Selective neuronal nitric oxide synthase inhibitors with azole substituents
Non-peptide, azole-substituted nitric oxide snythase inhibitor compounds, compositions and related methods, as can be used to enhance bioavailability and inhibit production of nitric oxide.
1. A compound selected from compounds of a formula
wherein X, Y and Z are independently selected from CR 1 , CH 2 , O, S, N and NR 2 moieties; each said R 1 is independently selected form H, alkyl and halo moieties and a covalent bond to said ethanamine moiety; and each said R 2 is independently selected from H and alkyl moieties; and salts thereof.
2. The compound of claim 1 wherein one of X, Y, and Z is a heteroatom moiety.
3. The compound of claim 2 wherein each of X and Z is CH, and Y is NH, said compound comprising an imidazolyl moiety.
4. The compound of claim 2 wherein each of X and Y is CH, and Z is S, said compound comprising a thiazolyl moiety.
5. The compound of claim 1 comprising a cis diastereomeric configuration.
6. The compound of claim 1 wherein said compound is an ammonium salt.
7. The compound of claim 6 wherein said ammonium salt has a counter ion that is a conjugate base of a protic acid.
8. The compound of claim 1 contacting a nitric oxide synthase.
9. The compound of claim 8 in a configuration for heme coordination of said azolyl moiety.
10. A compound selected from compounds of a formula
wherein X, Y and Z are independently selected from CR 1 , CH 2 , O, S, N and NR 2 moieties; each said R 1 is selected from H and alkyl moieties; and each said R 2 is independently selected from H and alkyl moieties; and salts thereof.
11. The compound of claim 10 wherein said azolyl moiety is selected from imidazol-4-yl and thiazol-2-yl moieties.
12. The compound of claim 11 wherein said compound is an ammonium salt, and said salt has a counter ion that is a conjugate base of a protic acid.
13. A method of using azolyl basicity to affect bioavailability of a nitric oxide synthase inhibitor compound, said method comprising:
providing a compound of claim 1 , said compound comprising an azolyl moiety with an imine nitrogen substantially unprotonated at physiological pH; and
contacting said compound with a lipophilic medium.
14. The method of claim 13 wherein said azolyl moiety has a pK a value ≦ about 5.4.
15. The method of claim 13 wherein said medium models one of a cellular membrane and the brain blood barrier.
16. A method of inhibiting a nitric oxide synthase comprising contacting a nitric oxide synthase with an effective amount of a compound of a formula
wherein X, Y and Z are independently selected from CRi, CH 2 , O, S, N and NR 2 moieties; each said R 1 is selected from H and alkyl moieties; and each said R 2 is independently selected from H and alkyl moieties; and salts thereof.
17. The method of claim 16 wherein said azolyl moiety is selected from imidazolyl and thiazolyl moieties.
18. The method of claim 17 wherein said compound is selected from (S,S) and (R,R) enantiomers.
19. The method of claim 18 wherein said compound is the (R,R) enantiomer, said method selective for inhibition of neuronal nitric oxide synthase.