Treatment of focal segmental glomerulosclerosis with CCR2 antagonists

1. A method of treating focal segmental glomerulosclerosis, said method comprising administering to a subject in need thereof a therapeutically effective amount of a CCR2 antagonist, wherein the CCR2 antagonist is a compound of Formula II

or a pharmaceutically acceptable form thereof,

wherein

R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen C 1-8 alkyl, CN, or C 1-8 haloalkyl, provided that at least one of R 1 or R 2 is other than hydrogen;

R 6 is halogen or C 1-8 alkyl;

X 2 is CR 7 , N, or NO:

R 7 is independently selected from the group consisting of hydrogen, halogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, —CN, —NO 2 , —OC(O)R 8 , —CO 2 R 8 , —C(O)R 8 , —C(O)NR 9 R 8 , —OC(O)NR 9 R 8 , —NR 10 C(O)R 8 , —NR 10 C(O)NR 9 R 8 , —NR 9 R 8 , —NR 10 CO 2 R 8 , —SR 8 , —S(O)R 8 , —S(O) 2 R 8 , —S(O) 2 NR 9 R 8 , —NR 10 S(O) 2 R 8 , C 6-10 aryl, 5- to 10-membered heteroaryl and 3- to 10-membered heterocyclyl;

each R 8 , R 9 and R 10 is independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, or heteroaryl; or R 9 and R 8 or R 10 and R 8 , together with the atom(s) to which they are attached, form a 5-, 6-, or 7-membered ring; and

R 11 is selected from the group consisting of hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 6-10 aryl, 5- to 10-membered heteroaryl and 3- to 10-membered heterocycle,

wherein the CCR2 antagonist is administered in combination with one or more additions therapeutic agents, the one or more additional therapeutic agents being a Renin-angiotensin-aldosterone (RAAS) blocker or an endothelin receptor antagonist.

2. The method of claim 1 , wherein

R 1 and R 2 are each independently selected from the group consisting of halogen, C 1-8 alkyl, or C 1-8 haloalkyl, provided that at least one of R 1 or R 2 is other than hydrogen;

R 5 is halogen or C 1-8 alkyl;

X 2 is CR 7 or N;

R 7 is independently selected from the group consisting of hydrogen, halogen, C 1-8 alkyl, —CN, —NO 2 , —OR 8 , and —NR 9 R 8 ;

R 11 is hydrogen or C 1-8 alkyl.

3. The method of claim 1 , wherein

R 1 is halogen

R 2 C 1-8 haloalkyl;

R 5 is C 1-8 alkyl;

X 2 is CR 7 or N;

R 7 is independently selected from the group consisting of hydrogen, halogen, C 1-8 alkyl;

R 11 is hydrogen or C 1-8 alkyl.

4. The method of claim 1 , wherein

R 1 is chloro

R 2 trifluoromethyl;

R 5 is methyl;

X 2 is CR 7 or N;

R 7 is independently selected from the group consisting of hydrogen, halogen, C 1-8 alkyl;

R 11 is hydrogen or C 1-8 alkyl.

5. The method of claim 1 , wherein the compound of Formula II has the structure of Compound 1

or a pharmaceutically acceptable form thereof.

6. The method of claim 1 , wherein the compound of Formula II has the structure of Compound 2

or a pharmaceutically acceptable form thereof.

7. The method of claim 1 , wherein the CCR2 antagonist is administered daily.

8. The method of claim 1 , wherein administration of the CCR2 antagonist to the subject in need thereof reduces a urine albumin-to-creatinine ratio in said subject.

9. The method of claim 8 , wherein the urine album in-to-creatinine ratio in said subject is reduced by at least 20% after 3 weeks of administering the CCR2 antagonist as compared to the albumin to creatinine ratio in said subject prior to treatment.

10. The method of claim 8 , wherein the urine album in-to-creatinine ratio in said subject is reduced by at least 30% after 3 weeks of administering the CCR2 antagonist as compared to the albumin to creatinine ratio in said subject prior to treatment.

11. The method of claim 8 , wherein the urine albumin-to-creatinine ratio in said subject is reduced by at least 40% after 3 weeks of administering the CCR2 antagonist as compared to the albumin to creatinine ratio in said subject prior to treatment.

12. The method of claim 8 , wherein the urine albumin-to-creatinine ratio in said subject is reduced by at least 50% after 3 weeks of administering the CCR2 antagonist as compared to the albumin to creatinine ratio in said subject prior to treatment.

13. The method of claim 8 , wherein the urine albumin-to-creatinine ratio in said subject is reduced by at least 60% after 3 weeks of administering the CCR2 antagonist as compared to the albumin to creatinine ratio in said subject prior to treatment.

14. The method of claim 1 , wherein the CCR2 antagonist is a selective CCR2 antagonist.

15. The method of claim 1 , wherein the additional therapeutic agent is a Renin-angiotensin-aldosterone (RAAS) blocker.

16. The method of claim 15 , wherein the RAAS blocker is a renin inhibitor.

17. The method of claim 16 , wherein the renin inhibitor is selected from the group consisting of aliskiren, remikiren, H-142, SPP635, SPP1148, SPP676, and SPP1234.

18. The method of claim 15 , wherein the RAAS blocker is an ACE inhibitor.

19. The method of claim 18 , wherein the ACE inhibitor is enazepril, captopril, enalapril, fosinopril, lisinopril, perindopril, quinapril, rampipril, and trandolapril.

20. The method of claim 15 , wherein the RAAS blocker an angiotensin receptor blocker (ARB).

21. The method of claim 20 , wherein the ARB is selected from the group consisting of sparsentan, eprosartan, candesartan, irbesartan, losartan, olmesartan, telmisartan, valsartan, CGP-42112A, DuP753, saralasin, and sarthran.

22. The method of claim 20 , wherein the ARB is selected from the group consisting of eprosartan, candesartan, irbesartan, losartan, olmesartan, telmisartan, valsartan, CGP-42112A, DuP753, saralasin, and sarthran.

23. The method of claim 20 , wherein the ARB is candesartan.

24. The method of claim 1 , wherein the additional therapeutic agent is an endothelin receptor antagonist.

25. The method of claim 24 , wherein the endothelin receptor antagonist is selected from the group consisting of sparsentan, bosentan, macitentan, ambrisentan, sitazentan, aprocitentan, and artasentan.

26. The method of claim 24 , wherein the endothelin receptor antagonist is sparsentan.