Potent and selective neuronal nitric oxide synthase inhibitors with improved membrane permeability
Compounds and related compositions and methods as can be used to inhibit neuronal nitric oxide synthase and can be employed in the treatment of various neurodegenerative diseases, such compounds of a formula
1. A nitric oxide synthase inhibitor compound of a formula
wherein X is selected from divalent ethylene oxide, cyclopropyl, monofluoroethylene and difluoroethylene moieties; and Φ is selected from phenyl, substituted phenyl, piperidinyl and substituted piperidinyl moieties, or a salt thereof.
2. The compound of claim 1 wherein X is selected from cyclopropyl and difluoroethylene moieties.
3. The compound of claim 2 wherein Φ is selected from phenyl and substituted phenyl moieties.
4. The compound of claim 3 wherein said substituent is selected from halide and alkyl substituents.
5. The compound of claim 4 wherein Φ is m-fluorophenyl.
6. The compound of claim 1 selected from the (S,S) and (R,R) enantiomers.
7. The compound of claim 1 wherein said compound is an ammonium salt.
8. The compound of claim 7 wherein said ammonium salt has a counter ion that is a conjugate base of a protic acid.
9. The compound of claim 1 complexed with a nitric oxide synthase enzyme.
10. A nitric oxide synthase inhibitor compound of a formula
wherein X is selected from divalent ethylene oxide, cyclopropyl, monofluoroethylene and difluoroethylene moieties; and Φ is selected from phenyl, substituted phenyl, piperidinyl and substituted piperidinyl moieties, or a salt thereof wherein the pyridine of said compound is at least partially reduced.
11. The compound of claim 10 complexed with a nitric oxide synthase enzyme.
12. A nitric oxide synthase inhibitor compound of a formula
wherein R is selected from H, halide and alkyl moieties; or a salt thereof.
13. The compound of claim 12 wherein R is halide.
14. The compound of claim 13 wherein R is meta-substituted fluoride.
15. The compound of claim 12 wherein said compound is an ammonium salt.
16. The compound of claim 15 wherein said ammonium salt has a counter ion that is a conjugate base of a protic acid.
17. A method inhibiting a nitric oxide synthase comprising contacting a nitric oxide synthase with an effective amount of a compound of a formula
wherein X is selected from divalent ethylene oxide, cyclopropyl, monofluoroethylene and difluoroethylene moieties; and Φ is selected from phenyl, substituted phenyl, piperidinyl and substituted piperidinyl moieties, or a salt thereof.
18. The method of claim 17 wherein X is selected from cyclopropyl and difluoroethylene moieties.
19. The method of claim 18 wherein Φ is selected from phenyl and substituted phenyl moieties.
20. The method of claim 19 wherein Φ is m-fluorophenyl.
21. The method of claim 17 wherein X is a difluoroethylene moiety and said compound is selected from the (S,S) and (R,R) enantiomers.
22. The method of claim 21 wherein said compound is the (R,R) enantiomer, and said method selective for inhibition of neuronal nitric oxide synthase.