Evaluating the Differences in Cycloalkyl Ether Metabolism Using the Design Parameter “Lipophilic Metabolism Efficiency” (LipMetE) and a Matched Molecular Pairs Analysis

We have observed previously that modification of ring size and substitution pattern may be used as a strategy to mitigate the metabolic instability of cycloalkyl ethers. In this article, we introduce a medicinal chemistry design parameter named "lipophilic metabolism efficiency" (LipMetE) that indicates that these changes in metabolic stability can be largely ascribed to changes in lipophilicity. Our matched molecular pair analysis also indicates that this finding is a general phenomenon, widely observed across different chemotypes. It is our hope that both the LipMetE design parameter and the results from our pairwise analysis will be useful tools for medicinal chemists.