Phosphodiesterase inhibitors and uses thereof
The invention provides for compounds that are phosphodiesterase inhibitors. The invention further provides for a method for screening compounds that bind to and modulate a phosphosdiesterase protein. The invention also provides methods for treating conditions associated with accumulated amyloid-beta peptide deposit accumulations by administering a phosphodiesterase-binding compound to a subject.
1. A method for treating a subject afflicted with Alzheimer's disease, Lewy body dementia, inclusion body myositis, or cerebral amyloid angiopathy, the method comprising:
administering to the subject an effective amount of a composition comprising a PDE5 inhibitor compound of Formula (V):
wherein:
A is O or N;
X is —(CH 2 ) n , C(O), S(O), or S(O) 2 ;
R 1 is C 3 -C 8 cycloalkyl, —NR 7 R 8 , or —SR 7 ;
R 2 is —CH 2 OR 6 or —CO 2 R 8 ;
R 3 is hydrogen or halogen;
R 4 is —CN or halogen;
R 5 is hydrogen or —OR 6 ;
R 6 is hydrogen, —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl, or —C(O)R 9 ;
R 7 and R 8 are each independently hydrogen, —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl, or —C(O)R 9 , wherein the C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl are optionally substituted with —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl, —NR 9 R 10 , —SR 9 , or heterocyclyl; or, R 7 and R 8 together with the nitrogen atom to which they are attached form a 3 to 8-membered heterocycle, wherein any one of the ring carbon atoms is optionally replaced with a heteroatom, and wherein the heterocycle is optionally substituted with C 1 -C 6 alkyl; and
R 9 and R 10 are each independently hydrogen, C 1 -C 6 alkyl, or C 3 -C 8 cycloalkyl; and n is 1, 2, or 3,
or a pharmaceutically acceptable salt or tautomer thereof.
2. The method of claim 1 , wherein the effective amount is at least about 1 mg/kg body weight, at least about 2 mg/kg body weight, at least about 3 mg/kg body weight, at least about 4 mg/kg body weight, at least about 5 mg/kg body weight, at least about 6 mg/kg body weight, at least about 7 mg/kg body weight, at least about 8 mg/kg body weight, at least about 9 mg/kg body weight, or at least about 10 mg/kg body weight.
3. The method of claim 1 , wherein A is N.
4. The method of claim 1 , wherein R 5 is hydrogen.
5. The method of claim 1 , wherein R 5 is —OCH 3 .
6. The method of claim 1 , wherein the compound is of formula (V-1):
wherein:
R 1 is C 3 -C 8 cycloalkyl, —NR 7 R 8 , or —SR 7 ;
R 2 is —CH 2 OR 6 or —CO 2 R 8 ;
R 3 is hydrogen or halogen;
R 4 is —CN or halogen;
R 6 is hydrogen, —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl, or —C(O)R 9 ;
R 7 and R 8 are each independently hydrogen, —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl, or —C(O)R 9 , wherein the C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl are optionally substituted with —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl, —NR 9 R 10 , —SR 9 , or heterocyclyl; or, R 7 and R 8 together with the nitrogen atom to which they are attached form a 3 to 8-membered heterocycle, wherein any one of the ring carbon atoms is optionally replaced with a heteroatom, and wherein the heterocycle is optionally substituted with C 1 -C 6 alkyl; and
R 9 and R 10 are each independently hydrogen, C 1 -C 6 alkyl, or C 3 -C 8 cycloalkyl,
or a pharmaceutically acceptable salt or tautomer thereof.
7. The method of claim 5 , wherein R 6 is CH 3 .
8. The method of claim 1 , wherein the compound is of formula (V-1a):
wherein:
R 1 is C 3 -C 8 cycloalkyl, —NR 7 R 8 , or —SR 7 ;
R 2 is —CH 2 OR 6 or —CO 2 R 8 ;
R 3 is hydrogen or halogen;
R 4 is —CN or halogen;
R 7 and R 8 are each independently hydrogen, —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl, or —C(O)R 9 , wherein the C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl are optionally substituted with —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl, —NR 9 R 10 , —SR 9 , or heterocyclyl; or, R 7 and R 8 together with the nitrogen atom to which they are attached form a 3 to 8-membered heterocycle, wherein any one of the ring carbon atoms is optionally replaced with a heteroatom, and wherein the heterocycle is optionally substituted with C 1 -C 6 alkyl; and
R 9 and R 10 are each independently hydrogen, C 1 -C 6 alkyl, or C 3 -C 8 cycloalkyl,
or a pharmaceutically acceptable salt or tautomer thereof.
9. The method of claim 1 , wherein R 2 is CH 2 —OH.
10. The method of claim 1 , wherein R 3 is H.
11. The method of claim 1 , wherein R 3 is a halogen.
12. The method of claim 1 , wherein R 3 is chlorine.
13. The method of claim 1 , wherein R 4 is —CN.
14. The method of claim 1 , wherein R 4 is a halogen.
15. The method of claim 1 , wherein R 4 is fluorine.
16. The method of claim 1 , wherein the compound is of formula (V-1a1):
wherein:
R 1 is C 3 -C 8 cycloalkyl, —NR 7 R 8 , or —SR 7 ;
R 7 and R 8 are each independently hydrogen, —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl, or —C(O)R 9 , wherein the C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl are optionally substituted with —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl, —NR 9 R 10 , —SR 9 , or heterocyclyl; or, R 7 and R 8 together with the nitrogen atom to which they are attached form a 3 to 8- membered heterocycle, wherein any one of the ring carbon atoms is optionally replaced with a heteroatom, and wherein the heterocycle is optionally substituted with C 1 -C 6 alkyl; and
R 9 and R 10 are each independently hydrogen, C 1 -C 6 alkyl, or C 3 -C 8 cycloalkyl,
or a pharmaceutically acceptable salt or tautomer thereof.
17. The method of claim 1 , wherein R 1 is C 3 -C 8 cycloalkyl or —NR 7 R 8 .
18. The method of claim 1 , wherein R 1 is —NR 7 R 8 .
19. The method of claim 1 , wherein R 1 is —NR 7 R 8 , and wherein R 7 and R 8 are each independently hydrogen, —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl, or —C(O)R 9 , wherein the C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl are optionally substituted with —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl,or —NR 9 R 10 ; or, R 7 and R 8 together with the nitrogen atom to which they are attached form a 3 to 8- membered heterocycle, wherein any one of the ring carbon atoms is optionally replaced with O, NR 9 or N—C(O)R 9 .
20. The method of claim 1 , wherein R 1 is —SR 7 .
21. The method of claim 1 , wherein R 1 is —S—(C 1 -C 6 )-alkyl.
22. The method of claim 1 , wherein R 1 is C 3 -C 8 cycloalkyl.
23. The method of claim 1 , wherein R 1 is cyclopropyl.
24. The method of claim 1 , wherein R 1 is dimethylamino.
25. The method of claim 1 , wherein the compound is
26. The method of claim 1 , wherein the compound is
27. A method for the treatment of at least one condition selected from the group consisting of erectile dysfunction, pulmonary hypertension, cardiovascular disorder, and gastrointestinal disorder in a subject in need of such treatment, the method comprising:
administering to the subject an effective amount of a composition comprising a PDE5 inhibitor compound of Formula (V):
wherein:
A is O or N;
X is —(CH 2 ) n , C(O), S(O), or S(O) 2 ;
R 1 is C 3 -C 8 cycloalkyl, —NR 7 R 8 , or —SR 7 ;
R 2 is —CH 2 OR 6 or —CO 2 R 8 ;
R 3 is hydrogen or halogen;
R 4 is —CN or halogen;
R 5 is hydrogen or —OR 6 ;
R 6 is hydrogen, —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl, or —C(O)R 9 ;
R 7 and R 8 are each independently hydrogen, —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl, or —C(O)R 9 , wherein the C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl are optionally substituted with —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl, —NR 9 R 10 , —SR 9 , or heterocyclyl; or, R 7 and R 8 together with the nitrogen atom to which they are attached form a 3 to 8-membered heterocycle, wherein any one of the ring carbon atoms is optionally replaced with a heteroatom, and wherein the heterocycle is optionally substituted with C 1 -C 6 alkyl; and
R 9 and R 10 are each independently hydrogen, C 1 -C 6 alkyl, or C 3 -C 8 cycloalkyl; and n is 1, 2, or 3,
or a pharmaceutically acceptable salt or tautomer thereof.
28. The method of claim 27 , wherein the effective amount is at least about 1 mg/kg body weight, at least about 2 mg/kg body weight, at least about 3 mg/kg body weight, at least about 4 mg/kg body weight, at least about 5 mg/kg body weight, at least about 6 mg/kg body weight, at least about 7 mg/kg body weight, at least about 8 mg/kg body weight, at least about 9 mg/kg body weight, or at least about 10 mg/kg body weight.
29. The method of claim 27 , wherein A is N.
30. The method of claim 27 , wherein R 5 is hydrogen.
31. The method of claim 27 , wherein R 5 is —OCH 3 .
32. The method of claim 27 , wherein the compound is of formula (V-1):
wherein:
R i is C 3 -C 8 cycloalkyl, —NR 7 R 8 , or —SR';
R 2 is —CH 2 OR 6 or —CO 2 R 8 ;
R 3 is hydrogen or halogen;
R 4 is —CN or halogen;
R 6 is hydrogen, —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl, or —C(O)R 9 ;
R 7 and R 8 are each independently hydrogen, —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl, or —C(O)R 9 , wherein the C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl are optionally substituted with —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl, —NR 9 R 10 , —SR 9 , or heterocyclyl; or, R 7 and R 8 together with the nitrogen atom to which they are attached form a 3 to 8-membered heterocycle, wherein any one of the ring carbon atoms is optionally replaced with a heteroatom, and wherein the heterocycle is optionally substituted with C 1 -C 6 alkyl; and
R 9 and R 10 are each independently hydrogen, C 1 -C 6 alkyl, or C 3 -C 8 cycloalkyl,
or a pharmaceutically acceptable salt or tautomer thereof.
33. The method of claim 32 , wherein R 6 is CH 3 .
34. The method of claim 27 , wherein the compound is of formula (V-1a):
wherein:
R i is C 3 -C 8 cycloalkyl, —NR 7 R 8 , or —SR';
R 2 is —CH 2 OR 6 or —CO 2 R 8 ;
R 3 is hydrogen or halogen;
R 4 is —CN or halogen;
R 7 and R 8 are each independently hydrogen, —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl, or —C(O)R 9 , wherein the C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl are optionally substituted with —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl, —NR 9 R 10 , —SR 9 , or heterocyclyl; or, R 7 and R 8 together with the nitrogen atom to which they are attached form a 3 to 8-membered heterocycle, wherein any one of the ring carbon atoms is optionally replaced with a heteroatom, and wherein the heterocycle is optionally substituted with C 1 -C 6 alkyl; and
R 9 and R 10 are each independently hydrogen, C 1 -C 6 alkyl, or C 3 -C 8 cycloalkyl,
or a pharmaceutically acceptable salt or tautomer thereof.
35. The method of claim 27 , wherein R 2 is CH 2 —OH.
36. The method of claim 27 , wherein R 3 is H.
37. The method of claim 27 , wherein R 3 is a halogen.
38. The method of claim 27 , wherein R 3 is chlorine.
39. The method of claim 27 , wherein R 4 is —CN.
40. The method of claim 27 , wherein R 4 is a halogen.
41. The method of claim 27 , wherein R 4 is fluorine.
42. The method of claim 27 , wherein the compound is of formula (V-1a1):
wherein:
R 1 is C 3 -C 8 cycloalkyl, —NR 7 R 8 , or —SR 7 ;
R 7 and R 8 are each independently hydrogen, —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl, or —C(O)R 9 , wherein the C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl are optionally substituted with —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl, —NR 9 R 10 , —SR 9 , or heterocyclyl; or, R 7 and R 8 together with the nitrogen atom to which they are attached form a 3 to 8-membered heterocycle, wherein any one of the ring carbon atoms is optionally replaced with a heteroatom, and wherein the heterocycle is optionally substituted with C 1 -C 6 alkyl; and
R 9 and R 10 are each independently hydrogen, C 1 -C 6 alkyl, or C 3 -C 8 cycloalkyl,
or a pharmaceutically acceptable salt or tautomer thereof.
43. The method of claim 27 , wherein R 1 is —NR 7 R 8 .
44. The method of claim 27 , wherein R 1 is —NR 7 R 8 , and wherein R 7 and R 8 are each independently hydrogen, —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl, or —C(O)R 9 , wherein the C 3 -C 6 alkyl or C 3 -C 8 cycloalkyl are optionally substituted with —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl,or —NR 9 R 10 or, R 7 and R 8 together with the nitrogen atom to which they are attached form a 3 to 8- membered heterocycle, wherein any one of the ring carbon atoms is optionally replaced with O, NR 9 or N—C(O)R 9 .
45. The method of claim 27 , wherein R 1 is —SR 7 .
46. The method of claim 27 , wherein R 1 is —S—(C 1 -C 6 )-alkyl.
47. The method of claim 27 , wherein R 1 is C 3 -C 8 cycloalkyl.
48. The method of claim 27 , wherein R 1 is cyclopropyl.
49. The method of claim 27 , wherein R 1 is dimethylamino.
50. The method of claim 27 , wherein the compound is
51. The method of claim 27 , wherein the compound is