Specific nNOS inhibitors for the therapy and prevention of human melanoma
Methods for melanoma treatment and prevention with selective nitric oxide synthase inhibitor compounds and related pharmaceutical compositions, alone or in conjunction with one or more other melanoma therapies.
1. A method of reducing expression of neuronal nitric oxide synthase, said method comprising:
providing a compound selected from compounds of a formula
wherein R 1 is selected from H, halogen, methyl and halomethyl moieties; R 2 is selected from H, alkyl and haloalkyl moieties; Z is selected from O and NH; and R 4 is selected from H, alkyl, halogen and haloalkyl moieties, and salts thereof; and
contacting said compound with a cellular medium comprising one of human melanocytes, melanoma cells and a combination thereof, said compound in an amount sufficient to reduce induction of neuronal nitric oxide synthase expression, thereby reducing ultra-violet induced nitric oxide production in a human melanocyte or melanoma cell.
2. The method of claim 1 wherein R 2 is H, Z is NH, and R 4 is selected from H and halogen moieties, said compound selected from cis and trans stereoisomers.
3. The method of claim 2 wherein said compound is selected from
N 1 -((3R,4R)-4-((6-amino-4-methylpyridin-2,y 1 )methy 1 )pyrrolidin-3-y 1 )-N 2 -(3-fluorophenethyl)ethane-1,2-diamine (1);
N 1 -((3S, 4 S)- 4 (( 6 -amino- 4 -methylplyridin- 2 -yl)methyl)pyrrolidin-3-yl)-N 2 -( 4 -chlorobenzyl)ethane-1,2-diamine (6);
N 1 -((3S, 4 S)-4-S(( 6 -amino- 4 -methylpyridin- 2 -yl)methyl)pyrrolidin-3-yl)-N 2 -phenethylethane-1,2-diamine (7); and
N 1 -((3R,4S)-4-((6-amino-4-methylpyridin-2-l)methyl)pyrrolidin-3-yl)-N 2 -(3- fluorophenethyl)ethane-1,2-diamine (8),
4. The method of claim 1 wherein said compound is an ammonium salt.
5. The method of claim 4 wherein said ammonium salt has a counter ion that is a conjugate base of a protic acid.
6. The method of claim 1 wherein said compound is provided in a pharmaceutical composition.
7. The method of claim 1 wherein R 1 is selected from H and methyl.
8. The method of claim 7 wherein R 2 is H and Z is NH.
9. The method of claim 8 wherein R 4 is selected from H and halogen moieties.
10. The method of claim 9 wherein said compound is selected from cis and trans stereoisomers.
11. The method of claim 10 wherein said compound is provided in a pharmaceutical composition.
12. The method of claim 7 wherein said compound is selected from
N 1 -((3R,4R)-4-((6-amino-4-methylpyridin-2-yl)pyrrolidin-3-yl)-N 2 -(3-fluorophenethyl)pethane-1,2-diamine (1);
N- 1 ((3S,4S)-4((6-amino-4-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)-N 2 -(4-chlorobenzyl)ethane-1,2-diamine (6);
N 1 -((3S,4S)-4-((6-amino-4-methylpyridin-2-yl)methyppyrrolidin-3-yl)-N 2 -phenethylethane-1,2-diamine (7); and
N 1 -((3R,4S)-4-((6-amino-4-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)-N 2 (3- fluorophenethyl)ethane-1,2-diamine (8).
13. The method of claim 12 wherein said compound is an ammonium salt.
14. The method of claim 13 wherein said ammonium salt has a counter ion that is a conjugate base of a protic acid.
15. The method of claim 14 wherein said compound is provided in a pharmaceutical composition.