期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 60, 期 24, 页码 10013-10025出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.7b00883
关键词
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资金
- European Community's Seventh Framework Programme under BioStruct-X [283570]
- Research Council of Norway
- Jane and Aatos Erkko Foundation
- Sigrid Juselius Foundation
- Biocenter Oulu and Academy of Finland [287063, 294085]
- Russian Ministry of Education and Science [14.N08.11.0056]
A structure-guided hybridization approach using two privileged substructures gave instant access to a new series of tankyrase inhibitors. The identified inhibitor 16 displays high target affinity on tankyrase 1 and 2 with biochemical and cellular IC50 values of 29 nM, 6.3 nM and 19 nM, respectively, and high selectivity toward other poly (ADP-ribose) polymerase enzymes. The identified inhibitor shows a favorable in vitro ADME profile as well as good oral bioavailability in mice, rats, and dogs. Critical for the approach was the utilization of an appropriate linker between 1,2,4-triazole and benzimidazolone moieties, whereby a cyclobutyl linker displayed superior affinity compared to a cyclohexane and phenyl linker.
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