Erica Benedetti; Laurent Micouin
Expert Opin. Drug Discov., 2024
https://doi.org/10.1080/17460441.2024.2305735

Abstract

Spirocycles are structures in which two or more rings are linked by one common atom. Although the use of such scaffolds has been known for more than 60 years in medicinal chemistry, the increasing interest in compounds with enhanced three-dimensionality and higher proportion of sp3-hybridized atoms has led to a growing number of examples of potential drug candidates incorporating spirocyclic elements [Citation1,Citation2]. Shifting from planar, aromatic structures to compounds with a higher fraction of saturated carbon (Fsp3) generally correlates with improved physicochemical properties as well as pharmacokinetic (PK) profiles. The modulation of these properties has been nicely illustrated by works on azaspirocycles, showing higher solubility, higher basicity, decreased liphophilicity and better metabolic stability than their six-membered ring piperazine, piperidines, morpholines or thiomorpholines counterparts [Citation3]. A similar trend can be observed with spirocyclic oxetanes [Citation4]. Furthermore, the rigidity of the spirocyclic system can lock the conformation of the molecule and optimize the orientation of binding elements in a controlled manner, leading to an improved efficacy and/or selectivity profile.
In this editorial, we discuss how the advantages of using a spirocyclic scaffold have been exploited in drug design, with a focus on recent examples reported in this field.