Volume 65, Issue 2 pp. 209-217
Original Article

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

Haitao Ji PhD

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 author
Sidhartha Tan MD

Sidhartha Tan MD

Department of Pediatrics, Evanston Northwestern Healthcare and Northwestern University, Evanston, IL

Search for more papers by this author
Jotaro Igarashi PhD

Jotaro Igarashi PhD

Departments of Molecular Biology and Biochemistry, Pharmaceutical Sciences, and Chemistry, University of California, Irvine, CA

Search for more papers by this author
Huiying Li PhD

Huiying Li PhD

Departments of Molecular Biology and Biochemistry, Pharmaceutical Sciences, and Chemistry, University of California, Irvine, CA

Search for more papers by this author
Matthew Derrick MD

Matthew Derrick MD

Department of Pediatrics, Evanston Northwestern Healthcare and Northwestern University, Evanston, IL

Search for more papers by this author
Pavel Martásek MD

Pavel 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 author
Linda J. Roman PhD

Linda J. Roman PhD

Department of Biochemistry, University of Texas Health Science Center, San Antonio, TX

Search for more papers by this author
Jeannette Vásquez-Vivar PhD

Jeannette Vásquez-Vivar PhD

Department of Biophysics, Medical College of Wisconsin, Milwaukee, WI

Search for more papers by this author
Thomas L. Poulos PhD

Thomas L. Poulos PhD

Departments of Molecular Biology and Biochemistry, Pharmaceutical Sciences, and Chemistry, University of California, Irvine, CA

Search for more papers by this author
Richard B. Silverman PhD

Corresponding 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 author
First published: 20 February 2009
Citations: 67

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

The full text of this article hosted at iucr.org is unavailable due to technical difficulties.

click me