title: Selective neuronal nitric oxide synthase inhibitors and the prevention of cerebral palsy.
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.
  
  
  CONCLUSIONS
  This approach may lead to new preventive strategies for CP.
authors.affiliation: Department of Chemistry, Center for Drug Discovery and Chemical Biology, Northwestern University, Evanston, IL 60208-3113, USA.
authors.forename: Haitao
authors.initials: H
authors.lastname: Ji
authors.forename: Sidhartha
authors.initials: S
authors.lastname: Tan
authors.forename: Jotaro
authors.initials: J
authors.lastname: Igarashi
authors.forename: Huiying
authors.initials: H
authors.lastname: Li
authors.forename: Matthew
authors.initials: M
authors.lastname: Derrick
authors.forename: Pavel
authors.initials: P
authors.lastname: Martásek
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Roman
authors.forename: Jeannette
authors.initials: J
authors.lastname: Vásquez-Vivar
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Poulos
authors.forename: Richard B
authors.initials: RB
authors.lastname: Silverman
mesh_terms: 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
chemical_list: D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D002956:Citrulline; D009569:Nitric Oxide; D001120:Arginine; D052248:Nitric Oxide Synthase Type I