Research, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
Research, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
Bioorg Med Chem. 2023 Oct 1;93:117462. doi: 10.1016/j.bmc.2023.117462. Epub 2023 Aug 29.
Enteropeptidase is located in the duodenum that involved in intestinal protein digestion. We have reported enteropeptidase inhibitors with low systemic exposure. The aim of this study was to discover novel enteropeptidase inhibitors showing more potent in vivo efficacy while retaining low systemic exposure. Inhibitory mechanism-based drug design led us to cyclize ester 2 to medium-sized lactones, showing potent enteropeptidase inhibitory activity and improving the ester stability, thus increasing fecal protein output in vivo. Optimization on the linker between two benzene rings resulted in discovery of ether lactone 6b, exhibiting further enhanced enteropeptidase inhibitory activity and long duration of inhibitory state. Oral administration of 6b in mice significantly elevated fecal protein output compared with the lead 2. In addition, 6b showed low systemic exposure along with low intestinal absorption. Furthermore, we identified the 10-membered lactonization method for scale-up synthesis of 6b, which does not require high-dilution conditions.
肠肽酶位于参与肠道蛋白质消化的十二指肠中。我们已经报道了具有低全身暴露的肠肽酶抑制剂。本研究的目的是发现新型肠肽酶抑制剂，在保留低全身暴露的同时，表现出更强的体内疗效。基于抑制机制的药物设计使我们将酯 2 环化成中等大小的内酯，表现出强大的肠肽酶抑制活性，并提高酯的稳定性，从而增加体内粪便蛋白的输出。对两个苯环之间的连接子进行优化，发现了醚内酯 6b，表现出进一步增强的肠肽酶抑制活性和更长的抑制状态持续时间。在小鼠中口服给予 6b 可显著增加粪便蛋白的排出量，与先导化合物 2 相比。此外，6b 表现出低的全身暴露和低的肠道吸收。此外，我们确定了 10 元环化方法，用于 6b 的规模化合成，该方法不需要高稀释条件。
