Synthesis, in vitro and in vivo biological evaluation, and comprehensive understanding of structure-activity relationships of dipeptidyl boronic acid proteasome inhibitors constructed from β-amino acids.

An extensive structure-activity relationship (SAR) study of 72 dipeptidyl boronic acid proteasome inhibitors constructed from β-amino acids is reported. SAR analysis revealed that bicyclic groups at the R¹ position, 3-F substituents at the R² position, and bulky aliphatic groups at the R³ position were favorable to the activities. Enzymatic screening results showed that compound 78, comprising all of these features, was the most active inhibitor against the 20S human proteasome at less than a 2 nM level, as active as the marketed drug bortezomib. Cellular assays confirmed that compound 78 was the most potent against two hematologic and some solid tumor cells with IC₅₀ values less than 1 μM. Pharmacokinetic profiles suggested that 78 showed higher plasma exposure and a longer half-life than bortezomib.