F. Toselli, Marléne Fredenwall, P. Svensson
Jul 16, 2019
Citations
1
Influential Citations
19
Citations
Journal
Journal of medicinal chemistry
Abstract
Oxetane-containing ring systems are increasingly used in medicinal chemistry programs to modulate drug-like properties. We have shown previously that oxetanes are hydrolyzed to diols by human microsomal epoxide hydrolase (mEH). Mapping the enzymes which contribute to drug metabolism is important, since an exaggerated dependence on one specific isoenzyme increases the risk of drug-drug interactions with co-administered drugs. Herein we illustrate that mEH-catalyzed hydrolysis is an important metabolic pathway for a set of more structurally diverse oxetanes and the degree of hydrolysis is modulated by minor structural modification. A homology model based on the Bombyx mori EH crystal structure was used to rationalize substrate binding. This study shows that oxetanes can be used as drug design elements for directing metabolic clearance via mEH, thus potentially decreasing the dependence on cytochromes P450. Metabolism by mEH should be assessed early in the design process to understand the complete metabolic fate of oxetane-containing compounds and further study is required to allow accurate PK prediction of its substrates.