Oxane

Oxane (tetrahydropyran, THP) occupies a distinctive position in drug discovery. Oxane is a substructure of biologically abundant nutrients, including glucose and galactose, providing a classical framework for glycomimetics designed to inhibit proteins that recognise sugar moieties. The ring presents an endocyclic oxygen with lone pairs capable of hydrogen bond acceptance, a well-defined chair conformation that projects substituents at equatorial or axial positions with predictable spatial relationships, and a high degree of sp³ character that contributes to improved aqueous solubility and reduced promiscuity relative to aromatic ring systems. Unlike many planar heterocycles, oxane-containing compounds offer a non-aromatic, three-dimensional architecture that is well suited to occupying the binding pockets of transporters, enzymes, and receptor active sites that have evolved to accommodate carbohydrate substrates, and the multiple stereocentres accessible on the ring provide a wide range of diastereomeric building blocks for structure-activity relationship investigations. The scaffold also serves as a bioisostere for cyclohexane in cases where additional polarity is required to improve solubility or reduce hERG channel interaction, and the oxygen atom provides a useful synthetic handle through glycosylation and O-alkylation chemistry for attaching diverse pharmacophoric fragments.

Examples of oxane-containing compounds in the clinic include Canagliflozin (Invokana, Janssen), a first-in-class oral C-glucoside SGLT2 inhibitor built around a tetrahydropyranyl (oxane) glucoside core, approved in March 2013 as the first member of the SGLT2 inhibitor drug class for the treatment of type 2 diabetes mellitus, acting by inhibiting glucose reabsorption in the proximal renal tubules independently of insulin. Empagliflozin (Jardiance, Boehringer Ingelheim/Eli Lilly) is an FDA-approved selective SGLT2 inhibitor bearing the same oxane glucoside pharmacophore, which was the first in its class to demonstrate cardiovascular outcome benefits in the landmark EMPA-REG OUTCOME trial and has since received expanded FDA approvals for the reduction of cardiovascular death and hospitalisation for heart failure in adults with and without type 2 diabetes. Gentamicin (Garamycin, Schering), an FDA-approved broad-spectrum aminoglycoside antibiotic approved in 1964 for the treatment of serious gram-negative bacterial infections including those caused by Pseudomonas aeruginosa, is constructed from three rings: a central 2-deoxystreptamine core linked via glycosidic bonds to two aminosugar oxane rings, purpurosamine and garosamine, both of which are substituted tetrahydropyran units bearing multiple amine and hydroxyl substituents that are essential for productive binding to the 16S rRNA decoding site of the bacterial 30S ribosomal subunit, where they form direct contacts with key nucleotides to disrupt mRNA translation fidelity.

Our range of Oxanes features novel substitutions and the incorporation of synthetically tractable functional groups such as boronic acids and esters, amines, carboxylic acids, ketones, hydroxyls and halogens to enable expedient synthetic strategies. The full range can be found using the substructure feature of our Search tools.