Peroxynitrite decomposition catalysts and methods of use thereof

Abstract

This invention provides a novel class of substituted macrocyclic metallic complexes. The complexes are useful as peroxynitrite decomposition catalysts. Pharmaceutical compositions, and methods of making and using the compounds, or a pharmaceutically acceptable salt, hydrate, prodrug, or mixture thereof are also described.

1 - 25 . (canceled)  
   
   
       26 . A 2-pyridyl-subtstituted porphyrin, wherein said 2-pyridyl subtstituted porphyrin is non-toxic or an effective peroxynitrite decomposition catalyst.  
   
   
       27 . The 2-pyridyl-subtstituted porphyrin of  claim 26 , wherein said 2-pyridyl substituted porphyrin is non-toxic.  
   
   
       28 . The 2-pyridyl-subtstituted porphyrin of  claim 26 , wherein said 2-pyridyl substituted porphyrin is an effective peroxynitrite decomposition catalyst.  
   
   
       29 . The 2-pyridyl-subtstituted porphyrin of  claim 27 , wherein said 2-pyridyl substituted porphyrin is an effective peroxynitrite decomposition catalyst.  
   
   
       30 . The 2-pyridyl-subtstituted porphyrin of  claim 28 , wherein the 2-pyridyl-subtstituted porphyrin yields >95% nitrate as a decomposition product.  
   
   
       31 . The 2-pyridyl-substiuted porphyrin of  claim 27 , wherein the 2-pyridyl-subtstituted porphyrin does not bind DNA in conditions in which a corresponding 4-pyridyl-subtstituted porphyrin binds DNA.  
   
   
       32 . A metallic complex comprising the 2-pyridyl-subtstituted porphyrin of  claim 26 , or a pharmaceutically acceptable base or acid addition salt, hydrate, ester, solvate, prodrug, metabolite, stereoisomer, or mixtures thereof.  
   
   
       33 . The 2-pyridyl-subtstituted porphyrin of  claim 26 , further comprising a linked PEG substituent.  
   
   
       34 . A pharmaceutical composition comprising a pharmacologically effective amount of the compound of  claim 26  and a pharmaceutically acceptable carrier.  
   
   
       35 . A pharmaceutical composition comprising a pharmacologically effective amount of the compound of  claim 32  and a pharmaceutically acceptable carrier.  
   
   
       36 . A pharmaceutical composition comprising a pharmacologically effective amount of the compound of  claim 33  and a pharmaceutically acceptable carrier.  
   
   
       37 . A metallic complex comprising the 2-pyridyl-subtstituted porphyrin of  claim 26 , or a pharmaceutically acceptable base or acid addition salt, hydrate, ester, solvate, prodrug, metabolite, stereoisomer, or mixtures thereof.  
   
   
       38 . A method of lowering peroxynitrite levels in a cell or tissue in need thereof, the method comprising contacting said cell or tissue with a 2-pyridyl-subtstituted porphyrin, wherein said 2-pyridyl subtstituted porphyrin is non-toxic or an effective peroxynitrite decomposition catalyst.  
   
   
       39 . A method of treating or inhibiting the development of a pathology associated with peroxynitrite damage in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a 2-pyridyl-subtstituted porphyrin, wherein said 2-pyridyl subtstituted porphyrin is non-toxic or an effective peroxynitrite decomposition catalyst.  
   
   
       40 . The method of  claim 39 , wherein said 2-pyridyl-subtstituted porphyrin is administered provided as metallic complex, or a pharmaceutically acceptable base or acid addition salt, hydrate, ester, solvate, prodrug, metabolite, stereoisomer, or mixtures thereof.  
   
   
       41 . The method of  claim 39 , wherein said 2-pyridyl-subtstituted porphyrin further comprises a linked PEG substituent.  
   
   
       42 . The method of  claim 39 , wherein said pathology is selected from the group consisting of Alzheimer's disease, amyotrophic lateral sclerosis, stroke, AIDS dementia, Huntington's disease, atherosclerosis; chronic inflammation; autoimmune diseases, cancer, ischemia-reperfusion injury; septic shock, and chronic graft rejection.  
   
   
       43 . The method of  claim 39 , wherein said subject is a human.