Anti‐Tumor Effects and Pharmacokinetics of S‐40542, a Novel Non‐Steroidal Anti‐Androgen,in Mice

Objectives: The current study was undertaken to explore novel anti‐androgens. We investigated a series of tetrahydroquinoline compounds and identified 1‐(8‐nitro‐3a,4,5,9b‐tetrahydro‐3H‐cyclopentac]quinolin‐4‐yl)ethane‐1,2‐diol (S‐40542). Methods: Affinity for androgen receptor of S‐40542 was evaluated in receptor binding assay. Effects of repeated treatment with S‐40542 and bicalutamide on prostate weight were examined in mice subcutaneously treated for 14days. Efficacy of S‐40542 and bicalutamide against prostate cancer was evaluated in an androgen‐dependent prostate cancer xenograft model using KUCaP‐2 cell line. Plasma concentrations of these agents in mice after oral and subcutaneous administration were measured by liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) system. Results: S‐40542 displayed twofold higher affinity to androgen receptor than bicalutamide in vitro. Subcutaneous repeated administration of S‐40542 (10–100 mg/kg) significantly reduced the prostate weight. Oral repeated treatment with S‐40542 (30, 100 mg/kg) for 28 days significantly suppressed growth of KUCaP‐2 tumor. Similar administration of bicalutamide also exerted significantly anti‐tumor effect in the model. The serum prostate‐specific antigen level was little influenced by the S‐40542 treatment, while significantly decreased by bicalutamide. Oral treatment with S‐40542 resulted in a dose‐dependent elevation of the plasma concentration, and its C_max and AUC were much lower than those of bicalutamide. The pharmacokinetic study showed that this agent had relatively short plasma half‐life and low oral bioavailability. Conclusion: S‐40542 as well as bicalutamide has shown as an anti‐androgen by reducing the prostate weight of mice. Repeated oral treatment with S‐40542 was shown to significantly suppress tumor growth in the KUCaP‐2 xenograft model.