Azetidines in medicinal chemistry: emerging applications and approved drugs

Azetidines are four-membered nitrogen-containing heterocycles that have emerged as vital motifs in drug discovery and medicinal chemistry due to their unique physicochemical and pharmacokinetic profiles. Owing to their distinctive structural features such as high ring strain, sp3-rich character, and conformational rigidity, which confer enhanced pharmacokinetic properties, solubility, metabolic stability and make them highly attractive scaffolds for the design of bioactive molecules. Natural and synthetic azetidine derivatives demonstrate broad pharmacological potential, ranging from muscarinic antagonists and central nervous system (CNS) modulators to potent antibacterial and anticancer agents. Additionally, significant progress in green and stereoselective synthesis such as visible-light-mediated cycloadditions, strain-release methodologies, and biocatalytic routes have enhanced their accessibility and medicinal relevance. Synthetic derivatives like PF-3635659 (M3 antagonist) and azetidine-modified nicotine analogs highlight the scaffold’s utility in neurodegenerative and inflammatory disease therapeutics. Azetidine-based ligands also serve as efficient auxiliaries in asymmetric catalysis and late-stage drug functionalization. Specifically, several Food and Drug Administration (FDA)-approved drugs, such as baricitinib, cobimetinib, sarolaner, and azelnidipine, incorporate azetidine motifs to enhance metabolic stability, receptor selectivity, and pharmacokinetics. Recently, in vitro and in vivo evaluations have further highlighted their therapeutic promise across oncology, infectious diseases, and inflammation. With their growing impact on drug development and chemical biology, azetidines represent a dynamic frontier for next-generation pharmaceutical innovation and real-world therapeutic success.