Method for treating ADAMTS-5-associated disease
View Patent ↗The present invention relates to methods of treating ADAMTS-5-associated diseases and particularly osteoarthritis comprising administering an agent capable of modulating ADMATS-5 activity to a subject afflicted with the disease. The agent is preferably a biaryl sulfonamide compound. The invention is based, in part, on the discovery that transgenic animals that do not express functional ADAMTS-5 show a reduction in the degree of osteoarthritis after the induction of osteoarthritis as compared to WT animals. Furthermore, the ADAMTS-5 transgenic animals have reduced aggrecanase activity in articular tissue as compared to WT animals. These animals are good models for ADAMTS-5-associated diseases, and for screening of drugs useful in the treatment and/or prevention of these diseases. There are no other animal models in which the deletion of the activity of a single gene is capable of abrogating the course of osteoarthritis. Accordingly, these animals also show that osteoarthritis can be prevented and/or treated by administering to a subject an ADAMTS-5 inhibitory agent and particularly an agent capable of inhibiting the aggrecanase activity of ADAMTS-5.
1. A method for treating osteoarthritis, comprising administering to a subject in need thereof a therapeutically effective amount of an agent which inhibits ADAMTS-5, wherein the agent is a biaryl sulfonamide compound according to formula I:
wherein:
R 1 is H or unsubstituted C1-C6 alkyl;
R 2 is H, C1-C6 alkyl, (CH 2 ) n R 2 ′, phenyl, or benzyl;
n is 0-6;
R 2 ′ is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;
R 3 is, independently with respect to each occurrence, H, halogen, OC(halogen) 3 , C(halogen) 3 , alkoxy, or C1-C6 alkyl;
X is selected from CH 2 O, OCH 2 , C(R 3 )═C(R 3 ) 2 —C(R 3 ) 2 , CH 2 NHC(═O), O(C═O)NH, O, C(═O)CH 2 , SO 2 CH 2 C(═O)NH, SO 2 NH, OC(═O), CH 2 S(O), and CH 2 S(O) 2 ; and
Z is at least one aryl or heteroaryl moiety.
2. The method of claim 1 , wherein the agent inhibits the metalloprotease activity of ADAMTS-5.
3. The method of claim 1 , wherein the agent inhibits the aggrecanase activity of ADAMTS-5.
4. The method of claim 1 , wherein Z is pyridine, pyrimidine, pyrazine, pyridazine, phenyl, naphthalene, furan, thiophene, pyrrole, pyrazole, imidazole, oxazole, isoxazole, thiazole, benzothiazole, quinoline, or isoquinoline, or
wherein:
U is selected from S, O, C(R 3 )═C(R 3 ), C(R 3 )═N, and N(R 4 );
W is selected from C(R 3 ), and N;
M is selected from C(R 3 ), and N;
L is selected from S, O, C(R 3 )═C(R 3 ), C(R 3 )═N, and N(R 4 );
R 4 and R 5 are, independently with respect to each occurrence, a bond to the other, H, C1-C6 alkyl, or phenyl;
R 7 is selected from a bond to R 3 , H, halogen, C(halogen) 3 , NR 4 R 5 , N[(CH 2 ) 2 ] 2 O, N[(CH 2 ) 2 ] 2 NR 4 , NHSO 2 R 4 , NR 4 C(═O)R 5 , NHC(═O)OR 4 , NO 2 , SO 2 NR 4 R 5 , SO 2 R 4 , OR 4 , C(═O)R 4 , COOR 4 , CONR 4 R 5 , CN, phenyl, heteroaryl, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl.
5. The method of claim 4 wherein R 7 is substituted with NR 4 R 5 , N[(CH 2 ) 2 ] 2 O, N[(CH 2 ) 2 ] 2 NR 4 , NHSO 2 R 4 , NR 4 C(═O)R 5 , NHC(═O)OR 4 , NO 2 , SO 2 NR 4 R 5 , SO 2 R 4 , C(═O)R 4 , COOR 4 , CONR 4 R 5 , CN, phenyl, or heteroaryl, wherein R 8 is H, phenyl, heteroaryl, or C1-C6 alkyl.
6. The method of claim 5 wherein R 8 is substituted with NR 4 R 5 , N[(CH 2 ) 2 ] 2 O, N[(CH 2 ) 2 ] 2 NR 4 , NR 4 SO 2 R 5 , NR 4 C(═O)R 5 , NHC(═O)OR 4 , NO 2 , SO 2 NR 4 R 5 , SO 2 R 4 , C(═O)R 4 , COOR 4 , CONR 4 R 5 , CN, phenyl, or heteroaryl.
7. The method of claim 1 wherein R 1 is H or branched alkyl.
8. The method of claim 1 wherein R 1 is isopropyl.
9. The method of claim 1 wherein R 3 is halogen, CF 3 , OCH 3 , or CH 3 .
10. The method of claim 1 wherein X is CH 2 O, OCH 2 , C(R 3 )═C(R 3 ), or CH 2 NHC(═O).
11. The method of claim 4 wherein R 7 is CH 3 , ethyl, isopropyl, CF 3 , CN, or OCH 3 .
12. The method of claim 5 wherein R 8 is CH 3 , phenyl, and benzyl.
13. The method of claim 1 wherein Z is bicyclic.
14. The method of claim 6 wherein R 8 is CH 3 , phenyl, or benzyl.
15. A method for modulating the activity of ADAMTS-5 comprising contacting ADAMTS-5 with a biaryl sulfonamide compound according to formula I:
wherein:
R 1 is H or unsubstituted C1-C6 alkyl;
R 2 is H, C1-C6 alkyl, (CH 2 ) n R 2′ , phenyl, or benzyl;
n is 0-6;
R 2′ is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;
R 3 is, independently with respect to each occurrence, H, halogen, OC(halogen) 3 , C(halogen) 3 , alkoxy, or C1-C6 alkyl;
X is selected from CH 2 O, OCH 2 , C(R 3 )═C(R 3 ), C(R 3 ) 2 —C(R 3 ) 2 , CH 2 NHC(═O), O(C═O)NH, O, C(═O)CH 2 , SO 2 CH 2 C(═O)NH, SO 2 NH, OC(═O), CH 2 S(O), and CH 2 S(O) 2 ; and
Z is at least one aryl or heteroaryl moiety.
16. The method of claim 15 , wherein Z is pyridine, pyrimidine, pyrazine, pyridazine, phenyl, naphthalene, furan, thiophene, pyrrole, pyrazole, imidazole, oxazole, isoxazole, thiazole, benzothiazole, quinoline, or isoquinoline, or
wherein:
U is selected from S, O, C(R 3 )═C(R 3 ), C(R 3 )═N, and N(R 4 );
W is selected from C(R 3 ), and N;
M is selected from C(R 3 ), and N;
L is selected from S, O, C(R 3 )═C(R 3 ), C(R 3 )═N, and N(R 4 );
R 4 and R 5 are, independently with respect to each occurrence, a bond to the other, H, C1-C6 alkyl, or phenyl;
R 7 is selected from a bond to R 3 , H, halogen, C(halogen) 3 , NR 4 R 5 , N[(CH 2 ) 2 ] 2 O, N[(CH 2 ) 2 ] 2 NR 4 , NHSO 2 R 4 , NR 4 C(═O)R 5 , NHC(═O)OR 4 , NO 2 , SO NR 4 R 5 , SO 2 NR 4 R 5 , SO 2 R 4 , OR 4 , C(═O)R 4 , COOR 4 , CONR 4 R 5 , CN, phenyl, heteroaryl, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl.
17. The method of claim 16 wherein R 7 is substituted with NR 4 R 5 , N[(CH 2 ) 2 ] 2 O, N[(CH 2 ) 2 ] 2 NR 4 , NHSO 2 R 4 , NR 4 C(═O)R 5 , NHC(═O)OR 4 , NO 2 , SO 2 NR 4 R 5 , SO 2 R 4 , OR 8 , C(═O)R 4 , COOR 4 , CONR 4 R 5 , CN, phenyl, or heteroaryl, wherein R 8 is H, phenyl, heteroaryl, or C1-C6 alkyl.
18. The method of claim 17 wherein R 8 is substituted with NR 4 R 5 , N[(CH 2 ) 2 ] 2 O, N[(CH 2 ) 2 ] 2 NR 4 , NR 4 SO 2 R 5 , NR 4 C(═O)R 5 , NHC(═O)OR 4 , NO 2 , SO 2 NR 4 R 5 , SO 2 R 4 , C(═O)R 4 , COOR 4 , CONR 4 R 5 , CN, phenyl, or heteroaryl.
19. The method of claim 15 wherein R 1 is H or branched alkyl.
20. The method of claim 15 wherein R 1 is isopropyl.
21. The method of claim 15 wherein R 3 is halogen, CF 3 , OCH 3 , or CH 3 .
22. The method of claim 15 wherein X is CH 2 O, OCH 2 , C(R 3 )═C(R 3 ), or CH 2 NHC(═O).
23. The method of claim 16 wherein R 7 is CH 3 , ethyl, isopropyl, CF 3 , CN, or OCH 3 .
24. The method of claim 17 wherein R 8 is CH 3 , phenyl, and benzyl.
25. The method of claim 15 wherein Z is bicyclic.
26. The method of claim 15 , wherein the activity is metalloproteinase activity.
27. The method of claim 26 , wherein the activity is aggrecanase activity.
28. The method of claim 1 or 15 , wherein the biaryl sulfonamide compound is selected from the group consisting of
29. The method of claim 18 , wherein R 8 is CH 3 , phenyl, or benzyl.