The inflammatory caspases (caspase-1, -4 and -5) are potential therapeutic targets for autoimmune and inflammatory diseases due to their involvement in the immune response upon inflammasome formation. A series of small molecules based on the 4-(piperazin-1-yl)-2,6-di(pyrrolidin-1-yl)pyrimidine scaffold were synthesized with varying substituents on the piperazine ring. Several compounds were pan-selective inhibitors of the inflammatory caspases, caspase-1, -4 and -5, with the ethylbenzene derivative CK-1–41 displaying low nanomolar K _i values across this family of caspases. Three analogs were nearly 10 fold selective for caspase-5 over caspase-1 and -4. The compounds display non-competitive, time dependent inhibition profiles. To our knowledge, this series is the first example of small molecule inhibitors of all three inflammatory caspases.

中文翻译：

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4-（哌嗪-1-基）-2,6-二（吡咯烷-1-基）嘧啶骨架中哌嗪环上芳基取代基的变化揭示了强力，非竞争性炎性胱天蛋白酶的抑制剂

炎性胱天蛋白酶（caspase-1，-4和-5）是自身免疫和炎性疾病的潜在治疗靶标，因为它们参与了炎症小体形成时的免疫应答。合成了一系列基于4-（哌嗪-1-基）-2,6-二（吡咯烷-1-基）嘧啶骨架的小分子，在哌嗪环上具有不同的取代基。几种化合物是炎性胱天蛋白酶的半选择抑制剂，caspase-1，-4和-5，乙苯衍生物CK-1–41显示出低纳摩尔浓度的K _i这个胱天蛋白酶家族的价值观。三种类似物对caspase-5的选择性是caspase-1和-4的近10倍。这些化合物显示出非竞争性的，时间依赖性的抑制曲线。据我们所知，该系列是所有三种炎性胱天蛋白酶的小分子抑制剂的第一个实例。