Structure-activity relationships of potent, selective inhibitors of neuronal nitric oxide synthase based on the 6-phenyl-2-aminopyridine structure.
The synthesis and structure-activity relationships of a series of 6-phenyl-2-aminopyridines that potently and selectively inhibit the neuronal isoform of nitric oxide synthase (nNOS) are described. Compound 14bi from this series exhibits potent in vivo activity in harmaline-induced cGMP formation in rat cerebellum, a functional model of nNOS inhibition, and in the PCP-induced hypermotility model in the rat. These results suggest that 14bi may be a useful reagent for evaluating potential therapeutic applications of nNOS inhibitors in the central nervous system.
Pfizer Global Research and Development, Pfizer Inc., Eastern Point Road, Groton Connecticut 06340, USA. john_a_lowe@groton.pfizer.com
John A
JA
Lowe
Weimin
W
Qian
Susan E
SE
Drozda
Robert A
RA
Volkmann
Deane
D
Nason
Robert B
RB
Nelson
Charles
C
Nolan
Dane
D
Liston
Karen
K
Ward
Steve
S
Faraci
Kim
K
Verdries
Pat
P
Seymour
Michael
M
Majchrzak
Anabella
A
Villalobos
W Frost
WF
White
D000631:Aminopyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D006152:Cyclic GMP / Q000096:biosynthesis; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D052248:Nitric Oxide Synthase Type I; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013764:Tetrahydronaphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C483901:6-(4-(N,N-dimethylaminoethoxy)-5,6,7,8-tetrahydronaphthalen-1-yl)pyridin-2-ylamine; D000631:Aminopyridines; D013764:Tetrahydronaphthalenes; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat; D006152:Cyclic GMP