Discovery of Easily Synthesizable 4, 4-Dimethylimidazolidin-2-ones as Potent Androgen Receptor Antagonists for Prostate Cancer

Androgen deprivation therapy (ADT), also known as suppression of androgen activity, is a first-line treatment option for patients with prostate cancer (PC). ADT became ineffective after several years of treatment due to the development of castration-resistant prostate cancer (CRPC), which resulted in more deaths in PC patients, but it is still androgen receptor (AR) dependent. Under these conditions, the U.S. Food and Drug Administration (FDA) approved enzalutamide for the treatment of patients with metastatic CRPC (mCRPC) and, more recently, nonmetastatic CRPC (nmCRPC). Despite the fact that this drug has extended overall and progression-free survival in a wide range of CRPC patients, more research is needed to better understand the mechanisms of resistance challenges and analogues chemical lead structures as next generation AR antagonists. In this regard, we discovered simple and easily synthesizable new pharmacophore, 4,4-dimethylimidazolidin-2-one, based derivatives MDV1-MDV8 for potent AR antagonists; here, the thiohydantoin pharmacophore in enzalutamide is replaced by 4,4-dimethylimidazolidin-2-one. The antiproliferative activities of these molecules have been assessed against androgen dependent PC cell line (LNCaP). The structure-activity relationship of these molecules, as well as their relationship with enzalutamide, is investigated. Among the reported molecules, MDV4 showed significantly improved in vitro activity with the IC50 value of 780.85 nM.

Automated summary

Androgen deprivation therapy is a first-line treatment option for prostate cancer patients, but may lead to the development of castration-resistant prostate cancer. Enzalutamide has been approved by the US FDA for the treatment of CRPC, and more recently for nmCRPC. Research has discovered new pharmacophore structures as potential next generation AR antagonists.