Identifying therapeutic compounds based on their physical-chemical properties
View Patent ↗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 reversibility of one or more oxidation waves or reversibility of one or more reduction waves; 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.
2. The method of claim 1 , wherein the physical-chemical profile comprises the parameter for reversibility of one or more oxidation waves.
3. The method of claim 1 , wherein the physical-chemical profile comprises the parameter for reversibility of one or more reduction waves.
4. The method of claim 3 , wherein 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.
5. The method of claim 4 , 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.
6. The method of claim 5 , wherein the physical-chemical profile additionally comprises one or more parameters selected from the energy profile parameters and the transport profile parameters.
7. The method of claim 5 wherein the compound is for the treatment of a condition characterized by oxidative stress.
8. The method of claim 1 , wherein the 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.
9. The method of claim 8 , 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.
10. The method of claim 9 , wherein the physical-chemical profile additionally comprises one or more parameters selected from the energy profile parameters and the transport profile parameters.
11. The method of claim 9 , wherein the therapeutic compound is for the treatment of a condition characterized by oxidative stress.
12. The method of claim 8 , 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.
13. The method of claim 12 , wherein the physical-chemical profile additionally comprises one or more parameters selected from the energy profile parameters and the transport profile parameters.
14. The method of claim 12 , wherein the therapeutic compound is for the treatment of a condition characterized by oxidative stress.
15. The method of claim 8 , 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%.
16. The method of claim 15 , wherein the physical-chemical profile additionally comprises one or more parameters selected from the energy profile parameters and the transport profile parameters.
17. The method of claim 15 , wherein the therapeutic compound is for the treatment of a condition characterized by oxidative stress.
18. 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 a parameter for onset of oxidation; and wherein the biological activity is measured in an assay comprising the E-selectin (ELAM) cell based assay detecting compounds with an EC 50 lower than 30 μM;
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.
19. The method of claim 18 , wherein the therapeutic compound is selected if it comprises a flavonoid core structure of Formula II:
wherein none of the substituents are hydroxy groups;
and if its physical-chemical profile comprises the parameter for onset of oxidation that falls between about 850 mV and 1050 mV versus a silver/silver chloride reference electrode.
20. The method of claim 19 , wherein the physical-chemical profile additionally comprises one or more parameters selected from the energy profile parameters and the transport profile parameters.
21. The method of claim 19 , wherein the therapeutic compound is for the treatment of a condition characterized by inflammation.
22. The method of claim 18 , wherein the therapeutic compound is selected if it comprises a flavonoid core structure of Formula II:
wherein one or more of the substituents are hydroxy groups;
and if its physical-chemical profile comprises the parameter for onset of oxidation that falls between about 350 mV and 650 mV versus a silver/silver chloride reference electrode.
23. The method of claim 22 , wherein the physical-chemical profile additionally comprises one or more parameters selected from the energy profile parameters and the transport profile parameters.
24. The method of claim 22 , wherein the therapeutic compound is for the treatment of a condition characterized by inflammation.
25. 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 a parameter for potential of oxidation wave; and wherein the biological activity is measured in an assay comprising an HGOS assay protecting at least 30% of the cells against stressor induced cell death;
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.
26. The method of claim 25 , wherein the therapeutic compound is selected if it comprises a flavonoid core structure and if its physical-chemical profile comprises the parameter for oxidation potential that falls between about 1050 mV and 1450 mV versus a silver/silver chloride reference electrode.
27. The method of claim 26 , wherein the physical-chemical profile additionally comprises one or more parameters selected from the energy profile parameters and the transport profile parameters.
28. The method of claim 26 , wherein the therapeutic compound is for the treatment of a condition characterized by oxidative stress.
29. The method of claim 25 , 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.
30. The method of claim 29 , wherein the physical-chemical profile additionally comprises one or more parameters selected from the energy profile parameters and the transport profile parameters.