Selective neuronal nitric oxide synthase inhibitors and the prevention of cerebral palsy†
Haitao Ji PhD
Department of Chemistry, Department of Biochemistry, Molecular Biology, and Cell Biology, Center for Drug Discovery and Chemical Biology, Northwestern University, Evanston, IL
Search for more papers by this authorSidhartha Tan MD
Department of Pediatrics, Evanston Northwestern Healthcare and Northwestern University, Evanston, IL
Search for more papers by this authorJotaro Igarashi PhD
Departments of Molecular Biology and Biochemistry, Pharmaceutical Sciences, and Chemistry, University of California, Irvine, CA
Search for more papers by this authorHuiying Li PhD
Departments of Molecular Biology and Biochemistry, Pharmaceutical Sciences, and Chemistry, University of California, Irvine, CA
Search for more papers by this authorMatthew Derrick MD
Department of Pediatrics, Evanston Northwestern Healthcare and Northwestern University, Evanston, IL
Search for more papers by this authorPavel Martásek MD
Department of Biochemistry, University of Texas Health Science Center, San Antonio, TX
Department of Pediatrics and Center for Applied Genomics, 1st School of Medicine, Charles University, Prague, Czech Republic
Search for more papers by this authorLinda J. Roman PhD
Department of Biochemistry, University of Texas Health Science Center, San Antonio, TX
Search for more papers by this authorJeannette Vásquez-Vivar PhD
Department of Biophysics, Medical College of Wisconsin, Milwaukee, WI
Search for more papers by this authorThomas L. Poulos PhD
Departments of Molecular Biology and Biochemistry, Pharmaceutical Sciences, and Chemistry, University of California, Irvine, CA
Search for more papers by this authorCorresponding Author
Richard B. Silverman PhD
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 60208-3113Search for more papers by this authorHaitao Ji PhD
Department of Chemistry, Department of Biochemistry, Molecular Biology, and Cell Biology, Center for Drug Discovery and Chemical Biology, Northwestern University, Evanston, IL
Search for more papers by this authorSidhartha Tan MD
Department of Pediatrics, Evanston Northwestern Healthcare and Northwestern University, Evanston, IL
Search for more papers by this authorJotaro Igarashi PhD
Departments of Molecular Biology and Biochemistry, Pharmaceutical Sciences, and Chemistry, University of California, Irvine, CA
Search for more papers by this authorHuiying Li PhD
Departments of Molecular Biology and Biochemistry, Pharmaceutical Sciences, and Chemistry, University of California, Irvine, CA
Search for more papers by this authorMatthew Derrick MD
Department of Pediatrics, Evanston Northwestern Healthcare and Northwestern University, Evanston, IL
Search for more papers by this authorPavel Martásek MD
Department of Biochemistry, University of Texas Health Science Center, San Antonio, TX
Department of Pediatrics and Center for Applied Genomics, 1st School of Medicine, Charles University, Prague, Czech Republic
Search for more papers by this authorLinda J. Roman PhD
Department of Biochemistry, University of Texas Health Science Center, San Antonio, TX
Search for more papers by this authorJeannette Vásquez-Vivar PhD
Department of Biophysics, Medical College of Wisconsin, Milwaukee, WI
Search for more papers by this authorThomas L. Poulos PhD
Departments of Molecular Biology and Biochemistry, Pharmaceutical Sciences, and Chemistry, University of California, Irvine, CA
Search for more papers by this authorCorresponding Author
Richard B. Silverman PhD
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 60208-3113Search for more papers by this authorPotential 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
Supporting Information
Additional Supporting Information may be found in the online version of this article.
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Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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