gem -Dimethylcarbinol: A tert -Butyl Bioisostere with Greatly Reduced Lipophilicity

Abstract The tert-butyl group is a large substituent that could be useful in some contexts for filling protein pockets, but this highly lipophilic group typically worsens the ADMET properties of the parent scaffold. Although many bioisosteres of tert-butyl are similarly lipophilic, gem-dimethylcarbinol could be a bioisostere with greatly reduced lipophilicity, bestowing balanced properties to a lead compound. This could benefit multi-parameter optimization that includes solubility, permeability, and in vitro clearance. Although one downside of installing the gem-dimethylcarbinol group is greater efflux, making it a poor motif for CNS applications, small structural modifications could mitigate this issue. The gem-dimethylcarbinol group is not chemically reactive under physiological conditions, is not a blacklisted toxicophore, and is present in a small but growing number of approved drugs. Furthermore, the simplicity of its installation in organic chemistry makes it an attractive option as a tert-butyl bioisostere with great opportunities in medicinal chemistry.