A series of 1-benzyloxy-5-phenyltetrazole derivatives and similar compounds were synthesized and evaluated for their in vitro inhibitory activity against androgen-receptor-dependent (22Rv1) and androgen-receptor independent (PC3) prostate cancer cells. The most active compounds had in vitro IC50 values against 22Rv1 cells of <50 nM and showed apparent selectivity for this cell type over PC3 cells; however, these active compounds had short half-lives when incubated with mouse liver microsomes and/or when plasma concentration was monitored during in vivo pharmacokinetic studies in mice or rats. Importantly, lead compound 1 exhibited promising inhibitory effects on cell proliferation, expression of AR and its splicing variant AR-v7 as well as AR regulated target genes in 22Rv1 cells, which are so called castration-resistant prostate cancer (CRPC) cells, and a 22Rv1 CRPC xenograft tumour model in mice. Structural changes which omitted the N-O-benzyl moiety led to dramatic or total loss of activity and S-benzylation of a cysteine derivative, as a surrogate for in vivo S-nucleophiles, by representative highly active compounds, suggested a possible chemical reactivity basis for this "activity cliff" and poor pharmacokinetic profile. However, representative highly active compounds did not inhibit a cysteine protease, indicating that the mode of activity is unlikely to be protein modification by S-benzylation. Despite our efforts to elucidate the mode of action, the mechanism remains unclear.
Keywords: Androgen receptor; Mouse xenograft; Pharmacokinetic; Prostate cancer; SAR; Synthesis; Tetrazole.
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