Rational design of conformationally restricted quinazolinone inhibitors of poly(ADP-ribose)polymerase

Rational design of conformationally restricted quinazolinone inhibitors of poly(ADP-ribose)polymerase

A successful design of conformationally restricted novel quinazolinone derivatives linked via a cyclopentene moiety as potent poly(ADP-ribose)polymerase-1 (PARP-1) inhibitors has been developed. One selected member of the new series, 8-chloro-2-[(3 S)-3-(4-phenylpiperidin-1-yl)cyclopent-1-en-1-yl]qu...

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Veröffentlicht in:Bioorganic & medicinal chemistry letters 2007-10, Vol.17 (20), p.5577-5581
Hauptverfasser: Hattori, Kouji, Kido, Yoshiyuki, Yamamoto, Hirofumi, Ishida, Junya, Iwashita, Akinori, Mihara, Kayoko
Format: Artikel
Sprache:eng
Schlagworte:
Analytical, structural and metabolic biochemistry
Animals
Biological and medical sciences
Cattle
Conformationally restricted
Cross-Linking Reagents - chemistry
Drug Design
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacokinetics
Enzyme Inhibitors - pharmacology
Enzymes and enzyme inhibitors
Fundamental and applied biological sciences. Psychology
Medical sciences
Microsomes, Liver - drug effects
Microsomes, Liver - metabolism
Miscellaneous
Molecular Conformation
Molecular Structure
Pharmacology. Drug treatments
Poly(ADP-ribose) Polymerase Inhibitors
Poly(ADP-ribose) Polymerases - chemistry
Poly(ADP-ribose) Polymerases - metabolism
Poly(ADP-ribose)polymerase PARP-1
Quinazolinone
Quinazolinones - chemical synthesis
Quinazolinones - chemistry
Quinazolinones - pharmacokinetics
Quinazolinones - pharmacology
SBDD
Structure-Activity Relationship
Transferases
X-ray
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Zusammenfassung:A successful design of conformationally restricted novel quinazolinone derivatives linked via a cyclopentene moiety as potent poly(ADP-ribose)polymerase-1 (PARP-1) inhibitors has been developed. One selected member of the new series, 8-chloro-2-[(3 S)-3-(4-phenylpiperidin-1-yl)cyclopent-1-en-1-yl]quinazolin-4(3H)-one ( S- 16d), was found to be highly potent with IC 50 = 8.7 nM and good brain penetration.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2007.07.091