Novel β- and γ‑Amino Acid-Derived Inhibitors of Prostate-Specific Membrane Antigen

Prostate-specific membrane antigen (PSMA) is an excellent biomarker
for the early diagnosis of prostate cancer progression and metastasis.
The most promising PSMA-targeted agents in the clinical phase are
based on the Lys–urea–Glu motif, in which Lys and Glu
are α-(l)-amino acids. In this study, we aimed to determine
the effect of β- and γ-amino acids in the S1 pocket on
the binding affinity for PSMA. We synthesized and evaluated the β-
and γ-amino acid analogues with (S)- or (R)-configuration with keeping α-(l)-Glu as
the S1′-binding pharmacophore. The structure–activity
relationship studies identified that compound 13c, a
β-amino acid analogue with (R)-configuration,
exhibited the most potent PSMA inhibitory activity with an IC50 value of 3.97 nM. The X-ray crystal structure of PSMA in
complex with 13c provided a mechanistic basis for the
stereochemical preference of PSMA, which can guide the development
of future PSMA inhibitors.