Discovery of spirocyclic secondary amine-derived tertiary ureas as highly potent, selective and bioavailable soluble epoxide hydrolase inhibitors
详细信息 查看全文
- 作者：Hong C. Shen ; Fa-Xiang Ding ; Siyi Wang ; Suoyu Xu ; Hsuan-shen Chen ; Xinchun Tong ; Vincent Tong ; Kaushik Mitra ; Sanjeev Kumar ; Xiaoping Zhang ; Yuli Chen ; Gaochao Zhou ; Lee-Yuh Pai ; Magdalena Alonso-Gali
- 关键词：Soluble epoxide hydrolase ; sEH ; Spirocyclic secondary amines ; Spontaneously hypertensive rats ; Tertiary ureas
- 刊名：Bioorganic and Medicinal Chemistry Letters
- 出版年：2009
- 出版时间：1 July 2009
- 年：2009
- 卷：19
- 期：13
- 页码：3398-3404
- 全文大小：788 K
文摘
Spirocyclic secondary amine-derived trisubstituted ureas were identified as highly potent, bioavailable and selective soluble epoxide hydrolase (sEH) inhibitors. Despite good oral exposure and excellent ex vivo target engagement in blood, one such compound, rac-1a, failed to lower blood pressure acutely in spontaneously hypertensive rats (SHRs). This study posed the question as to whether sEH inhibition provides a robust mechanism leading to a significant antihypertensive effect.