Synthetic oxetanes in drug discovery: where are we in 2025?
File(s)
Author(s)
Ishikura, Hikaru
Bull, James
Type
Journal Article
Abstract
Introduction
Oxetanes are increasingly prevalent motifs in medicinal chemistry. While oxetanes feature famously in the taxol family, it was not until the recent approval of rilzabrutinib that they have been validated in a fully synthetic drug. These four-membered oxygen-containing rings are valued for their ability to modulate key physicochemical properties such as polarity, lipophilicity, and metabolic stability. Their incorporation can improve aqueous solubility, reduce metabolic liability, reduce basicity of adjacent amines, and redirect metabolic clearance away from cytochrome P450 enzymes.
Areas covered
This review examines the role of the oxetane in nine clinical candidates, one very recently approved, two recently discontinued clinical candidates, two tool compounds, and three lead compounds disclosed in 2024. Recent advances indexed in SciFinder-n (2017–2024) in the process-scale and laboratory-scale synthetic routes are discussed, highlighting ongoing innovation required to access these motifs efficiently and sustainably.
Expert opinion
The regulatory approval of rilzabrutinib and likely approval of ziresovir provide confidence in using oxetanes as important elements in drug design. While oxetanes have so far been incorporated primarily as pendant groups to optimize physicochemical properties, their use as scaffolding and binding elements presents an exciting opportunity. Enhanced synthetic accessibility to oxetane derivatives will expedite their inclusion in drug discovery campaigns.
Oxetanes are increasingly prevalent motifs in medicinal chemistry. While oxetanes feature famously in the taxol family, it was not until the recent approval of rilzabrutinib that they have been validated in a fully synthetic drug. These four-membered oxygen-containing rings are valued for their ability to modulate key physicochemical properties such as polarity, lipophilicity, and metabolic stability. Their incorporation can improve aqueous solubility, reduce metabolic liability, reduce basicity of adjacent amines, and redirect metabolic clearance away from cytochrome P450 enzymes.
Areas covered
This review examines the role of the oxetane in nine clinical candidates, one very recently approved, two recently discontinued clinical candidates, two tool compounds, and three lead compounds disclosed in 2024. Recent advances indexed in SciFinder-n (2017–2024) in the process-scale and laboratory-scale synthetic routes are discussed, highlighting ongoing innovation required to access these motifs efficiently and sustainably.
Expert opinion
The regulatory approval of rilzabrutinib and likely approval of ziresovir provide confidence in using oxetanes as important elements in drug design. While oxetanes have so far been incorporated primarily as pendant groups to optimize physicochemical properties, their use as scaffolding and binding elements presents an exciting opportunity. Enhanced synthetic accessibility to oxetane derivatives will expedite their inclusion in drug discovery campaigns.
Date Issued
2025-12-01
Date Acceptance
2025-11-20
Citation
Expert Opinion on Drug Discovery, 2025, 20 (12), pp.1621-1638
ISSN
1746-0441
Publisher
Taylor and Francis Group
Start Page
1621
End Page
1638
Journal / Book Title
Expert Opinion on Drug Discovery
Volume
20
Issue
12
Copyright Statement
© 2025 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent
License URL
Publication Status
Published
Date Publish Online
2025-12-01