Discovery of highly potent and selective inhibitors of neuronal nitric oxide synthase by fragment hopping.

Abstract

Selective inhibition of neuronal nitric oxide synthase (nNOS) has been shown to prevent brain injury and is important for the treatment of various neurodegenerative disorders. This study shows that not only greater inhibitory potency and isozyme selectivity but more druglike properties can be achieved by fragment hopping. On the basis of the structure of lead molecule 6, fragment hopping effectively extracted the minimal pharmacophoric elements in the active site of nNOS for ligand hydrophobic and steric interactions and generated appropriate lipophilic fragments for lead optimization. More potent and selective inhibitors with better druglike properties were obtained within the design of 20 derivatives (compounds 7-26). Our structure-based inhibitor design for nNOS and SAR analysis reveal the robustness and efficiency of fragment hopping in lead discovery and structural optimization, which implicates a broad application of this approach to many other therapeutic targets for which known druglike small-molecule modulators are still limited.

• Authors: Haitao Ji, Huiying Li, Pavel Martásek, Linda J Roman, Thomas L Poulos, Richard B Silverman
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 52 Issue 3 Pg. 779-97 (Feb 12 2009) ISSN: 1520-4804 [Electronic] United States
• PMID: 19125620 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Aminopyridines
• Enzyme Inhibitors
• Pyrrolidines
• Nitric Oxide Synthase Type I
• Nitric Oxide Synthase Type II
• Nitric Oxide Synthase Type III
• Nos2 protein, mouse

Topics

• Aminopyridines
• Animals
• Catalytic Domain (drug effects)
• Cattle
• Combinatorial Chemistry Techniques
• Crystallography, X-Ray
• Drug Design
• Enzyme Inhibitors (chemical synthesis, pharmacology)
• Mice
• Models, Molecular
• Nitric Oxide Synthase Type I (antagonists & inhibitors)
• Nitric Oxide Synthase Type II (antagonists & inhibitors)
• Nitric Oxide Synthase Type III (antagonists & inhibitors)
• Pyrrolidines
• Rats