In this study, we designed new ligands to explore the chemical space of VHL. Particular attention was paid to the RHS phenylene part of prototypical VH298 analogs. Inspired by the computational insights into specific VHL-ligand interactions and driven by the obtained biodata, an iterative optimization of the ligand structures was realized. However, sole modifications of the substitution pattern at the phenylene unit did not provide a groundbreaking improvement, indicating only limited space for structural alterations at this site. Therefore, a combinatorial assembly was undertaken which included the LHS cyano-versus-fluoro replacement and the introduction of an (S)-configured methyl group at the benzylic position of the ligands. For the latter variation, a stereoselective synthetic entry to diversely substituted 1-phenylethan-1-amine building blocks was accomplished. The stepwise improvement related not only to the affinity of the ligands to VHL, as it was monitored by biophysical techniques, but also to their cellular activity as a measure of the compounds' ability to penetrate cells, stabilize the protein level of HIF-1α and induce HIF transcriptional activity.