Metabolism-Guided Selective Androgen Receptor Antagonists: Design, Synthesis, and Biological Evaluation for Activity against Enzalutamide-Resistant Prostate Cancer

A major challenge for new drug discovery in the area
of androgen
receptor (AR) antagonists lies in predicting the druggable properties
that will enable small molecules to retain their potency and stability
during further studies in vitro and in vivo. Indole (compound 8) is a first-in-class AR antagonist
with very high potency (IC50 = 0.085 μM) but is metabolically
unstable. During the metabolic studies described herein, we synthesized
new small molecules that exhibit significantly improved stability
while retaining potent antagonistic activity for an AR. This structure–activity
relationship (SAR) study of more than 50 compounds classified with
three classes (Class I, II, and III) and discovered two compounds (32c and 35i) that are potent AR antagonists
(e.g., IC50 = 0.021 μM, T1/2 = 120 min for compound 35i). The new antagonists exhibited
improved in vivo pharmacokinetics (PK) with high
efficacy antiandrogen activity in Hershberger and antiandrogen Enz-Res
tumor xenograft models that overexpress AR (LNCaP-AR).