Selective neuronal nitric oxide synthase inhibitors
Compounds and related methods for selective inhibition of neuronal nitric oxide synthase over inducible and endothelial isoforms, such compounds as can provide reduced cationic character and enhanced bioavailability.
1. A nitric oxide synthase inhibitor compound of a formula
wherein n is selected from 0 and 1; Y is selected from CH 2 , O, NH, CH 2 O, CH 2 NH, CH 2 CH 2 and CH═CH moieties; X is selected from N and CH; and R 1 and R 2 are independently selected from H, amono, methyl, methoxy, fluoro, chloro,and mono-, di- and trifluoromethyl, and mono-, di, and trichloromethyl substituents, and combinations thereof, or a salt thereof.
2. The compound of claim 1 wherein n is 1, Y is CH 2 CH 2 and X is N.
3. The compound of claim 2 wherein R 1 is selected from H and a 4-methyl substituent; and R 2 is independently selected from H and a 2-amino substituent.
4. The compound of claim 3 wherein said compound is an ammonium salt.
5. The compound of claim 4 wherein said ammonium salt has a counterion that is a conjugate base of a protic acid.
6. A nitric oxide synthase inhibitor compound of a formula
wherein Y is selected from CH 2 CH 2 and CH═CH moieties; and R 1 and R 2 are independently selected from H, Cl and F, or a salt thereof.
7. The compound of claim 6 wherein at least one of R 1 and R 2 is F.
8. The compound of claim 7 wherein R 1 is selected from H and a 3-chloro substitutent; and R 2 is a 5-fluoro substituent.
9. The compound of claim 8 wherein said compound is an ammonium salt.
10. The compound of claim 9 wherein said ammonium salt has a counterion that is a conjugate base of a protic acid.
11. A compound selected from
6-(((3R,4R)-4-((5-(3-chloro-5-fluorophenyl)pentyl)oxy)pyrrolidin-3-yl)methyl)-4-methylpyridin-2-amine (HH002); and
6-(((3R,4R)-4-(((E)-5-(3-fluorophenyl)pent-4-en-1-yl)oxy)pyrrolidin-3-yl)methyl)-4-methylpyridin-2-amine (HH003).
12. A pharmaceutical composition comprising the compound of claim 6 .
13. A nitric oxide synthase inhibitor compound of a formula
wherein Y is selected from CH 2 CH 2 and CH═CH moieties; R 3 is selected from H and CH 3 ; and R 4 is selected from H and NH 2 , or a salt thereof.
14. The compound of claim 13 wherein Y is CH 2 CH 2 , and one of R 3 and R 4 is not H.
15. The compound of claim 14 wherein R 3 is selected from H and a 4-methyl substituent; and R 4 is a 2-amino substituent.
16. The compound of claim 15 wherein said compound is an ammonium salt.
17. The compound of claim 16 wherein said ammonium salt has a counterion that is a conjugate base of a protic acid.
18. A compound selected from
4-methyl-6-(((3R,4R)-4-((5-(pyridin-2-yl)pentyl)oxy)pyrrolidin-3-yl)methyl)pyridin-2-amine;
4-methyl-6-(((3R,4R)-4-((5-(4-methylpyridin-2-yl)pentyl)oxy)pyrrolidin-3-yl)methyl)pyridin-2-amine ;
6-(((3R,4R)-4-((5-(3-aminophenyl)pentyl)oxy)pyrrolidin-3-yl)methyl)-4-methylpyridin-2-amine; and
6-(((3R,4R)-4-((5-(3-amino-5-methylphenyl)pentyl)oxy)pyrrolidin-3-yl)methyl)-4-methylpyridin-2-amine.
19. A pharmaceutical composition comprising the compound of claim 13 .
20. A nitric oxide synthase inhibitor compound of a formula
wherein Ar is selected from naphthalenylene and isoquinolinylene moieties; X is selected from CH and N; R 1 is selected from H and CH 3 ; and R 2 is independently selected from H and NH 2 , and or salt thereof.
21. The compound of claim 20 wherein X is N.
22. The compound of claim 21 wherein R 1 is selected from H and a 4-methyl substituent; and R 2 is a 2-amino substituent.
23. The compound of claim 22 wherein said compound is an ammonium salt.
24. The compound of claim 23 wherein said ammonium salt has a counterion that is a conjugate base of a protic acid.
25. A compound selected from
4-(((3R,4R)-4-((6-amino-4-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)oxy)-N-(pyridin-2-yl)isoquinolin-7-amine; and
4-methyl-6-(((3R,4R)-4-((6-(pyridin-2-ylamino)naphthalen-1-yl)oxy)pyrrolidin-3-yl)methyl)pyridin-2-amine.
26. A pharmaceutical composition comprising the compound of claim 20 .
27. A method of inhibiting a nitric oxide synthase, said method comprising contacting a nitric oxide synthase with an effective amount of a compound of claim 1 .
28. The method of claim 27 wherein n is 1, Y is CH 2 CH 2 and X is N.
29. The method of claim 28 wherein said compound is selected from
4-methyl-6-(((3R,4R)-4-((5-(pyridin-2-yl)pentyl)oxy)pyrrolidin-3-yl)methyl)pyridin-2-amine;
4-methyl-6-(((3R,4R)-4-((5-(4-methylpyridin-2-yl)pentyl)oxy)pyrrolidin-3-yl)methyl)pyridin-2-amine;
6-(((3R,4R)-4-((5-(3-aminophenyl)pentyl)oxy)pyrrolidin-3-yl)methyl)-4-methylpyridin-2-amine; and
6-(((3R,4R)-4-((5-(3-amino-5-methylphenyl)pentyl)oxy)pyrrolidin-3-yl)methyl)-4-methylpyridin-2-amine.
30. The method of claim 29 wherein said compound is provided in a pharmaceutical composition.