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Rational Approaches to Discovery of Orally Active and Brain-Penetrable Quinazolinone Inhibitors of Poly(ADP-ribose)polymerase

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journal contribution
posted on 12.08.2004, 00:00 by Kouji Hattori, Yoshiyuki Kido, Hirofumi Yamamoto, Junya Ishida, Kazunori Kamijo, Kenji Murano, Mitsuru Ohkubo, Takayoshi Kinoshita, Akinori Iwashita, Kayoko Mihara, Syunji Yamazaki, Nobuya Matsuoka, Yoshinori Teramura, Hiroshi Miyake
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+.

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