| Autor: |
Degorce, Sébastien L., Anjum, Rana, Bloecher, Andrew, Carbajo, Rodrigo J., Dillman, Keith S., Drew, Lisa, Halsall, Christopher T., Lenz, Eva M., Lindsay, Nicola A., Mayo, Michele F., Pink, Jennifer H., Robb, Graeme R., Rosen, Alan, Scott, James S., Xue, Yafeng |
| Zdroj: |
Journal of Medicinal Chemistry; November 2019, Vol. 62 Issue: 21 p9918-9930, 13p |
| Abstrakt: |
In this article, we report the discovery of a series of 5-azaquinazolines as selective IRAK4 inhibitors. From modestly potent quinazoline 4, we introduced a 5-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 13toward IRAK4. |
| Databáze: |
Supplemental Index |
| Externí odkaz: |
|
