Recent in vivo advances of spirocyclic scaffolds for drug discovery

Spirocyclic scaffolds are an exceptional tool in drug design, allowing fine-tuning of a molecule's conformational and physicochemical properties. As it expands and diversifies, so does the number of therapeutics that contain this core. Several spirocyclic drugs are already marketed, and considerably more have shown promising results.

This review addresses recent in vivo studies (2017-2021) on applying spirocyclic compounds to treat various diseases, mainly grouped within neurological, infectious, and metabolic diseases and cancer. An emphasis is given on the influence of the spiro-structure on activity and consequent structure-activity study. In vivo results and their significance in the future progression towards clinical trials are also presented.

Spirocyclic compounds present an exciting opportunity as an unexplored chemical space in medicinal chemistry. However, their development is hindered by their complexity and synthesis challenges. Furthermore, a clear preference is still seen for readily available spirocyclic compounds involving amine or amide bonds. Nevertheless, these are temporary as high-throughput synthesis, and computational techniques allow fast optimization studies. In our opinion, the field of spirocyclic chemistry will continue to thrive and contribute to drug development, improving activity and selectivity on emergent ailments, such as cancer, metabolic, infectious, and neurological diseases.