2-aminoquinoline-based compounds for potent and selective neuronal nitric oxide synthase inhibition
Various 2-aminoquinoline compounds as can be used, in vivo or in vitro, for selective inhibition of neuronal nitric oxide synthase.
1. A compound of a formula
wherein X is selected from O and CH 2 ; Y is selected from CH and N; n is an integer selected from 1-2; m is an integer selected from 0-2; o is an integer selected from 0-3; and each R is independently selected from H, halo, alkyl, haloalkyl, alkoxy, cyano, amino, N-alkylamino, N,N-dialkylamino, aminealkyl, N-alkylaminealkyl, and N,N-dialkylaminealkyl; and R′ is selected from H, halo, alkyl, haloalkyl and cyano moieties, or a salt thereof.
2. The compound of claim 1 wherein X is O and Y is CH.
3. The compound of claim 2 wherein n is 1 and m is 0.
4. The compound of claim 3 wherein o is 1-3 and each R is independently select from H, halo, cyano and N-alkylaminealkyl moieties.
5. The compound of claim 4 wherein one R is cyano and said phenyl moiety is substituted at the 5-position thereof.
6. The compound of claim 5 wherein R′ is methyl and said quinoline moiety is substituted at the 4-position thereof.
7. The compound of claim 1 wherein X is CH 2 and Y is CH.
8. The compound of claim 7 wherein n is 1 and m is 0.
9. The compound of claim 8 wherein o is 1-3 and each R is independently selected from H, halo, cyano and N-alkylaminealkyl moieties.
10. The compound of claim 9 wherein one R is cyano and said phenyl moiety is substituted at the 5-position thereof.
11. The compound of claim 1 wherein said compound is an ammonium salt.
12. The compound of claim 11 wherein said salt has a counter ion that is the conjugate base of a protic acid.
13. A compound of a formula
wherein X is selected from O and CH 2 ; each of R 1 -R 3 is independently selected from H, halo, alkyl, haloalkyl, alkoxy, cyano and N-alkylaminealkyl moieties and R′ is selected from H, alkyl and haloalkyl moieties, or a salt thereof.
14. The compound of claim 13 wherein X is O and R 1 is an N-methylaminealkyl moiety.
15. The compound of claim 14 wherein R 2 is selected from H and a halo moiety; and R 3 is selected from H and a cyano moiety.
16. The compound of claim 15 wherein R 2 is H and R 3 is cyano.
17. The compound of claim 13 wherein R′ is methyl.
18. The compound of claim 13 wherein said compound is an ammonium salt.
19. The compound of claim 18 wherein said salt has a counter ion that is the conjugate base of a protic acid.
20. A compound of a formula
wherein X is selected from O and CH 2 ; Z is select from methylene, ethylene and methyl-substituted ethylene moieties; each of R 2 -R 3 is independently selected from H, halo, alkyl and cyano moieties and R′ is selected from H and a methyl moiety, or a salt thereof.
21. The compound of claim 20 wherein X is O and Z is a methyl-substituted ethylene moiety.
22. The compound of claim 21 wherein said phenyl is substituted with a 2-(methylamino) propyl moiety.
23. The compound of claim 22 wherein said moiety has an (S)-configuration.
24. The compound of claim 23 wherein R 2 is selected from H and a halo moiety; and R 3 is selected from H and a cyano moiety.
25. The compound of claim 24 wherein R 2 is H and R 3 is cyano.
26. The compound of claim 20 wherein said compound is an ammonium salt.
27. The compound of claim 26 wherein said salt has a counter ion that is the conjugate base of a protic acid.
28. A method of modulating nitric oxide synthase activity, said method comprising contacting a nitric oxide synthase with an effective amount of a compound of claim 1 .
29. The method of claim 28 wherein the sum of n and m is 1.
30. The method of claim 29 wherein o is 2-3, and R is selected from a combination of halo, alkyl, cyano and N-alkylaminealkyl moieties.
31. The method of claim 25 wherein o is 2, said phenyl substituted at the 3-position with an N-alkylaminealkyl moiety and at the 5-position with a cyano moiety.
32. A method of inhibiting a nitric oxide synthase, said method comprising:
providing a compound of claim 20 ; and
contacting said compound with a nitric oxide synthase, said compound in an amount effective to inhibit nitric oxide synthase activity, thereby reducing nitric oxide production.
33. The method of claim 32 wherein X is O.
34. The method of claim 32 selective for inhibition of neuronal nitric oxide synthase.
35. The method of claim 34 selective for inhibition of human neuronal nitric oxide synthase.
36. The method of claim 32 wherein said compound is provided in a pharmaceutical composition.