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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(More)
Two classes of quinazolinone derivatives and quinoxaline derivatives were identified as potent and selective poly(ADP-ribose) polymerase-1 and 2 (PARP-1) and (PARP-2) inhibitors, respectively. In PARP enzyme assays using recombinant PARP-1 and PARP-2, quinazolinone derivatives displayed relatively high selectivity for PARP-1 and quinoxaline derivatives(More)
As an extension of our study on discovering a novel substance P (SP) antagonist, we designed new branched tripeptides containing L-aspartic acid (2 and 5), L-ornithine (3 and 6), and L-lysine (4 and 7) by reconstructing the structure of the previously reported tripeptide SP antagonist [Ac-Thr-D-Trp(CHO)-Phe-NMeBzl (1), FR113680]. The strategy for this(More)
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(More)
We describe herein the synthesis and biological evaluation of a series of novel cephalosporins with potent activity against Pseudomonas aeruginosa. Introduction of various amino groups to the 4-position of a 3-amino-2-methylpyrazole cephalosporin 3-side chain resulted in enhanced MIC values against multiple Pseudomonas aeruginosa strains and ultimately led(More)
AmpC beta-lactamase is one of the leading causes of Pseudomonas aeruginosa (P. aeruginosa) resistance to cephalosporins. FR259647 is a cephalosporin having a novel pyrazolium substituent at the 3-position and exhibits excellent activity (MIC=1 microg/mL) against the AmpC beta-lactamase overproducing P. aeruginosa FP1380 strain in comparison with the(More)
To interpret differences in the anticholinergic activity among the four stereoisomers of 4-(dimethylamino)-2-phenyl-2-(2-pyridyl)pentanamide (1-4), we performed conformational studies using the semiempirical molecular orbital method. The structures of the global minimum-energy conformations obtained for 1-4, however, could not explain the different(More)
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