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1. WO2009004380 - METHOD AND USE OF CIRCULATING LEVELS OF ENDOCANNABINOID LIGANDS FOR THE DETERMINATION OF PATIENT IN NEED AND/OR SUITABLE FOR CB1R ANTAGONIST DRUG TREATMENT AS WELL AS METHOD FOR INDUCING WEIGHT LOSS/MAINTENANCE/GAIN

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CLAIMS

1. Use of an endogenous cannabinoid ligand as a biomarker of suitability for treatment with a cannabinoid 1 receptor (CBlR) antagonist drug.

2. The use as claimed in claim 1 , wherein the endogenous cannabinoid ligand is used as a biomarker of susceptibility to effective weight loss or appetite suppression treatment with a CBlR antagonist drug.

3. The use as claimed in claim 1 or 2, wherein the levels of the endogenous cannabinoid ligand is measured in a blood sample previously isolated from a patient and the levels present indicate whether or not the patient is likely to benefit from CBlR antagonist treatment.

4. The use as claimed in claim 3, wherein the patient is selected from a group of patients that are overweight or obese subjects.

5. The use as claimed in claim 2, wherein if the patient has high circulating levels of endogenous cannabinoid ligand(s) they are likely to benefit from CBlR antagonist treatment.

6. The use as claimed in any of the preceding claims wherein the endogenous cannabinoid ligand is AEA or 2-AG.

7. The use as claimed in any of the preceding claims wherein the levels of at least two endogenous cannabinoid ligands are determined.

8. The use as claimed in claim 7, wherein a biomarker composite score of the levels of the at least two endogenous cannabinoid ligands is generated.

9. The use as claimed in any of the preceding claims, for selecting patients for inclusion in a CBlR antagonist drug clinical trial or selecting patient for treatment with a CBlR antagonist drug.

10. The use as claimed in any of the preceding claims, wherein the CBlR antagonist is selected from: rimonabant, taranabant, surinabant, CP945598 and SLV319.

11. The use as claimed in any of claims 1 - 9, wherein the CBlR antagonist is a compound selected from:
1-propanesulfonic acid, 3,3,3-trifluoro-, 4-[l-(2,4-dichlorophenyl)-3-[[(2-hydroxycyclohexyl)amino]carbonyl]-4-(hydroxymethyl)-lH-pyrazol-5-yl]phenyl ester; 1-propanesulfonic acid, 3,3,3-trifluoro-, 4-[3-[(cyclohexylamino)carbonyl]-l-(2,4-dichlorophenyl)-4-(hydroxymethyl)-lH-pyrazol-5-yl]phenyl ester; 1-propanesulfonic acid, 3,3,3-trifluoro-, 4-[l-(2,4-dichlorophenyl)-4,5,6,7-tetrahydro-3-methyl-4-oxo-5-(l-piperidinyl)-lH-pyrrolo[3,2-c]pyridin-2-yl]phenyl ester; 1-propanesulfonic acid, 3,3,3-trifluoro-, 4-[l-(2,4-dichlorophenyl)-4-methyl-3-[(l-piperidinylamino)carbonyl]-lH-pyrazol-5-yl]phenyl ester; 1-propanesulfonic acid, 4-[l-(2,4-dichlorophenyl)-4-methyl-3-[(l-piperidinylamino)carbonyl]-lH-pyrazol-5-yl]phenyl ester; 3,3,3-trifluoropropane-l-sulfonic acid , 4-[2-(2,4-dichlorophenyl)-5-methyl-4-(piperidin-l-ylcarbamoyl)imidazol-l-yl]phenyl ester; and 3,3,3-trifluoropropane-l-sulfonic acid 4-[l-(2-chloro-4-fluorophenyl)-3 -methyl-4-oxo-5-piperidin- 1 -yl-4,5 ,6,7-tetrahydro- 1 H-pyrrolo[3 ,2-c]pyridin-2-yl]phenyl ester, or a pharmaceutically acceptable salt thereof.

12. A method of selecting a mammal in need of treatment with a cannabinoid 1 receptor (CBlR) antagonist drug which comprises determining the level of at least one circulating endogenous cannabinoid ligand in the mammal, whereby to predict an increased likelihood of response to the CBlR antagonist drug.

13. The method as claimed in claim 12, wherein the mammal is a human.

14. The method as claimed in claim 12, wherein the mammal is in need of weight loss and/or weight maintenance and/or prevention of weight gain treatment.

15. The method as claimed in claim 12, 13 or 14, wherein if the mammal has high circulating levels of the endogenous cannabinoid ligand(s) they have an increased likelihood of responding to a CBlR antagonist drug.

16. The method as claimed in any of claims 12 to 15, wherein the levels of
endocannabinoid ligand(s) is detected by immunoassay.

17. The method as claimed in claim 16, wherein the immunoassay is selected from: enzyme linked immunosorbent assay (ELISA/EIA), radio immunoassay (RIA), fluorescence immunoassay, luminescence immunoassay, electrochemical luminescence immunossay and SELDI-based immunoassay in combination with mass spectrometry.

18. The method as claimed in any of claims 12 to 17, wherein the amount of circulating endocannabinoid ligand is detected by using the AEA degrading enzyme, fatty acid amide hydrolase (FAAH) and/or the 2-AG degrading enzyme, monoacylglycerol lipase.

19. A method of stratifying a group of patients to identify one or more patients suitable for treatment with a CBlR antagonist drug, comprising determining the amount or level of one or more circulating endogenous cannabinoid ligands present in blood previously isolated from the patients.

20. The method as claimed in claim 19, wherein the group of patients are overweight or obese subjects.

21. A method of inducing weight loss and/or weight maintenance and/or weight gain in a patient in need thereof, comprising determining the level of a one or more circulating endogenous cannabinoid ligands in said patient and selecting an appropriate therapy based on the level of endogenous cannabinoid ligand(s) detected.

22. The method as claimed in claim 21, wherein if the patient has high levels of circulating endogenous cannabinoid ligand(s) they are treated with a CBlR antagonist drug.

23. The method as claimed in any of claims 12 to 22, wherein the CBlR antagonist is selected from: rimonabant, taranabant, surinabant, CP945598 and SLV319.

24. The method as claimed in any of claims 12 to 22, wherein the CBlR antagonist is a compound selected from:
1-propanesulfonic acid, 3,3,3-trifluoro-, 4-[l-(2,4-dichlorophenyl)-3-[[(2-hydroxycyclohexyl)amino]carbonyl]-4-(hydroxymethyl)-lH-pyrazol-5-yl]phenyl ester; 1-propanesulfonic acid, 3,3,3-trifluoro-, 4-[3-[(cyclohexylamino)carbonyl]-l-(2,4-dichlorophenyl)-4-(hydroxymethyl)-lH-pyrazol-5-yl]phenyl ester; 1-propanesulfonic acid, 3,3,3-trifluoro-, 4-[l-(2,4-dichlorophenyl)-4,5,6,7-tetrahydro-3-methyl-4-oxo-5-(l-piperidinyl)-lH-pyrrolo[3,2-c]pyridin-2-yl]phenyl ester; 1-propanesulfonic acid, 3,3,3-trifluoro-, 4-[l-(2,4-dichlorophenyl)-4-methyl-3-[(l-piperidinylamino)carbonyl]-lH-pyrazol-5-yl]phenyl ester; 1-propanesulfonic acid, 4-[l-(2,4-dichlorophenyl)-4-methyl-3-[(l-piperidinylamino)carbonyl]-lH-pyrazol-5-yl]phenyl ester; 3,3,3-trifiuoropropane-l-sulfonic acid , 4-[2-(2,4-dichlorophenyl)-5-methyl-4-(piperidin-l-ylcarbamoyl)imidazol-l-yl]phenyl ester; and 3,3,3-trifluoropropane-l-sulfonic acid 4-[l-(2-chloro-4-fluorophenyl)-3 -methyl-4-oxo-5-piperidin- 1 -yl-4,5 ,6,7-tetrahydro- 1 H-pyrrolo[3 ,2-c]pyridin-2-yl]phenyl ester, or a pharmaceutically acceptable salt thereof.