Abstract
A novel class of quinazolinone derivatives as potent poly(ADP-ribose)polymerase-1 (PARP-1) inhibitors has been discovered. Key to success was application of a rational discovery strategy involving structure-based design, combinatorial chemistry, and classical SAR for improvement of potency and bioavailability. The new inhibitors were shown to bind to the nicotinamide-ribose binding site (NI site) and the adenosine-ribose binding site (AD site) of NAD+.
Copyright 2004 American Chemical Society
MeSH terms
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Administration, Oral
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Animals
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Biological Availability
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Blood-Brain Barrier / metabolism*
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Brain / metabolism
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Catalytic Domain
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Combinatorial Chemistry Techniques
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Dogs
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Humans
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In Vitro Techniques
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Mice
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Mice, Inbred C57BL
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Microsomes, Liver / metabolism
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Models, Molecular
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Parkinsonian Disorders / drug therapy
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Parkinsonian Disorders / pathology
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Poly(ADP-ribose) Polymerase Inhibitors*
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Poly(ADP-ribose) Polymerases / chemistry
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Quinazolines / chemical synthesis*
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Quinazolines / chemistry
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Quinazolines / pharmacokinetics
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Rats
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Structure-Activity Relationship
Substances
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Poly(ADP-ribose) Polymerase Inhibitors
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Quinazolines
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Poly(ADP-ribose) Polymerases