期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 24, 期 11, 页码 2466-2475出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2016.04.008
关键词
PKC theta inhibitors; 1,7-Disubstituted-2,2-dimethyl-2,3-dihydroquinazolin-4(1H)-ones; Inhibition of IL-2 production
资金
- National Institutes of Health
- National Institute of General Medical Sciences
- U.S. Department of Energy [DE-AC02-05CH11231]
A high-throughput screening campaign helped us to identify an initial lead compound (1) as a protein kinase C-theta (PKC theta) inhibitor. Using the docking model of compound 1 bound to PKC theta as a model, structure-based drug design was employed and two regions were identified that could be explored for further optimization, i.e., (a) a hydrophilic region around Thr442, unique to PKC family, in the inner part of the hinge region, and (b) a lipophilic region at the forefront of the ethyl moiety. Optimization of the hinge binder led us to find 1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one as a potent and selective hinge binder, which resulted in the discovery of compound 5. Filling the lipophilic region with a suitable lipophilic sub-stituent boosted PKC theta inhibitory activity and led to the identification of compound 10. The co-crystal structure of compound 10 bound to PKC theta confirmed that both the hydrophilic and lipophilic regions were fully utilized. Further optimization of compound 10 led us to compound 14, which demonstrated an improved pharmacokinetic profile and inhibition of IL-2 production in a mouse. (C) 2016 Elsevier Ltd. All rights reserved.
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