期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 56, 期 23, 页码 9556-9568出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm401394u
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资金
- Swedish Foundation for Strategic Research [RBc08-0014]
- Structural Genomics Consortium
- Swedish Foundation for Strategic Research (SSF) [RBc08-0014] Funding Source: Swedish Foundation for Strategic Research (SSF)
The racemic 3-(4-oxo-3,4-dihydroquinazolin-2-yl)-N-[1-(pyridin-2-yl)ethyl]propanamide, 1, has previously been identified as a potent but unselective inhibitor of diphtheria toxin-like ADP-ribosyltransferase 3 (ARTD3). Herein we describe synthesis and evaluation of SS compounds in this class. It was found that the stereochemistry is of great importance for both selectivity and potency and that substituents on the phenyl ring resulted in poor solubility. Certain variations at the meso position were tolerated and caused a large shift in the binding pose. Changes to the ethylene linker that connects the quinazolinone to the amide were also investigated but proved detrimental to binding. By combination of synthetic organic chemistry and structure-based design, two selective inhibitors of ARTD3 were discovered.
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