A new class of selective and potent inhibitors of neuronal nitric oxide synthase.
The synthesis and SAR of a series of 6-(4-(substituted)phenyl)-2-aminopyridines as inhibitors of nitric oxide synthase are described. Compound 3a from this series shows potent and selective inhibition of the human nNOS isoform, with pharmacokinetics sufficient to provide in vivo inhibition of nNOS activity.
Lowe
J A
JA
Central Research Division, Pfizer Inc. Groton, CT 06340, USA.
Qian
W
W
Volkmann
R A
RA
Heck
S
S
Nowakowski
J
J
Nelson
R
R
Nolan
C
C
Liston
D
D
Ward
K
K
Zorn
S
S
Johnson
C
C
Vanase
M
M
Faraci
W S
WS
Verdries
K A
KA
Baxter
J
J
Doran
S
S
Sanders
M
M
Ashton
M
M
Whittle
P
P
Stefaniak
M
M
D000631:Aminopyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D006207:Half-Life; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052248:Nitric Oxide Synthase Type I; D051381:Rats; D013329:Structure-Activity Relationship
D000631:Aminopyridines; D004791:Enzyme Inhibitors; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat