Selective neuronal nitric oxide synthase inhibitors and the prevention of cerebral palsy

Authors

  • Haitao Ji PhD,

    1. Department of Chemistry, Department of Biochemistry, Molecular Biology, and Cell Biology, Center for Drug Discovery and Chemical Biology, Northwestern University, Evanston, IL
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  • Sidhartha Tan MD,

    1. Department of Pediatrics, Evanston Northwestern Healthcare and Northwestern University, Evanston, IL
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  • Jotaro Igarashi PhD,

    1. Departments of Molecular Biology and Biochemistry, Pharmaceutical Sciences, and Chemistry, University of California, Irvine, CA
    Current affiliation:
    1. Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, 2-1-1 Katahira, Aoba-ku, Sendai 980-8577, Japan
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  • Huiying Li PhD,

    1. Departments of Molecular Biology and Biochemistry, Pharmaceutical Sciences, and Chemistry, University of California, Irvine, CA
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  • Matthew Derrick MD,

    1. Department of Pediatrics, Evanston Northwestern Healthcare and Northwestern University, Evanston, IL
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  • Pavel Martásek MD,

    1. Department of Biochemistry, University of Texas Health Science Center, San Antonio, TX
    2. Department of Pediatrics and Center for Applied Genomics, 1st School of Medicine, Charles University, Prague, Czech Republic
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  • Linda J. Roman PhD,

    1. Department of Biochemistry, University of Texas Health Science Center, San Antonio, TX
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  • Jeannette Vásquez-Vivar PhD,

    1. Department of Biophysics, Medical College of Wisconsin, Milwaukee, WI
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  • Thomas L. Poulos PhD,

    1. Departments of Molecular Biology and Biochemistry, Pharmaceutical Sciences, and Chemistry, University of California, Irvine, CA
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  • Richard B. Silverman PhD

    Corresponding author
    1. Department of Chemistry, Department of Biochemistry, Molecular Biology, and Cell Biology, Center for Drug Discovery and Chemical Biology, Northwestern University, Evanston, IL
    • Department of Chemistry, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208-3113
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  • Potential conflict of interest: Nothing to report.

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 NOx (NO and NO2) 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

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