Optimized Protein Kinase Cθ (PKCθ) Inhibitors Reveal Only Modest Anti-inflammatory Efficacy in a Rodent Model of Arthritis

作者：Dawn M. George, Eric C. Breinlinger, M.A. Argiriadi, Yang Zhang, Jianfei Wang, Pratima Bansal‐Pakala, David B. Duignan, Prisca Honoré, Qingyu Lang, Scott W. Mittelstadt, Lian Rundell, Annette Schwartz, Jiakang Sun, Jeremy J. Edmunds · 发表于：Journal of Medicinal Chemistry · 年份：2014 · DOI：10.1021/jm5013006 · 被引用次数：32 · 研究领域：Protein Kinase Regulation and GTPase Signaling、Research on Leishmaniasis Studies、Signaling Pathways in Disease

We previously demonstrated that selective inhibition of protein kinase Cθ (PKCθ) 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 PKCθ inhibition alone is insufficient for complete efficacy in this rodent arthritis model.