Design and Synthesis of Diversely Substituted Azacyclic Inhibitors of Endothelin Converting Enzyme

A series of azacyclic phosphonic acids were synthesized from l-pyroglutamic acid, 6-oxo-l-pipecolic
acid, and their enantiomers. The objective was to study the effect of constraining acyclic inhibitors of
endothelin converting enzyme on inhibitory activity. Potential pharmacophoric tethers were introduced
by stereocontrolled reactions to give highly substituted pyrrolidine- and piperidine-α-phosphonic acids.
Weak inhibitory activity was observed for one diastereomer in each series having the same relative
orientation of substituents.

本研究以L-焦谷氨酸（L-pyroglutamic acid）、6-氧代-L-哌啶酸（6-oxo-L-pipecolic acid）及其对映异构体为起始原料，合成了一系列氮杂环膦酸类化合物。本研究的核心目标为考察对内皮素转化酶（endothelin converting enzyme）非环状抑制剂进行环状约束后，其抑制活性的变化情况。通过立体可控反应引入潜在药效团连接臂，得到了高度取代的吡咯烷-α-膦酸与哌啶-α-膦酸类化合物。两类化合物系列中各有一个具备相同取代基相对空间构型的非对映异构体，表现出较弱的抑制活性。