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    • Later the same group designed and prepared several

    2023-09-18

    Later, the same group designed and prepared several Δ16-steroidal C17 benzoazoles and pyrazines and evaluated their CYP17 and 5α-reductase inhibitory activities, binding to and transactivation of the AR, as well as their antiproliferative effects against two human PC cell lines (LNCaP and LAPC4) [186], [189], [190]. Among the compounds synthesized, galeterone (159) (Fig. 10), a new steroid bearing a C17-benzimidazole group and its Δ4-3-keto derivative 242 (Fig. 15) showed a dual activity as potent CYP17 inhibitors and antagonists of both wild type and mutant AR. Galeterone (159) became the first example of a CYP17 inhibitor and antiandrogen that could effectively suppress androgen-dependent tumor growth better than castration [189]. The X-ray crystal structures of CYP17 in the presence of both abiraterone (157) and galeterone (159) evidenced that the nitrogen of C17 heterocycles of both compounds bind the heme iron (type II interaction) and that the 3β-OH interacts with asparagine 202 in the F helix [113]. This study demonstrated that the binding mode differs substantially from those that are predicted by homology models and from steroids in other cytochrome P450 enzymes with known structures, and that some features of this binding mode are, in fact, more similar to steroid receptors. The similarity of these binding modes is probably the reason for the dual mechanism of action of galeterone (159). The pharmacokinetic properties and antitumor activities of galeterone (159) were further studied with androgen-dependent LAPC4 human prostate tumor xenografts in severe combined immunodeficient (SCID) mice. The in vivo antitumor activity of galeterone (159) was more effective than castration [186]. Vasaitis et al. demonstrated by in vitro and in vivo studies that galeterone (159) caused down-regulation of AR protein expression, unlike bicalutamide and castration, which appears to contribute to its antitumor efficacy. In addition to a significant regression of LAPC4 tumors in xenograft models, which is more effective than castration, the treatment with galeterone (159) was also very effective in preventing the formation of LAPC4 tumors [191]. An in vitro study using high-passage LNCaP TAK 165 demonstrated that galeterone (159) inhibited the proliferation of these cells that were no longer sensitive to bicalutamide and had increased AR expression. Moreover, the combination of galeterone (159) with inhibitors of signal transduction pathways such as gefitinib and everolimus, was proven to be synergistic, when compared to either agent alone and superior to their combination with bicalutamide [192]. In vivo studies with LNCaP and high-passage LNCaP tumor xenografts in SCID mice indicated that dual inhibition of AR and mammalian target of rapamycin (mTOR) in castration-resistant models can restore the sensitivity of tumors to anti-androgen therapy. The results observed in this study also indicated that the CYP17 and AR inhibitor galeterone (159) combined with the mTOR inhibitor everolimus may be effective in resistant PC [193]. A very recent in vitro study with LNCaP and LAPC4 cells demonstrated that both galeterone (159) and abiraterone (157) directly down-regulated the expression and activation of the AR via multiple mechanisms, in addition to their CYP17 inhibitory activities [194]. Due to its impressive biological activities observed, galeterone (159) is currently being evaluated in a phase I/II open label clinical trial (ARMOR1 study) as a potential drug for the treatment of CRPC. This study began in 2009 and has as primary outcomes the incidence of adverse effects (phase I) and the proportion of patients with 50% or greater decrease in PSA from baseline (phase II) [195], [196]. More recently, in a continuing study of the clinical candidate galeterone (159) and analogues as potential agents for PC treatment, putative metabolites of galeterone (159) and metabolically stable derivatives were prepared [197]. Putative metabolites included Δ16-reduced (compound 243), Δ5-reduced, Δ16- and Δ5-reduced galeterone (159) analogues. Metabolically stable analogues of galeterone (159), developed to optimize its potency and to increase its stability and oral bioavailability, included their 3α-azido, 3ξ-fluoro, 3β-mesylate and 3β-O-sulfamoyl derivatives (examples in Fig. 15, compounds 244 and 245). Several in vitro studies, including CYP17 inhibitory activity, binding to and transactivation of AR and antiproliferative effects against LNCaP and LAPC-4 cell lines demonstrated that none of the compounds were superior to galeterone (159). Interesting results were, however, observed with the 3ξ-fluoro analogue 244 evidencing results compared to those observed with galeterone (159). In vivo studies revealed that the 3ξ-fluoro derivative 244 was near 2 fold more efficacious versus LAPC-4 xenografts than galeterone (159), but the toxicity observed with this halogenated compound is of concern [197].