Prostate cancer is a leading cause of cancer death in males worldwide. All stages of prostate cancer have been shown to depend on the androgen receptor (AR), which affects prostate cancer by multiple signaling pathways. Second generation anti-androgens such as enzalutamide are commonly used to combat advanced prostate cancer, but they usually fail to prevent progression to terminal disease due to drug resistance. Furthermore, anti-androgens are often associated with neurotoxicity. Consequently, there exists an urgent clinical need for novel anti-androgens with improved safety profiles that can overcome drug resistance.<br/>In a medicinal chemistry campaign to develop a new generation of anti-androgens, we used a known AR antagonist, BMS-641988 as the starting point for rational design. Structure-activity relationship (SAR) studies at C5-position of the oxabicyclic ring were carried out to explore substituents with different properties. <i>In vitro,</i> our compounds antagonized AR in luciferase assays. Additionally, our preclinical leads inhibited the growth of LNCaP prostate cancer cells expressing T877A mutant AR, contrary to BMS-641988. Computational models and microsomal metabolism studies were used to evaluate the safety profiles of our compounds. Our lead compounds were predicted to have low blood-brain barrier permeability and were not metabolized to the toxic metabolite BMS-501949.<br/>In conclusion, we identified efficacious and safe lead compounds that are suitable for further preclinical development as the next generation of prostate cancer treatment.

Design, synthesis and evaluation of antagonists of human androgen receptor

ACS Fall 2020 Virtual Meeting

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