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 . A method of identifying and selecting therapeutic compounds having a predetermined core structure, said method comprising:
 establishing a relationship between physical-chemical profile and biological activity; 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 therapeutic compounds based on their physical-chemical parameters falling within a range predefined by the physical-chemical/biological relationship of the previously tested subset of compounds;   wherein said core structure is selected from the group consisting of: a quinone core structure,   
       
         
           
           
               
               
           
         
       
     
     
         2 . The method of  claim 1 , wherein said physical-chemical profile comprises a cyclic voltammetric profile. 
     
     
         3 . The method of  claim 1 , wherein the physical-chemical profile comprises the parameter for onset of oxidation. 
     
     
         4 . The method of  claim 1 , wherein the physical-chemical profile comprises the parameter for potential of oxidation wave. 
     
     
         5 . The method of  claim 1 , wherein the physical-chemical profile comprises the parameter for reversibility of one or more oxidation waves. 
     
     
         6 . The method of  claim 1 , wherein the physical-chemical profile comprises the parameter for reversibility of one or more reduction waves. 
     
     
         7 . The method of  claim 1 , wherein the physical-chemical profile comprises the parameter for potential of reduction wave. 
     
     
         8 . The method of  claim 1 , wherein the physical-chemical profile additionally comprises one or more parameters selected from the energy profile parameters and the transport profile parameters. 
     
     
         9 . (canceled) 
     
     
         10 . The method of  claim 1 , 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 subset group 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 subset group of compounds exhibit an EC 50  lower than about 30 μM. 
     
     
         11 . The method of  claim 10 , wherein the therapeutic compound is selected if it comprises a stilbene core structure and if its 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. 
     
     
         12 . The method of  claim 11 , wherein the physical-chemical profile additionally comprises one or more parameters selected from the energy profile parameters and the transport profile parameters. 
     
     
         13 . The method of  claim 11 , wherein the therapeutic compound is for the treatment of a condition characterized by oxidative stress. 
     
     
         14 . The method of  claim 10 , wherein the therapeutic compound is selected if it comprises a core structure of Formula I: 
       
         
           
           
               
               
           
         
         wherein additional substitution at the phenyl rings does not include a nitro group; 
         and if its 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. 
       
     
     
         15 . The method of  claim 14 , wherein the physical-chemical profile additionally comprises one or more parameters selected from the energy profile parameters and the transport profile parameters. 
     
     
         16 . The method of  claim 14 , wherein the therapeutic compound is for the treatment of a condition characterized by oxidative stress. 
     
     
         17 . The method of  claim 10 , wherein the therapeutic compound is selected if it comprises a core structure of Formula I: 
       
         
           
           
               
               
           
         
         wherein additional substitution at the phenyl rings includes a nitro group; 
         and if its 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%. 
       
     
     
         18 . The method of  claim 17 , wherein the physical-chemical profile additionally comprises one or more parameters selected from the energy profile parameters and the transport profile parameters. 
     
     
         19 . The method of  claim 17 , wherein the therapeutic compound is for the treatment of a condition characterized by oxidative stress. 
     
     
         20 - 25 . (canceled) 
     
     
         26 . The method of  claim 3 , wherein the physical-chemical profile comprises the parameter for onset of oxidation and the biological assay comprises the E-selectin (ELAM) cell based assay detecting compounds with an EC 50  lower than 30 μM. 
     
     
         27 - 32 . (canceled) 
     
     
         33 . The method of  claim 4 , 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. 
     
     
         34 - 40 . (canceled) 
     
     
         41 . The method of  claim 4 , 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. 
     
     
         42 . The method of  claim 41 , wherein the compound is selected if it comprises 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. 
       
     
     
         43 . The method of  claim 42 , wherein the physical-chemical profile additionally comprises one or more parameters selected from the energy profile parameters and the transport profile parameters. 
     
     
         44 . The method of  claim 41 , wherein the compound is selected if it comprises 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. 
       
     
     
         45 . The method of  claim 44 , wherein the physical-chemical profile additionally comprises one or more parameters selected from the energy profile parameters and the transport profile parameters. 
     
     
         46 - 49 . (canceled) 
     
     
         50 . The method of  claim 6 , 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 versus a silver/silver chloride reference electrode. 
     
     
         51 . The method of  claim 50 , wherein the therapeutic compound is selected if it comprises a quinone core structure and if its physical-chemical profile comprises a parameter for the total reversibility of reduction of 75% or more. 
     
     
         52 . The method of  claim 51 , wherein the physical-chemical profile additionally comprises one or more parameters selected from the energy profile parameters and the transport profile parameters. 
     
     
         53 . The method of  claim 51  wherein the compound is for the treatment of a condition characterized by oxidative stress. 
     
     
         54 - 55 . (canceled) 
     
     
         56 . The method of  claim 33 , wherein the therapeutic compound is selected if it comprises a chroman core structure of Formula IV, 
       
         
           
           
               
               
           
         
         and if its 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. 
       
     
     
         57 . The method of  claim 56 , wherein the physical-chemical profile additionally comprises one or more parameters selected from the energy profile parameters and the transport profile parameters. 
     
     
         58 . (canceled)