Rational approaches to discovery of orally active and brain-penetrable quinazolinone inhibitors of poly(ADP-ribose)polymerase.
Hattori K,
Kido Y,
Yamamoto H,
Ishida J,
Kamijo K,
Murano K,
Ohkubo M,
Kinoshita T,
Iwashita A,
Mihara K,
Yamazaki S,
Matsuoka N,
Teramura Y,
Miyake H.
Medicinal Chemistry Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., 2-1-6 Kashima, Yodogawa-ku, Osaka 532-8514, Japan. kouji_hattori@ po.fujisawa.co.jp
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
PMID: 15293985 [PubMed - indexed for MEDLINE]