Identifying therapeutic compounds based on their physical-chemical properties

Abstract

The present invention is directed to rapid and efficient methods of identifying therapeutic compounds by allowing only the most favorable molecules initially selected based on their physical-chemical profile falling within a range predefined by the physical-chemical/biological relationship of a previously tested small subset of compounds of same core structure to be assayed; and to the therapeutic compositions identified by said methods.

1 - 58 . (canceled) 
     
     
         59 . A therapeutic composition for treating a condition characterized by oxidative stress comprising one or more therapeutic compounds selected by establishing a relationship between physical-chemical profile and biological activity of a first subset of compounds; wherein the physical-chemical profile comprises one or more parameters selected from onset of oxidation, potential of oxidation, potential of reduction, reversibility of oxidation, reversibility of reduction, current of oxidation or current of reduction; and wherein the biological activity is measured in an assay effective in detecting compounds for the treatment of a targeted disorder;
 testing further potential therapeutic candidates with said core structure for their physical-chemical properties; and   selecting the one or more therapeutic compounds based on its or their physical-chemical parameters falling within a range predefined by the physical-chemical/biological relationship of the previously tested first subset of compounds;   wherein said core structure is selected from the group consisting of: a quinone core structure,   
       
         
           
           
               
               
           
         
         and a therapeutically acceptable excipient. 
       
     
     
         60 . The composition of  claim 59 , wherein the biological assay is a cell-based assay comprising one or more assays selected from the High Glutamate-induced Oxidative Stress (HGOS) assay wherein the compounds in the previously tested first subset of compounds have the ability to protect at least 30% of energetically competent cells against stressor induced cell death and the E-selectin (ELAM) assay wherein the compounds in the previously tested first subset of compounds exhibit an EC 50  lower than about 30 μM; and
 wherein the one or more therapeutic compounds are selected if it or they comprise a stilbene core structure and if its or their physical-chemical profile comprises one or more parameters selected from the parameter for potential of the first oxidation wave that falls between about 800 mV and 1400 mV versus a silver/silver chloride reference electrode, and the parameter for the reversibility of the first oxidation wave that measures about 20% or more.   
     
     
         61 . The composition of  claim 60 , wherein the condition is inflammation, neurodegeneration or ischemia. 
     
     
         62 . The compound of  claim 59 , wherein the biological assay is a cell-based assay comprising one or more assays selected from the High Glutamate-induced Oxidative Stress (HGOS) assay wherein the compounds in the previously tested first subset of compounds have the ability to protect at least 30% of energetically competent cells against stressor induced cell death and the E-selectin (ELAM) assay wherein the compounds in the previously tested first subset of compounds exhibit an EC 50  lower than about 30 μM; and
 wherein the one or more therapeutic compounds are selected if it or they comprise a core structure of Formula I:   
       
         
           
           
               
               
           
         
         wherein additional substitution at the phenyl rings does not include a nitro group; 
         and if its or their physical-chemical profile comprises the parameter for potential of the first oxidation wave that falls below 1000 mV versus a silver/silver chloride reference electrode. 
       
     
     
         63 . The composition of  claim 62 , wherein the condition is inflammation, neurodegeneration or ischemia. 
     
     
         64 . The composition of  claim 59 , wherein the biological assay is a cell-based assay comprising one or more assays selected from the High Glutamate-induced Oxidative Stress (HGOS) assay wherein the compounds in the previously tested first subset of compounds have the ability to protect at least 30% of energetically competent cells against stressor induced cell death and the E-selectin (ELAM) assay wherein the compounds in the previously tested first subset of compounds exhibit an EC 50  lower than about 30 μM;
 wherein the one or more therapeutic compounds are selected if it or they comprise a core structure of Formula I:   
       
         
           
           
               
               
           
         
         wherein additional substitution at the phenyl rings includes a nitro group; 
         and if its or their physical-chemical profile comprises one or more parameters selected from the parameter for potential of the first oxidation wave that falls between about 950 mV and 1250 mV versus a silver/silver chloride reference electrode, and the parameter for reversibility of the first oxidation wave measures more than 20%. 
       
     
     
         65 . The composition of  claim 62 , wherein the condition is inflammation, neurodegeneration or ischemia. 
     
     
         66 . A composition of  claim 59  for treating a condition characterized by amyloid-β fibril formation, wherein the physical-chemical profile comprises the parameter for potential of the first oxidation wave and the biological activity assay is the Thioflavin T binding assay measuring reduction of amyloid-β fibril formation; and wherein the one or more compounds are selected if it or they comprise an apomorphine core structure of Formula III: 
       
         
           
           
               
               
           
         
         and if the physical-chemical profile comprises the parameter for potential of the first oxidation wave that falls under 1250 mV versus a silver/silver chloride reference electrode. 
       
     
     
         67 . The composition of  claim 66 , wherein the condition is Alzheimer's disease. 
     
     
         68 . A composition of  claim 59  for treating a condition characterized by amyloid-β fibril formation, wherein the physical-chemical profile comprises the parameter for potential of the first oxidation wave and the biological activity assay is the Thioflavin T binding assay measuring reduction of amyloid-β fibril formation; wherein the one or more compounds are selected if it or they comprise an apomorphine core structure of Formula III: 
       
         
           
           
               
               
           
         
         and if the physical-chemical profile comprises the parameter for potential of the first reduction is more negative than about −790 mV versus a silver/silver chloride reference electrode. 
       
     
     
         69 . The composition of  claim 68 , wherein the condition is Alzheimer's disease. 
     
     
         70 . A composition of  claim 59  for treating a condition characterized by oxidative stress, wherein the physical-chemical profile comprises the parameter for reversibility of reduction wave and the biological activity assay comprises the E-selectin (ELAM) cell based assay detecting compounds with an EC 50  lower than 30 μM, and
 wherein the one or more therapeutic compounds are selected if it or they comprise a quinone core structure and if its or their physical-chemical profile comprises a parameter for the total reversibility of reduction of 75% or more.   
     
     
         71 . The composition of  claim 70 , wherein the condition is inflammation, neurodegeneration, or ischemia. 
     
     
         72 . A therapeutic composition of  claim 59  for treating a condition characterized by oxidative stress, wherein the physical-chemical profile comprises the parameter for potential of oxidation wave and the cell based assay comprises the HGOS assay protecting at least 30% of the cells against stressor induced cell death;
 wherein the one or more therapeutic compounds are selected if it or they comprise a chroman core structure of Formula IV:   
       
         
           
           
               
               
           
         
       
       if its or their physical-chemical profile comprises the parameter for oxidation potential that falls between about 850 mV and 1200 mV versus a silver/silver chloride reference electrode; and
 wherein the physical-chemical profile additionally comprises one or more parameters selected from the energy profile parameters and the transport profile parameters. 
 
     
     
         73 . The composition of  claim 72 , wherein the condition is inflammation, neurodegeneration, or ischemia.