Selective neuronal nitric oxide synthase inhibitors and the prevention of cerebral palsy.
OBJECTIVE
To design a new class of selective neuronal nitric oxide synthase (NOS) inhibitors, and demonstrate that administration in a rabbit model for cerebral palsy (CP) prevents hypoxia-ischemia-induced deaths and reduces the number of newborn kits exhibiting signs of CP.


METHODS
We used a novel computer-based drug design method called fragment hopping to identify new chemical entities, synthesized them, and conducted in vitro enzyme inhibition studies with the three isozymes of NOS and in vivo experiments to monitor cardiovascular effects on pregnant rabbit dams, NOS activity, and NO(x) (NO and NO(2)) concentration in fetal brain, and assess neurobehavioral effects on kits born to saline- and compound treated dams.


RESULTS
The computer-based design led to the development of powerful and highly selective compounds for inhibition of neuronal NOS over the other isozymes. After maternal administration in a rabbit model of CP, these compounds were found to distribute to fetal brain, to be nontoxic, without cardiovascular effects, inhibit fetal brain NOS activity in vivo, reduce NO concentration in fetal brain, and dramatically ameliorate deaths and number of newborn kits exhibiting signs of CP.


CONCLUSIONS
This approach may lead to new preventive strategies for CP.
Ji
Haitao
H
Department of Chemistry, Center for Drug Discovery and Chemical Biology, Northwestern University, Evanston, IL 60208-3113, USA.
Tan
Sidhartha
S
Igarashi
Jotaro
J
Li
Huiying
H
Derrick
Matthew
M
Martásek
Pavel
P
Roman
Linda J
LJ
Vásquez-Vivar
Jeannette
J
Poulos
Thomas L
TL
Silverman
Richard B
RB
D000818:Animals; D000831:Animals, Newborn; D001120:Arginine / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002547:Cerebral Palsy / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D002956:Citrulline / Q000378:metabolism; D018360:Crystallography, X-Ray / Q000379:methods; D004195:Disease Models, Animal; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000627:therapeutic use*; D005260:Female; D008297:Male; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D009569:Nitric Oxide / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011247:Pregnancy; D011817:Rabbits; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D002956:Citrulline; D009569:Nitric Oxide; D001120:Arginine; D052248:Nitric Oxide Synthase Type I