The adamantane scaffold: Beyond a lipophilic moiety

Adamantyl-based compounds have been successful clinically for the treatment of neurological disorders and viral infections. Whilst the effects of incorporating adamantane into a drug scaffold is contextual by nature, its unique structural and physicochemical properties have attracted considerable attention. Previous reviews have highlighted its ability to alter physicochemical properties such as lipophilicity. However, with the movement to incorporate structural complexity and escape the 'flat land' of modern drug discovery, adamantane provides value beyond a hydrophobic substituent. The non-planar three-dimensional rigid scaffold allows for the precise positioning of substituents to probe drug targets more effectively. This review evaluates the synthetic accessibility and subsequent integration of multi-substituted and hetero-adamantane containing ligands in drug discovery programs. The vast benefits of adamantyl-based motifs beyond increasing the lipophilicity of a target compound are discussed thus emphasising its multi-dimensional value in drug discovery.