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. INTERPRETATION:This approach may lead to new preventive strategies for CP.

journal_name

Ann Neurol

journal_title

Annals of neurology

authors

Ji H,Tan S,Igarashi J,Li H,Derrick M,Martásek P,Roman LJ,Vásquez-Vivar J,Poulos TL,Silverman RB

doi

10.1002/ana.21555

subject

Has Abstract

pub_date

2009-02-01 00:00:00

pages

209-17

issue

2

eissn

0364-5134

issn

1531-8249

journal_volume

65

pub_type

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