期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 58, 期 1, 页码 333-346出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm5013006
关键词
-
资金
- U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-06CH11357]
We previously demonstrated that selective inhibition of protein kinase C theta (PKC theta) with triazinone 1 resulted in dose-dependent reduction of paw swelling in a mouse model of arthritis.1,2 However, a high concentration was required for efficacy, thus providing only a minimal safety window. Herein we describe a strategy to deliver safer compounds based on the hypothesis that optimization of potency in concert with good oral pharmacokinetic (PK) properties would enable in vivo efficacy at reduced exposures, resulting in an improved safety window. Ultimately, transformation of 1 yielded analogues that demonstrated excellent potency and PK properties and fully inhibited IL-2 production in an acute model. In spite of good exposure, twice-a-day treatment with 17l in the glucose-6-phosphate isomerase chronic in vivo mouse model of arthritis yielded only moderate efficacy. On the basis of the exposure achieved, we conclude that PKC theta inhibition alone is insufficient for complete efficacy in this rodent arthritis model.
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