化学
亲脂性
取代基
吡唑
立体化学
氢键
分子模型
组合化学
分子
有机化学
作者
Iain Cumming,Sébastien L. Degorce,Anna Aagaard,Erin L Braybrooke,Nichola L. Davies,C. R. Diène,Andrew J. Eatherton,Hannah R Felstead,Sam D. Groombridge,Eva M. Lenz,Yunxia Li,Youfeng Nai,Stuart E. Pearson,Graeme R. Robb,James S. Scott,Oliver Steward,Chengyan Wu,Yafeng Xue,Lanping Zhang,Yanxiu Zhang
标识
DOI:10.1016/j.bmc.2022.116729
摘要
In this article, we report the discovery of a series of pyrimidopyridones as inhibitors of IRAK4 kinase. From a previously disclosed 5-azaquinazoline series, we found that switching the pyridine ring for an N-substituted pyridone gave a novel hinge binding scaffold which retained potency against IRAK4. Importantly, introduction of the carbonyl established an internal hydrogen bond with the 4-NH, establishing a conformational lock and allowing truncation of the large basic substituent to a 1-methylcyclopyl group. Subsequent optimisation, facilitated by X-ray crystal structures, allowed identification of preferred substituents at both the pyridone core and pyrazole. Subsequent combinations of optimal groups allowed control of lipophilicity and identification of potent and selective inhibitors of IRAK4 with better in vitro permeability and lower clearance.
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