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 synaptic dysfunction and memory loss in a subject in need thereof, 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 , or heterocyclyl;
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 6 , 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. The method of claim 1 , wherein the composition is administered at least once daily for up to 18 days, up to 19 days, up to 20 days, up to 21 days, up to 22 days, up to 23 days, up to 24 days, or up to 25 days.
28. The method of claim 1 , wherein PDE5 activity is inhibited up to 3 months post-treatment, up to 4 months post-treatment, up to 5 months post-treatment, or up to 6 months post-treatment.