5-Phenyl-1,3,4-oxadiazol-2(3H)-ones Are Potent Inhibitors of Notum Carboxylesterase Activity Identified by the Optimization of a Crystallographic Fragment Screening Hit,Journal of Medicinal Chemistry

当前位置： X-MOL 学术 › J. Med. Chem. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

5-Phenyl-1,3,4-oxadiazol-2(3H)-ones Are Potent Inhibitors of Notum Carboxylesterase Activity Identified by the Optimization of a Crystallographic Fragment Screening Hit
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-10-30 , DOI: 10.1021/acs.jmedchem.0c01391
William Mahy ₁ , Nicky J Willis ₁ , Yuguang Zhao ₂ , Hannah L Woodward ₁ , Fredrik Svensson _{1,

3} , James Sipthorp _{1,

3} , Luca Vecchia ₂ , Reinis R Ruza ₂ , James Hillier ₂ , Svend Kjær ₃ , Sarah Frew ₁ , Amy Monaghan ₁ , Magda Bictash ₁ , Patricia C Salinas ₄ , Paul Whiting ₁ , Jean-Paul Vincent ₃ , E Yvonne Jones ₂ , Paul V Fish _{1,

3}

Affiliation

Carboxylesterase Notum is a negative regulator of the Wnt signaling pathway. There is an emerging understanding of the role Notum plays in disease, supporting the need to discover new small-molecule inhibitors. A crystallographic X-ray fragment screen was performed, which identified fragment hit 1,2,3-triazole 7 as an attractive starting point for a structure-based drug design hit-to-lead program. Optimization of 7 identified oxadiazol-2-one 23dd as a preferred example with properties consistent with drug-like chemical space. Screening 23dd in a cell-based TCF/LEF reporter gene assay restored the activation of Wnt signaling in the presence of Notum. Mouse pharmacokinetic studies with oral administration of 23dd demonstrated good plasma exposure and partial blood–brain barrier penetration. Significant progress was made in developing fragment hit 7 into lead 23dd (>600-fold increase in activity), making it suitable as a new chemical tool for exploring the role of Notum-mediated regulation of Wnt signaling.

中文翻译：

通过优化晶体片段筛选命中鉴定出 5-苯基-1,3,4-恶二唑-2(3H)-酮是 Notum 羧酸酯酶活性的有效抑制剂

羧酸酯酶 Notum 是 Wnt 信号通路的负调节因子。人们对 Notum 在疾病中的作用有了新的认识，支持发现新的小分子抑制剂的需要。进行了晶体学 X 射线片段筛选，确定片段命中 1,2,3-三唑7作为基于结构的药物设计命中到先导程序的有吸引力的起点。 7的优化确定了oxadiazol-2-one 23dd作为优选示例，其特性与类药物化学空间一致。在基于细胞的 TCF/LEF 报告基因测定中筛选23dd，在 Notum 存在的情况下恢复了 Wnt 信号传导的激活。口服23dd的小鼠药代动力学研究表明，具有良好的血浆暴露和部分血脑屏障渗透性。在将片段 hit 7开发为先导23dd方面取得了重大进展（活性增加了 600 倍以上），使其适合作为探索 Notum 介导的 Wnt 信号传导调节作用的新化学工具。

更新日期：2020-11-12

点击分享查看原文

点击收藏

阅读更多本刊新发论文本刊介绍/投稿指南