发现螺环仲胺衍生的叔脲作为高效、选择性和生物可利用的可溶性环氧化物水解酶抑制剂。
Discovery of spirocyclic secondary amine-derived tertiary ureas as highly potent, selective and bioavailable soluble epoxide hydrolase inhibitors.
作者信息
Shen Hong C, Ding Fa-Xiang, Wang Siyi, Xu Suoyu, Chen Hsuan-shen, Tong Xinchun, Tong Vincent, Mitra Kaushik, Kumar Sanjeev, Zhang Xiaoping, Chen Yuli, Zhou Gaochao, Pai Lee-Yuh, Alonso-Galicia Magdalena, Chen Xiaoli, Zhang Bei, Tata James R, Berger Joel P, Colletti Steven L
机构信息
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065-0900, USA.
出版信息
Bioorg Med Chem Lett. 2009 Jul 1;19(13):3398-404. doi: 10.1016/j.bmcl.2009.05.036. Epub 2009 May 18.
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.
螺环仲胺衍生的三取代脲被鉴定为高效、具有生物利用度且具有选择性的可溶性环氧化物水解酶（sEH）抑制剂。尽管在血液中具有良好的口服暴露和出色的体外靶点结合能力，但其中一种化合物rac-1a在自发性高血压大鼠（SHR）中未能急性降低血压。这项研究提出了一个问题，即sEH抑制是否提供了一种强大的机制，从而导致显著的降压效果。
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