Discovery and Characterization of Novel Piperidine Derivatives as Potent Cytochrome P450 17A1 Inhibitors for Prostate Cancer Therapy.

Castration-resistant prostate cancer relies on intratumoral androgen synthesis mediated by cytochrome P450 17A1 (CYP17A1). Treatment with the only clinically used CYP17A1 inhibitor, abiraterone, is limited by resistance and side effects, underscoring the urgent need for new CYP17A1 inhibitors with greater selectivity and improved safety profiles. In response to this challenge, we designed, synthesized, and biologically evaluated 30 novel piperidine derivatives. All compounds were initially screened in the H295R cell line to assess their inhibitory activity toward both CYP17A1 and off-target CYP21A2. Compounds were further evaluated in cell viability assays using prostate cancer cells and a normal prostate cell line. The most potent and selective compounds were subjected to further biological studies: IC50 determination, steroid profiling, cell migration assay, aldo-keto reductase family 1 member C3 inhibition assays, absorption, distribution, metabolism, and excretion prediction, and solubility testing. Several compounds emerged as the most active and selective leads, highlighting their potential for pharmaceutical development.