二肽基肽酶9（Dipeptidyl peptidase 9，简称DPP9）是一种选择丙氨酸的丝氨酸蛋白酶，在NLRP1和CARD8介导的炎性细胞死亡（火焰细胞死亡）中发挥关键作用。迄今为止，尚未报道过该酶的选择性抑制剂：所有已发表的分子均对DPP8和DPP9具有非常相似的活性位点结构，因此它们与DPP8和DPP9之间的亲和力极其相似。选择性的DPP9抑制剂对于解决关于该酶在火焰细胞死亡中的作用尚未解答的研究问题非常有帮助，同时还可以作为急性髓系白血病的治疗药物进行研究。本文介绍的化合物（42和47）结合了纳摩尔级别的DPP9亲和力和DPP9与DPP8选择性指数高达175，对于其他丙氨酸选择性蛋白酶的选择性指数也超过了1000。为了对实验得到的数据进行合理解释，我们进行了分子动力学研究。我们还提供了化合物42的体内药代动力学数据。

Dipeptidyl peptidase 9 (DPP9) is a proline-selective serine protease that plays a key role in NLRP1- and CARD8-mediated inflammatory cell death (pyroptosis). No selective inhibitors have hitherto been reported for the enzyme: all published molecules have grossly comparable affinities for DPP8 and 9 because of the highly similar architecture of these enzymes' active sites. Selective DPP9 inhibitors would be highly instrumental to address unanswered research questions on the enzyme's role in pyroptosis, and they could also be investigated as therapeutics for acute myeloid leukemias. Compounds presented in this manuscript (42 and 47) combine low nanomolar DPP9 affinities with unprecedented DPP9-to-DPP8 selectivity indices up to 175 and selectivity indices >1000 toward all other proline-selective proteases. To rationalize experimentally obtained data, a molecular dynamics study was performed. We also provide in vivo pharmacokinetics data for compound 42.