Investigation of a Bicyclo[1.1.1]pentane as a Phenyl Replacement within an LpPLA2 Inhibitor
Investigation of a Bicyclo[1.1.1]pentane as a Phenyl Replacement within an LpPLA2 Inhibitor
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DOI：
10.1021/acsmedchemlett.6b00281
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发表时间：
2017-01-01
影响因子：
4.2
通讯作者：
Somers, Don O.
中科院分区：
文献类型：
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作者：
Measom, Nicholas D.;Down, Kenneth D.;Somers, Don O.
我们描述了在两个已知的LpPLA(2)抑制剂中加入一个双环[1.1.1]戊烷部分作为生物等位异构苯基替代品。通过将二氯卡宾插入到双环[1.1.0]丁烷体系中，实现了目标化合物的有效合成。获得了效价、物理化学和X射线结晶学数据，将已知的缓蚀剂与其生物等构体相对应的缓蚀剂进行了比较，结果表明同功酶具有良好的耐受性，并对物理化学图谱产生了积极的影响。
We describe the incorporation of a bicyclo[1.1.1]pentane moiety within two known LpPLA(2) inhibitors to act as bioisosteric phenyl replacements. An efficient synthesis to the target compounds was enabled with a dichlorocarbene insertion into a bicyclo[1.1.0]butane system being the key transformation. Potency, physicochemical, and X-ray crystallographic data were obtained to compare the known inhibitors to their bioisosteric counterparts, which showed the isostere was well tolerated and positively impacted on the physicochemical profile.