Oxolane

Oxolane (tetrahydrofuran, THF) has established itself as one of the most productive oxygen heterocycles in drug discovery, with 13 FDA-approved drugs in multiple therapeutic areas containing an Oxolane. Oxolanes present an endocyclic oxygen with two lone pairs well-positioned for hydrogen bond acceptance, a puckered envelope conformation that projects substituents into well-defined spatial orientations accessible to protein binding sites, and an sp³-rich character that improves aqueous solubility relative to aromatic bioisosteres. The ring also serves as a versatile scaffold for glycomimetics and peptidomimetics given its structural relationship to the furanose form of ribose and deoxyribose, and as a C- or N-linked pharmacophoric fragment in kinase inhibitors, protease inhibitors, and receptor antagonists, with multiple substitution positions accessible via stereoselective synthesis routes. Unlike planar aromatic rings, the non-planarity and moderate polarity of oxolane allow it to fill hydrophobic enzyme pockets while contributing polar interactions, a combination that structure-based drug design programmes have exploited extensively in antiviral, cardiovascular, and CNS campaigns.

Examples of tetrahydrofurans in the clinic include Afatinib (Gilotrif, Boehringer Ingelheim), an FDA-approved first-in-class irreversible pan-ErbB tyrosine kinase inhibitor bearing a (3S)-tetrahydrofuran-3-yloxy group confirmed in the FDA label IUPAC name as an ether substituent at the 7-position of the quinazoline core, approved in July 2013 for the first-line treatment of EGFR mutation-positive metastatic non-small cell lung cancer and the first approved agent to covalently and irreversibly inhibit the entire ErbB family including EGFR, HER2, and HER4, where the tetrahydrofuranyloxy group was introduced to improve aqueous solubility and optimise the pharmacokinetic profile of the scaffold relative to earlier EGFR inhibitors, and the acrylamide warhead forms an irreversible covalent bond with Cys797 of EGFR at the ATP-binding site to achieve sustained pathway suppression. Terazosin (Hytrin, Abbott) is an FDA-approved selective α₁-adrenoceptor antagonist bearing a tetrahydrofuroyl group attached via a piperazine linker to a dimethoxyquinazoline core, approved for the treatment of hypertension and benign prostatic hyperplasia, where it relaxes vascular and prostatic smooth muscle by blocking α₁-adrenoceptors.

Our range of Oxolanes 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.

Please examine a selection of Oxolanes in our catalogue. The full range can be found using the substructure feature of our Search tools.