2.2 Amide-to-ester substitutions improve membrane permeability over a broad ALogP range In addition to lipophilicity, the number of HBDs in compounds is a crucial determinant of permeability. Reducing the presence of solvent-exposed HBDs through N-methylation or occlusion from solvent by β-branching or other steric shielding are some of the strategies used to increase a compound's membrane permeability. In a previous study, we demonstrated that substituting the tert-Leu amide of the VH032 ligand with an ester improved compound permeability by about 2-fold. We hypothesize that the relatively modest increase in permeability resulting from this amide-to-ester substitution was likely due to the partial shielding of the -NH from solvent by the adjacent β-branched α-carbon, limiting the permeability reducing effects of this HBD. Additionally, substituting this amide (between the VH032 ligand and the linker) for an ester reduced its binding affinity towards the VHL protein. Therefore, we created a new set of compounds with an amide-to-ester substitution at the other end of the linker (adjacent to where a POI ligand would be attached) in an effort to achieve a more significant increase in permeability while maintaining binding to the VHL E3 ligase.