Rational approaches to discovery of orally active and brain-penetrable quinazolinone inhibitors of poly(ADP-ribose)polymerase.
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+.
Hattori
Kouji
K
Medicinal Chemistry Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., 2-1-6 Kashima, Yodogawa-ku, Osaka 532-8514, Japan. kouji_hattori@ po.fujisawa.co.jp
Kido
Yoshiyuki
Y
Yamamoto
Hirofumi
H
Ishida
Junya
J
Kamijo
Kazunori
K
Murano
Kenji
K
Ohkubo
Mitsuru
M
Kinoshita
Takayoshi
T
Iwashita
Akinori
A
Mihara
Kayoko
K
Yamazaki
Syunji
S
Matsuoka
Nobuya
N
Teramura
Yoshinori
Y
Miyake
Hiroshi
H
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D020134:Catalytic Domain; D020650:Combinatorial Chemistry Techniques; D004285:Dogs; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D020734:Parkinsonian Disorders / Q000188:drug therapy / Q000473:pathology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000737:chemistry; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D013329:Structure-Activity Relationship
D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011799:Quinazolines; D011065:Poly(ADP-ribose) Polymerases