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

Abstract

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-2one, 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 IC 50 value of 780.85 nM.

Electronic effect‐dependent intramolecular non‐covalent interactions on the activity of 4,4‐dimethylimidazolidin‐2‐one pharmacophore‐based androgen receptor antagonists

“…The cyclic urea derivative ( 3 ) was synthesized by the route described in our earlier report (Yaragani et al, 2021). It then reacted with various benzyl bromides as shown in Schemes 1 and 2.…”

“…Small alterations in already well-established drug molecules are a preferable alternative for developing novel molecules for the treatment of patients with various CRPC than the molecules with totally diverse structural features. In this regard, we have developed AR antagonists based on the pharmacophore of 4,4-dimethylimidazolidin-2-one, which is a modified version of the enzalutamide pharmacophore thiohydantoin; the modifications are the removal of carbonyl group and the transformation of sulfinyl into a carbonyl group (Yaragani et al, 2021). The purpose of this modification is to reduce the steric hindrance of pharmacophore due to the presence of carbonyl and dimethyl groups in the adjacent locations, as shown in Figure 2 (Enzalutamide).…”