Prodrugs of kallikrein inhibitors
Disclosed are compounds of formula I, II, and III, and pharmaceutically acceptable salts thereof, which are inhibitors of kallikrein. Also provided are pharmaceutical compositions comprising such a compound, and methods involving use of the compounds and compositions in the treatment and prevention of acquired or hereditary angioedema, or other diseases and conditions characterized by aberrant kallikrein activity.
1. A compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof:
wherein, independently for each occurrence:
Z represents OR 1 or NH(OH);
R 1 represents
—C(R a )(R b )—O—C(O)-M-R 3 , or (C 2 -C 6 )alkyl optionally substituted by hydroxyl or heterocycloalkyl;
R a represents H or (C 1 -C 6 )alkyl;
R b represents H or (C 1 -C 6 )alkyl;
R x represents H or (C 1 -C 6 )alkyl;
M is a bond or represents O, S, NH, or N(CH 3 );
R 2 represents H, —OH, —C(O)OR 4 , —C(O)SR 4 , —C(O)O—[C(R c )(R d )] n —O—C(O)-L-R 5 , or
R 6 represents H, OH, —C(O)OR 4 , —C(O)SR 4 , —C(O)O—[C(R c )(R d )] n O—C(O)-L-R 5 , or
or R 2 and R 6 , taken together with the atoms to which they are attached, form an optionally substituted 1,2,4-oxadiazol-5-one group;
L, independently for each occurrence, is a bond or represents O, S, NH, or N(CH 3 );
R c , R d , R e , and R f each independently for each occurrence represent H or (C 1 -C 6 )alkyl;
R 3 represents (C 1 -C 6 )alkyl, aralkyl, or cycloalkyl, optionally substituted with one or more substituents each independently selected from the group consisting of amino, hydroxyl, optionally substituted heterocycloalkyl, —C(O)OH, and —C(O)O((C 1 -C 6 )alkyl);
R 4 , independently for each occurrence, represents (C 1 -C 6 )alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, optionally substituted with one or more substituents each independently selected from the group consisting of —C(O)OH, —C(O)O((C 1 -C 6 )alkyl), (C 1 -C 6 )alkoxy, hydroxyl, oxo, heterocycloalkyl, amino, (C 1 -C 6 )alkylamino, di((C 1 -C 6 )alkyl)amino, and silyl ether;
R 5 , independently for each occurrence, represents (C 1 -C 6 )alkyl, aryl, or heteroaryl, optionally substituted with one or more substituents each independently selected from the group consisting of amino, heterocycloalkyl, (C 1 -C 6 )alkoxy optionally substituted by (C 1 -C 6 )alkoxy or a polyether chain; and
n represents 1 or 2;
provided that at least one of R 2 and R 6 is not H; and
provided that if Z is OR 1 and R 1 is ethyl or 2-(morpholino)ethyl, then R 4 is not hexyl or butyl.
2. The compound of claim 1 , wherein R 1 represents
or —C(R a )(R b )—O—C(O)-M-R 3 .
3. The compound of claim 1 , wherein R a and R b each independently represent H or methyl.
4. The compound of claim 1 , wherein R 1 represents —C(R a )(R b )—O—C(O)-M-R 3 , and M is a bond or O.
5. The compound of claim 4 , wherein R 3 represents (C 1 -C 6 )alkyl, (C 3 -C 5 )alkyl, cycloalkyl, aralkyl optionally substituted with —NH 2 , (C 1 -C 6 )alkyl substituted with —NH 2 or —OH, or (C 3 -C 5 )alkyl substituted with —NH 2 or —OH.
6. The compound of claim 1 , wherein R 1 represents
and R x represents H or methyl; or
wherein R 1 represents (C 2 -C 6 )alkyl optionally substituted with hydroxyl.
7. The compound of claim 1 , wherein:
(a) R 2 represents H and R 6 represents OH;
(b) R 2 represents —C(O)OR 4 ;
(c) R 2 represents —C(O)O—[C(R c )(R d )] n —O—C(O)-L-R 5 ; or
(d) R 2 and R 6 , taken together with the atoms to which they are attached, form a 1,2,4-oxadiazol-5-one group.
8. The compound of claim 7 , wherein R 2 represents —C(O)OR 4 ;
and R 4 represents ethyl, isopropyl, hexyl, or (C 1 -C 6 )alkyl substituted with amino, hydroxy, or (C 1 -C 6 )alkoxy;
optionally wherein R 6 represents H.
9. The compound of claim 7 , wherein R 2 represents —C(O)O—[C(R c )(R d )] n —O—C(O)-L-R 5 , and n is 1; and
at least one of R c and R d is H or at least one of R c and R d is methyl;
optionally wherein R 6 represents H.
10. The compound of claim 9 , wherein L is a bond, and/or wherein R 5 represents (C 1 -C 4 )alkyl optionally substituted by amino.
11. The compound of claim 1 , wherein:
if R 1 is —CH 2 —O—C(O)—CH(iPr)NH 2 , then R 2 is not —C(O)O(ethyl); and
if R 1 is —CH 2 —O—C(O)—CH(iBu)NH 2 , then R 2 is not —C(O)O(hexyl).
12. The compound of claim 1 selected from the following table:
13. The compound of claim 12 selected from the following table:
14. A compound having the structure of formula (II) or a pharmaceutically acceptable salt thereof:
wherein, independently for each occurrence:
R 2 represents H, —OH, —C(O)OR 4 , —C(O)SR 4 , —C(O)O—[C(R c )(R d )] n —O—C(O)-L-R 5 , or
R 6 represents H, OH, —C(O)OR 4 , —C(O)SR 4 , —C(O)O—[C(R c )(R d )] n —O—C(O)-L-R 5 , or
or R 2 and R 6 , taken together with the atoms to which they are attached, form an optionally substituted 1,2,4-oxadiazol-5-one group;
L, independently for each occurrence, is a bond or represents O, S, NH, or N(CH 3 );
R c , R d , R e , and R f each independently for each occurrence represent H or (C 1 -C 6 )alkyl;
R 4 , independently for each occurrence, represents (C 1 -C 6 )alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, optionally substituted with one or more substituents each independently selected from the group consisting of —C(O)OH, —C(O)O((C 1 -C 6 )alkyl), (C 1 -C 6 )alkoxy, hydroxyl, oxo, heterocycloalkyl, amino, (C 1 -C 6 )alkylamino, di((C 1 -C 6 )alkyl)amino, and silyl ether;
R 5 , independently for each occurrence, represents (C 1 -C 6 )alkyl, aryl, or heteroaryl, optionally substituted with one or more substituents each independently selected from the group consisting of amino, heterocycloalkyl, (C 1 -C 6 )alkoxy optionally substituted by (C 1 -C 6 )alkoxy or a polyether chain; and
n represents 1 or 2;
provided that at least one of R 2 and R 6 is not H; and
the compound of formula (II) is not
15. The compound of claim 14 , wherein R 2 represents —C(O)OR 4 or —C(O)O—[C(R c )(R d )] n —O—C(O)-L-R 5 , optionally wherein R 6 represents H.
16. The compound of claim 15 , wherein R 2 represents —C(O)OR 4 ; and
R 4 represents ethyl, isopropyl, hexyl, or
R 4 represents (C 1 -C 6 )alkyl substituted with amino, hydroxy, or (C 1 -C 6 )alkoxy.
17. The compound of claim 15 , wherein R 2 represents
—C(O)O—[C(R c )(R d )] n O—C(O)-L-R 5 , and n is 1; and
at least one of R c and R d is H or at least one of R c and R d is methyl.
18. The compound of claim 17 , wherein L is a bond, and/or wherein R 5 represents (C 1 -C 6 )alkyl, optionally substituted by amino.
19. The compound of claim 14 , wherein R 2 and R 6 , taken together with the atoms to which they are attached, form a 1,2,4-oxadiazol-5-one group.
20. The compound of claim 14 selected from the following table:
21. A compound having the structure of formula (III) or a pharmaceutically acceptable salt thereof:
wherein, independently for each occurrence:
Z represents OR 1 or NH(OH);
R 1 represents
—C(R a )(R b )—O—C(O)-M-R 3 , or (C 2 -C 6 )alkyl optionally substituted by hydroxyl or heterocycloalkyl;
R a represents H or (C 1 -C 6 )alkyl;
R b represents H or (C 1 -C 6 )alkyl;
R x represents H or (C 1 -C 6 )alkyl;
M is a bond or represents O, S, NH, or N(CH 3 );
R 3 represents (C 1 -C 6 )alkyl, aralkyl, or cycloalkyl, optionally substituted with one or more substituents each independently selected from the group consisting of amino, hydroxyl, optionally substituted heterocycloalkyl, —C(O)OH, and —C(O)O((C 1 -C 6 )alkyl);
provided that the compound of formula (III) is not selected from the following table:
22. The compound of claim 21 , wherein R 1 represents
or, —C(R a )(R b )—O—C(O)-M-R 3 .
23. The compound of claim 21 , wherein R a and R b each independently represent H or methyl.
24. The compound of claim 21 , wherein R 1 represents —C(R a )(R b )—O—C(O)-M-R 3 , and M is a bond or O.
25. The compound of claim 24 , wherein R 3 represents (C 1 -C 6 )alkyl, (C 3 -C 5 ) alkyl, cycloalkyl, aralkyl optionally substituted with —NH 2 , (C 1 -C 6 )alkyl substituted with —NH 2 or —OH, or (C 3 -C 5 )alkyl substituted with —NH 2 or —OH.
26. The compound of claim 21 , wherein R 1 represents
and R x represents H or methyl, or
wherein R 1 represents (C 3 -C 6 )alkyl optionally substituted with hydroxyl.
27. The compound of claim 21 selected from the following table:
28. A method of treating acquired angioedema or hereditary angioedema, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 .
29. A method of treating a disease or condition associated with aberrant activity of kallikrein, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 .
30. A method of inhibiting blood coagulation, comprising administering to a subject in need thereof an effective amount of a compound of claim 1 .