Discovery of potent and orally bioavailable 17β-hydroxysteroid dehydrogenase type 3 inhibitors.

We have previously reported the discovery of a new class of potent inhibitors of 17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3) derived from benzylidene oxazolidinedione and thiazolidinedione scaffolds. In this study, these analogs were designed, synthesized, and evaluated in a human cell-based assay. The detailed structure-activity relationship (SAR) surrounding this pharmacophore were developed, and consequently a number of compounds from this series demonstrated single-digit nanomolar 17β-HDS3 inhibitory activity in vitro. Subsequent optimization work in pursuit of the improvement of oral bioavailability demonstrated in vivo proof-of-concept by prodrug strategy based on phosphate esters for these 17β-HSD3 inhibitors. When a phosphate ester 16 was administered orally at a high dose of 100mg/kg, 16 showed approximately two times more potent testosterone (T)-lowering effect against a positive control in the luteinizing hormone-releasing hormone (LH-RH)-induced T production assay. The T-lowering effect continued at ca 10% level of control over 4h after administration. The nonsteroidal molecules based on this series have the potential to provide unique and effective clinical opportunities for treatment of prostate cancer.