Biological properties of androgen receptor pure antagonist for treatment of castration‐resistant prostate cancer: Optimization from lead compound to CH5137291

Abstract

The molecular mechanism of the CH compounds, inhibition of AR translocation, was different from bicalutamide and this action could contribute to AR pure antagonist activity. Agonist metabolite diminished the antitumor activity of AR pure antagonist. CH5137291 exhibited antitumor activity in LNCaP-BC2 and VCaP-CRPC xenograft models, suggesting that the compound has potential for the treatment of CRPC.

Steroid derivatives as pure antagonists of the androgen receptor

“…Since there is always the risk than a compound having pure antiandrogenic activity in vitro be transformed into agonistic metabolites in vivo [61], an important characteristic of EM-5854 is that it shows potent and pure antiandrogenic activity in vivo on ventral prostate weight in the rat. As can be seen in Table 3, in orchidectomized immature male rats bearing DHT implants, daily oral administration of 0.1 mg/rat of EM-5854 reversed by 45 ± 2% (n = 16) the stimulatory effect of DHT on ventral prostate weight, while an approximately 5-time higher dose of FLU (0.5 mg/rat) was required to achieve comparable inhibition (48 ± 1%, n = 131) and a 53 ± 4% (n = 13) inhibition was obtained with daily 0.5 mg oral BICA.…”

“…Considering the well demonstrated clinical benefits and the important decrease in serum PSA which follow simple cessation of administration of the antiandrogen [18,22], the clinical benefits of new compounds used in CRPC patients need careful evaluation. Moreover, although some compounds have pure antagonistic activity in vitro in some assays, metabolism can generate agonistic compounds which compromise the usefulness of potentially pure antiandrogens [61]. It is clear, however, that a more potent blocker of AR having pure antagonistic activity is needed and is likely to play a major role in prostate cancer therapy at all stages of the disease.…”

New Approaches Targeting Androgen Receptor Signal Pathways for Treatment of Castration-Resistant Prostate Cancer

“…Other new AR LBD antagonists have also been described. For instance, similar to the above studies, a new series of thiohydantoin derivatives were generated for screening AR antagonistic activities and led to the identification of a metabolic stable compound, CH5137291 (Kawata et al, 2011;Yoshino et al, 2010). This compound also showed to repress AR nuclear translocation and AR mediated tumor growth in xenografts.…”

Recent Advances in Drug Design and Drug Discovery for Androgen- Dependent Diseases

“…The epileptic seizures exhibited in the in vivo experiments could be explained by the high concentrations of these non-steroidal antagonists in the brain [120-121]. Compound 67 has also been identified as an antiandrogen since it demonstrated antitumor activity in LNCaP-BC2 and VCaP-CRPC xenograft models, thus suggesting that 67 could be a suitable candidate for CRPC treatment [122]. …”