A New Avenue toward Androgen Receptor Pan-antagonists: C2 Sterically Hindered Substitution of Hydroxy-propanamides

The androgen receptor (AR) represents the primary target for prostate cancer (PC) treatment even when the disease progresses toward androgen-independent (AIPC) or castration-resistant (CRPC) forms. Because small chemical changes in the structure of nonsteroidal AR ligands determine the pharmacologic...

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Veröffentlicht in:Journal of medicinal chemistry 2014-09, Vol.57 (17), p.7263-7279
Hauptverfasser: Guerrini, Andrea, Tesei, Anna, Ferroni, Claudia, Paganelli, Giulia, Zamagni, Alice, Carloni, Silvia, Di Donato, Marzia, Castoria, Gabriella, Leonetti, Carlo, Porru, Manuela, De Cesare, Michelandrea, Zaffaroni, Nadia, Beretta, Giovanni Luca, Del Rio, Alberto, Varchi, Greta
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Sprache:eng
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Zusammenfassung:The androgen receptor (AR) represents the primary target for prostate cancer (PC) treatment even when the disease progresses toward androgen-independent (AIPC) or castration-resistant (CRPC) forms. Because small chemical changes in the structure of nonsteroidal AR ligands determine the pharmacological responses of AR, we developed a novel stereoselective synthetic strategy that allows sterically hindered C2-substituted bicalutamide analogues to be obtained. Biological and theoretical evaluations demonstrate that C2-substitution with benzyl and phenyl moieties is a new, valuable option toward improving pan-antagonist behavior. Among the synthesized compounds, (R)-16m, when compared to casodex, (R)-bicalutamide, and enzalutamide, displayed very promising in vitro activity toward five different prostate cancer cell lines, all representative of CPRC and AIPC typical mutations. Despite being less active than (R)-bicalutamide, (R)-16m also displayed marked in vivo antitumor activity on VCaP xenografts and thus it may serve as starting point for developing novel AR pan-antagonists.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm5005122