TY - JOUR
T1 - Selective neuronal nitric oxide synthase inhibitors and the prevention of cerebral palsy
AU - Ji, Haitao
AU - Tan, Sidhartha
AU - Igarashi, Jotaro
AU - Huiying, Li
AU - Derrick, Matthew
AU - Martásek, Pavel
AU - Roman, Linda J.
AU - Vasquez-Vivar, Jeannette
AU - Poulos, Thomas L.
AU - Silverman, Richard B.
PY - 2009/2
Y1 - 2009/2
N2 - 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 bopping 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 N0 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. Interpretation: This approach may lead to new preventive strategies for CP.
AB - 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 bopping 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 N0 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. Interpretation: This approach may lead to new preventive strategies for CP.
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U2 - 10.1002/ana.21555
DO - 10.1002/ana.21555
M3 - Article
C2 - 19235180
AN - SCOPUS:62549102043
SN - 0364-5134
VL - 65
SP - 209
EP - 217
JO - Annals of neurology
JF - Annals of neurology
IS - 2
ER -