期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 62, 期 21, 页码 9918-9930出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.9b01346
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In this article, we report the discovery of a series of S-azaquinazolines as selective IRAK4 inhibitors. From modestly potent quinazoline 4, we introduced a S-aza substitution to mask the 4-NH hydrogen bond donor (HBD). This allowed us to substitute the core with a 2-aminopyrazole, which showed large gains in cellular potency despite the additional formal HBD. Further optimization led to 6-cyanomethyl-5-azaquinazoline 13, a selective IRAK4 inhibitor, which proved efficacious in combination with ibrutinib, while showing very little activity as a single agent up to 100 mg/kg. This contrasted to previously reported IRAK4 inhibitors that exhibited efficacy in the same model as single agents and was attributed to the enhanced specificity of 13 toward IRAK4.
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