Toselli_2019_J.Med.Chem_62_7383

Reference

Title : Hip To Be Square: Oxetanes as Design Elements To Alter Metabolic Pathways - Toselli_2019_J.Med.Chem_62_7383
Author(s) : Toselli F , Fredenwall M , Svensson P , Li XQ , Johansson A , Weidolf L , Hayes MA
Ref : Journal of Medicinal Chemistry , 62 :7383 , 2019
Abstract : Oxetane-containing ring systems are increasingly used in medicinal chemistry programs to modulate druglike properties. We have shown previously that oxetanes are hydrolyzed to diols by human microsomal epoxide hydrolase (mEH). Mapping the enzymes that 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 modifications. 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 pharmacokinetic predictions of its substrates.
ESTHER : Toselli_2019_J.Med.Chem_62_7383
PubMedSearch : Toselli_2019_J.Med.Chem_62_7383
PubMedID: 31310524

Related information

Citations formats

Toselli F, Fredenwall M, Svensson P, Li XQ, Johansson A, Weidolf L, Hayes MA (2019)
Hip To Be Square: Oxetanes as Design Elements To Alter Metabolic Pathways
Journal of Medicinal Chemistry 62 :7383

Toselli F, Fredenwall M, Svensson P, Li XQ, Johansson A, Weidolf L, Hayes MA (2019)
Journal of Medicinal Chemistry 62 :7383