Potent and highly selective heteroaromatic inhibitors of neuronal nitric oxide synthase
Peptidomimetic compounds as can inhibit neuronal nitric oxide synthase (nNOS) for potential treatment in neurodegenerative diseases, such as but not limited to stroke, Alzheimer's disease, Parkinson's disease, Huntington's disease.
1. A neuronal nitric oxide synthase inhibitor compound of a formula
wherein X is selected from CR, N, O and S, and R is selected from H, methyl and substituted methyl moieties; m and n are integers independently selected from 0, 1 and 2, and 0<(m +n)≦2, and said heterocyclic ring is aromatic; R 1 is selected from H, alkyl, substituted alkyl and halogen moieties; Y is selected from CH, O, N and + NR 4 ; p and q are integers independently selected from 0, 1 and 2, and 1<(p +q)≦4; Z is selected from NH, O and NHC(O); R 2 is selected from H, alkyl, amino, hydroxyl, and substituted alkyl moieties; R 3 is selected from alkyl, substituted alkyl, hydroxyalkyl, substituted hydroxyalkyl, arylalkylaminoalkyl, substituted arylalkylaminoalkyl, arylalkyloxaalkyl substituted arylalkyloxaalkyl, arylalkylamidoalkyl, substituted arylalkylamidoalkyl, aminoalkyl, and substituted aminoalkyl moieties; R 4 is H; and cis and trans stereoisomers and salts thereof.
2. The compound of claim 1 wherein X is CR when (m+n)=2, and X is S when (m+n)=1.
3. The compound of claim 2 wherein Y is + NR 4 , and p and q are 1.
4. The compound of claim 3 wherein Z is selected from NH and O, and R 3 comprises a an aminoalkyl or substituted aminoalkyl moiety.
5. The compound of claim 4 wherein said R 3 moiety is selected from primary, secondary, tertiary, linear and cyclic amino groups and combinations thereof.
6. The compound of claim 5 wherein R 2 is selected from H and aminoalkyl moieties.
7. The compound of claim 1 wherein R is methyl.
8. The compound of claim 7 wherein Y is + NR 4 .
9. The compound of claim 8 wherein Z is NH or O, R 2 is selected from H, aminoalkyl and substituted aminoalkyl moieties, and R 3 is selected from aminoalkyl, substituted aminoalkyl, arylalkylaminoalkyl and substituted arylalkylaminoalkyl moieties.
10. The compound of claim 2 wherein Y is CH, and p and q are 1.
11. The compound of claim 10 wherein Z is selected from NH and O, R 2 is selected from H, aminoalkyl and substituted aminoalkyl moieties, and R 3 is selected from aminoalkyl, substituted aminoalkyl, arylalkylaminoalkyl and substituted arylalkylaminoalkyl moieties.
12. A neuronal nitric oxide synthase inhibitor compound of a formula
wherein X is CR 1 and R 1 is selected from H, methyl, and substituted methyl moieties; m and n are integers independently selected from 0, 1 and 2, and 0<(m +n)≦2; Y is selected from CH, N and + NR 4 ; p and q are integers independently selected from 1 and 2; R 2 is selected from H, alkyl, substituted alkyl, aminoalkyl, substituted aminoalkyl, hydroxyalkyl, and substituted hydroxyalkyl moieties; Z is selected from NH, O and NHC(O); R 3 is selected from alkyl, substituted alkyl, hydroxyalkyl, substituted hydroxyalkyl, aminoalkyl, substituted aminoalkyl, arylalkylaminoalkyl and substituted arylalkylaminoalkyl moieties; R 4 is H; and cis and trans stereoisomers and salts thereof.
13. The compound of claim 12 wherein R 1 is selected from methyl and substituted methyl moieties, and m and n are 1.
14. The compound of claim 12 wherein R 2 is H.
15. The compound of claim 14 wherein Z is selected from NH and O, and R 3 is selected from phenylethylaminoalkyl and substituted phenylethylaminoalkyl moieties.
16. The compound of claim 15 wherein R 1 is selected from H and methyl moieties.
17. A neuronal nitric oxide synthase inhibitor compound of a formula
wherein R 1 is selected from H, alkyl, substituted alkyl, aminoalkyl, substituted aminoalkyl, hydroxyalkyl, and substituted hydroxyalkyl moieties; Z is selected from NH, O and NHC(O); and R 2 is selected from alkyl, substituted alkyl, hydroxyalkyl, substituted hydroxyalkyl, aminoalkyl, substituted aminoalkyl moieties arylalkylaminoalkyl and substituted arylalkylaminoalkyl; and cis and trans stereoisomers and salts thereof.
18. The compound of claim 17 wherein R 1 is H.
19. The compound of claim 18 wherein R 2 is selected from arylalkylaminoalkyl and substituted arylalkylaminoalkyl moieties.
20. The compound of claim 19 wherein Z is selected from NH and O.