Rational approaches to discovery of orally active and brain-penetrable quinazolinone inhibitors of poly(ADP-ribose)polymerase

J Med Chem. 2004 Aug 12;47(17):4151-4. doi: 10.1021/jm0499256.

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+.

MeSH terms

  • Administration, Oral
  • Animals
  • Biological Availability
  • Blood-Brain Barrier / metabolism*
  • Brain / metabolism
  • Catalytic Domain
  • Combinatorial Chemistry Techniques
  • Dogs
  • Humans
  • In Vitro Techniques
  • Mice
  • Mice, Inbred C57BL
  • Microsomes, Liver / metabolism
  • Models, Molecular
  • Parkinsonian Disorders / drug therapy
  • Parkinsonian Disorders / pathology
  • Poly(ADP-ribose) Polymerase Inhibitors*
  • Poly(ADP-ribose) Polymerases / chemistry
  • Quinazolines / chemical synthesis*
  • Quinazolines / chemistry
  • Quinazolines / pharmacokinetics
  • Rats
  • Structure-Activity Relationship

Substances

  • Poly(ADP-ribose) Polymerase Inhibitors
  • Quinazolines
  • Poly(ADP-ribose) Polymerases