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Selective neuronal nitric oxide synthase inhibitors and the prevention of cerebral palsy
Author(s) -
Ji Haitao,
Tan Sidhartha,
Igarashi Jotaro,
Li Huiying,
Derrick Matthew,
Martásek Pavel,
Roman Linda J.,
VásquezVivar Jeannette,
Poulos Thomas L.,
Silverman Richard B.
Publication year - 2009
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.21555
Subject(s) - nitric oxide synthase , in vivo , fetus , cerebral palsy , pharmacology , nitric oxide , neuronal nitric oxide synthase , medicine , hypoxia (environmental) , saline , anesthesia , chemistry , biology , pregnancy , oxygen , genetics , microbiology and biotechnology , organic chemistry , psychiatry
Abstract 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. Interpretation This approach may lead to new preventive strategies for CP. Ann Neurol 2008