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Review
. 2023 Sep 28;66(18):12697-12709.
doi: 10.1021/acs.jmedchem.3c01101. Epub 2023 Sep 7.

Oxetanes in Drug Discovery Campaigns

Juan J Rojas  1 , James A Bull  1
Affiliations
Review

Oxetanes in Drug Discovery Campaigns

Juan J Rojas et al. J Med Chem. .

Abstract

The oxetane ring is an emergent, underexplored motif in drug discovery that shows attractive properties such as low molecular weight, high polarity, and marked three-dimensionality. Oxetanes have garnered further interest as isosteres of carbonyl groups and as molecular tools to fine-tune physicochemical properties of drug compounds such as pKa, LogD, aqueous solubility, and metabolic clearance. This perspective highlights recent applications of oxetane motifs in drug discovery campaigns (2017-2022), with emphasis on the effect of the oxetane on medicinally relevant properties and on the building blocks used to incorporate the oxetane ring. Based on this analysis, we provide an overview of the potential benefits of appending an oxetane to a drug compound, as well as potential pitfalls, challenges, and future directions.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
(a) Examples of bioactive four-membered heterocycles. (b) Appearance of four-membered heterocycles in the literature. (Left) Absolute number of publications. (Right) Normalized against the total number of publications recorded per year. Thietanes also include the sulfoxide and sulfone oxidation states. PrCP = prolylcarboxypeptidase.
Figure 2
Figure 2
(a) Taxol. (b) Oxetanes as potential isosteres of gem-dimethyl groups and carbonyl derivatives.
Figure 3
Figure 3
Substructure used for literature search.
Figure 4
Figure 4
Fully synthetic (nontaxane-related) drug candidates containing an oxetane scaffold and effect of introducing the oxetane ring (where information available).− (a) Crenolanib (no information on the discovery campaign), (b) fenebrutinib, (c) ziresovir, (d) lanraplenib, (e) danuglipron, (f) GDC-0349, and (g) PF-06821497 (9). Btk = Bruton’s tyrosine kinase; cAMP = cyclic adenosine monophosphate; Cl = clearance; Clint = intrinsic clearance; FLT3, fms like tyrosine kinase 3; HLM = human liver microsomes; HTS = high-throughput screening; PDGFRα, platelet-derived growth factor receptor α; and Y641N, mutant form of EZH2. a Therapeutic index (TI) = CC50/EC50. CC50 = concentration of compound that manifests cytotoxicity toward 50% of the uninfected HEp-2 cells.
Figure 5
Figure 5
Cocrystal structure of oxetane 9 with EZH2 (see Figure 4g). Available under PDB code 4W2R (2.8 Å) and illustrated using MOE software.
Figure 6
Figure 6
Selected examples of oxetanes in the patent literature (2017–2022). Cbl-b = Casitas B lymphoma-b; c-KIT, type III receptor tyrosine kinase; KHK = ketohexokinase; LRRK2, leucine rich repeat kinase 2; and PRMT5, protein arginine methyltransferase 5.
Figure 7
Figure 7
Oxetanes in drug discovery programs (2017–2022). (a) Selected examples in scientific articles. (b) Occurrence of the most popular oxetane building blocks used (from the refs in the Supporting Information). (c) Examples of recent methodologies developed for the synthesis of 3,3-disubstituted oxetanes., hWBu = human whole blood, unbound potency; IL-2, interleukin 2; and Pks13 = polyketide synthase 13.
See this image and copyright information in PMC

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