Optimized Protein Kinase Cθ (PKCθ) Inhibitors Reveal Only Modest Anti-inflammatory Efficacy in a Rodent Model of Arthritis
Optimized Protein Kinase Cθ (PKCθ) Inhibitors Reveal Only Modest Anti-inflammatory Efficacy in a Rodent Model of Arthritis
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DOI：
10.1021/jm5013006
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发表时间：
2015-01-08
影响因子：
7.3
通讯作者：
Edmunds, Jeremy J.
中科院分区：
文献类型：
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作者：
George, Dawn M.;Breinlinger, Eric C.;Edmunds, Jeremy J.
我们之前证明，用三嗪酮 1 选择性抑制蛋白激酶 C theta (PKC theta) 可导致关节炎小鼠模型中爪子肿胀的剂量依赖性减少。1,2 然而，需要高浓度才能发挥功效，因此仅提供最小的安全窗。在此，我们描述了一种提供更安全化合物的策略，该策略基于以下假设：效力优化与良好的口服药代动力学（PK）特性相结合，可以在减少暴露的情况下实现体内功效，从而提高安全窗。最终，1 的转化产生了类似物，在急性模型中表现出优异的效力和 PK 特性，并完全抑制 IL-2 的产生。尽管暴露良好，但在葡萄糖-6-磷酸异构酶慢性体内关节炎小鼠模型中每天两次用17μl治疗仅产生中等疗效。根据所达到的暴露量，我们得出结论，仅 PKC theta 抑制不足以在此啮齿动物关节炎模型中发挥完全功效。
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.