozeatin-O-glucoside, dihydrozeatin-O-glucoside riboside, dihydrozeatin riboside-5′-monophosphate, dihydrozeatin-O-acetyl, N6-isopentenyladenine, N6-isopentenyladenosine, N6-isopentenyladenosine-5′-monophosphate, N6-isopentenyladenine-7-glucoside, N6-isopentenyladenine-9-glucoside, 2-methylthio-N-6-isopentenyladenosine, 2-methylthio-N-6-isopentenyladenine, 2-thio-N-6-isopentenyladenine, 2-benzylthio-N-6-isopentenyladenine, kinetin, kinetin riboside, kinetin-9-glucoside, kinetin riboside-5′-monophosphate, meta-topolin, meta-topolin riboside, meta-topolin-9-glucoside, ortho-topolin, ortho-topolin riboside, ortho-topolin-9-glucoside, trans-zeatin, trans-zeatin riboside, cis-zeatin, cis-zeatin riboside, trans-zeatin-7-glucoside, trans-zeatin-9-glucoside, trans-zeatin-O-glucoside, trans-zeatin-O-glucoside riboside, trans-zeatin riboside-5′-monophosphate, trans-zeatin-O-acetyl, 2-chloro-trans-zeatin, N2-acyl-guanine, N2-acyl-guanosine, 2-methylthio-trans-zeatin, and 2-methylthio-trans-zeatin riboside.  
   
   
       36 . The pharmaceutical composition of  claim 34  wherein the compound having cytokinin activity comprises a moiety is selected from the group consisting of N6-benzyladenine, dihydrozeatin, N6-isopentenyladenine, 2-methylthio-N-6-isopentenyladenine, 2-thio-N-6-isopentenyl adenine, 2-benzylthio-N-6-isopentenyladenine, kinetin, meta-topolin, ortho-topolin, trans-zeatin, cis-zeatin, trans-zeatin-O-acetyl, 2-chloro-trans-zeatin, N2-acyl-guanine, and 2-methylthio-trans-zeatin.  
   
   
       37 . The pharmaceutical composition of  claim 34  wherein the compound having cytokinin activity is selected from the group consisting of trans-zeatin, cis-zeatin, trans-zeatin-O-acetyl, 2-chloro-trans-zeatin, and 2-methylthio-trans-zeatin, and wherein the compound is optionally covalently bound to a sugar.  
   
   
       38 . The pharmaceutical composition of  claim 34  wherein the compound is present as a pharmaceutically acceptable salt, a hydrate, or in form of a prodrug.  
   
   
       39 . The pharmaceutical composition of  claim 35  wherein the compound having cytokinin activity is selected from the group consisting of N2-acetylguanine, N6 benzyladenine, dihydrozeatin, cis-zeatin, trans-zeatin, N6-isopentenyladenine, kinetin, and meta-topolin.  
   
   
       40 . The pharmaceutical composition of  claim 34 , further comprising a second compound selected from the group consisting of a biguanide, a sulfonyl urea, a meglitinide, a thiazolidinedione, and a second compound having cytokinin activity.  
   
   
       41 . A method of modulating glucose metabolism in a mammal comprising a step of administering a compound according to  claim 34  at a dosage effective to modulate glucose metabolism in the mammal.  
   
   
       42 . The method of  claim 41  wherein the mammal is diagnosed with at least one of syndrome X, pre-diabetes, insulin resistance, type-2 diabetes, and dyslipidemia.  
   
   
       43 . The method of  claim 41  wherein the administration is prophylactic administration to prevent at least one of Syndrome X, pre-diabetes, insulin resistance, type-2 diabetes, and dyslipidemia.  
   
   
       44 . The method of  claim 41  wherein modulating glucose metabolism in a mammal comprises increasing glucose uptake in a muscle cell.  
   
   
       45 . The method of  claim 41  wherein modulating glucose metabolism in a mammal comprises decreasing gluconeogenesis in a hepatocyte.  
   
   
       46 . The method of  claim 41  wherein the compound having cytokinin activity is selected from the group consisting of trans-zeatin, cis-zeatin, trans-zeatin-O-acetyl, 2-chloro-trans-zeatin, and 2-methylthio-trans-zeatin, and wherein the compound is optionally covalently bound to a sugar.  
   
   
       47 . A method of modulating lipid metabolism in a mammal that comprises a step of administering a compound according to  claim 34  at a dosage effective to modulate glucose metabolism in the mammal, and wherein the compound is not N6-aralkyladenosine.  
   
   
       48 . The method of  claim 47  wherein the mammal is diagnosed with at least one of Syndrome X and dyslipidemia.  
   
   
       49 . The method of  claim 47  wherein the administration is prophylactic administration to prevent at least one of Syndrome X and dyslipidemia.  
   
   
       50 . The method of  claim 47  wherein modulating lipid metabolism in a mammal comprises at least one of decreasing total serum cholesterol, decreasing serum LDL-cholesterol, and decreasing serum triglycerides.  
   
   
       51 . The method of  claim 47  wherein the compound having cytokinin activity is selected from the group consisting of trans-zeatin, cis-zeatin, trans-zeatin-O-acetyl, 2-chloro-trans-zeatin, and 2-methylthio-trans-zeatin, and wherein the compound is optionally covalently bound to a sugar.  
   
   
       52 . A method of performing an analytic test in a mammal comprising: 
 determining a concentration of a compound according to  claim 34  in a biological fluid; and    correlating the concentration with at least one of a likelihood and presence of a metabolic disorder, wherein the disorder is selected from the group consisting of pre-diabetes, insulin resistance, type-2 diabetes, syndrome X, and dyslipidemia.    
   
   
       53 . The method of  claim 52  wherein a decrease in the concentration of the compound is associated with an increased likelihood or presence of the metabolic disorder.