437998-41-9Relevant academic research and scientific papers
Discovery of potent and selective PARP-1 and PARP-2 inhibitors: SBDD analysis via a combination of X-ray structural study and homology modeling
Ishida, Junya,Yamamoto, Hirofumi,Kido, Yoshiyuki,Kamijo, Kazunori,Murano, Kenji,Miyake, Hiroshi,Ohkubo, Mitsuru,Kinoshita, Takayoshi,Warizaya, Masaichi,Iwashita, Akinori,Mihara, Kayoko,Matsuoka, Nobuya,Hattori, Kouji
, p. 1378 - 1390 (2007/10/03)
We disclose herein our efforts aimed at discovery of selective PARP-1 and PARP-2 inhibitors. We have recently discovered several novel classes of quinazolinones, quinazolidinones, and quinoxalines as potent PARP-1 inhibitors, which may represent attractive therapeutic candidates. In PARP enzyme assays using recombinant PARP-1 and PARP-2, the quinazolinone derivatives displayed relatively high selectivity for PARP-1 and quinoxaline derivatives showed superior selectivity for PARP-2, and the quinazolidinone derivatives did not have selectivity for PARP-1/2. Structure-based drug design analysis via a combination of X-ray structural study utilizing the complexes of inhibitors and human PARP-1 catalytic domain, and homology modeling using murine PARP-2 suggested distinct interactions of inhibitors with PARP-1 and PARP-2. These findings provide a new structural framework for the design of selective inhibitors for PARP-1 and PARP-2.
Rational approaches to discovery of orally active and brain-penetrable quinazolinone inhibitors of poly(ADP-ribose)polymerase
Hattori, Kouji,Kido, Yoshiyuki,Yamamoto, Hirofumi,Ishida, Junya,Kamijo, Kazunori,Murano, Kenji,Ohkubo, Mitsuru,Kinoshita, Takayoshi,Iwashita, Akinori,Mihara, Kayoko,Yamazaki, Syunji,Matsuoka, Nobuya,Teramura, Yoshinori,Miyake, Hiroshi
, p. 4151 - 4154 (2007/10/03)
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+.
