Abiraterone and galeterone

As previously mentioned, abiraterone acetate 3 (Fig. 1) constitutes the first and still the only steroidal CYP17 inhibitor approved by the FDA in 2011, being indicated for the treatment of mCRPC after chemotherapy [14].

This drug was developed at the Institute of Cancer Research (UK) considering the known efficacy and limitations of ketoconazole in this field and following the observation that nonsteroidal 3-pyridyl esters had improved selectivity for the inhibition of CYP17. This led to the preparation of abiraterone 21 (Fig. 4), a A516-steroid with a 3-pyridyl group bound to C17, which revealed to be a potent and selective irreversible inhibitor of both 17a-hydroxy-lase and C17,20-lyase activities of CYP17 [86, 126, 127]. In fact, it was observed that abiraterone 21 is not only a more potent CYP17 inhibitor than ketoconazole but also is a less effective inhibitor of other CYP450 enzymes, responsible for the significant side effects and potential pharmacological interactions of ketoconazole in PC therapy [14, 128]. Accordingly, preclinical studies in mice demonstrated that abiraterone 21 reduced serumT to castrate levels, in spite of a compensatory significant increase in luteinizing hormone (LH) [126]. However, when abiraterone acetate 3was tested in human PC patients for the first time as a substitute to gonadotropin-releasing hormone (GnRH) analogues, sustained suppression of T production was not observed due to an increase in LH levels [129]. For this reason, abiraterone 21was developed to be concomitantly used with GnRH analogues in mCRPC [130]. Studies in xenograft models devoid of testicular and adrenal androgens further evidenced that abiraterone 21 inhibited CRPC growth and thus also seem to suppress androgen production in PC tumors [128].

Several Phase I clinical studies [131, 132] revealed that abiraterone acetate 3 is safe and effective on lowering serum androgen levels in both ketoconazole nai've and exposed patients. In addition, its antitumor activity was nearly equivalent in both groups. However, a significant increase in adrenocorticotrophic hormone (ACTH) was developed leading to hypokalemia and hypertension as the predominant toxicities. In order to reduce these side effects eplere-none, a mineralocorticoid antagonist, was introduced. As the highest studied dosage of abiraterone acetate 3 (1000mg) did not lead to limiting toxicities, the useof 1000mg daily was chosen in additional trials [8, 131, 133 135].

The concomitant use of the corticosteroids dexamethasone or prednisone in the efficacy of abiraterone acetate 3in several conditions was studied in Phase II trials [133-135]. A significant decrease in hyperaldosteronism-related symptoms was observed and therefore predni-sone 5mg b.i.d. was included in all subsequent studies, as well as in the FDA label indication. Other Phase II studies evaluated the efficacy of abiraterone in docetaxel-treated CRPC patients, and continued to evidence the importance of this steroidal drug in this stage of the pathology [135].

A Phase III study compared the use of abiraterone acetate 3and prednisone versus predni-sone alone in 1195 ketoconazole-naive men with mCRPCshowing disease progression dur ing or after therapy withdocetaxel. The primary endpoint was overall survival and the secondary endpoints were PSA decline, time to PSA progression and progression-free survival. In this study an increased median overall survival in the abiraterone acetate 3+ predis-one group was observed when compared to that of patients treated with prednisone alone (14.8 vs 10.9 months; hazard ratio of 0.65). In addition, all the other endpoints were met and as expected the toxicities caused by CYP17 blockage occurred mostly in the abiraterone acetate 3+ prednisone group. Another Phase III study set to be completed in 2014 is evaluating the use of abiraterone acetate 3 and prednisone versus prednisone alone in CRPC prior to chemotherapy [136].

Due to all these beneficial results and after the first Phase III studies, in April 2011, abiraterone acetate 3was approved by the FDA for the treatment of mCRPC after chemotherapy [14].

Abiraterone 3 is being used in the form of its 3p-acetyl prodrug in order to increase its oral bioavailability, and is quickly deacetylated to the active drug once absorbed. In spite of the fact that high-fat meals increase its oral absorption, it is recommended that this drug should be taken on an empty stomach. Other pharmacokinetic studies revealed that this drug is highly bound to plasma proteins and has a plasma half-life of 10-14h [131, 132]. At present, several other clinical trials are ongoing, mainly for the study of the combination of abiraterone acetate 3 with other relevant drugs in PC treatment [137].

Galeterone 4 (Fig. 1) is structurally similar to abiraterone 21 and was rationally designed as an androgen biosynthesis inhibitor via CYP17 inhibition [8]. In fact, as previously mentioned, several research works evidenced that modification of the C17 substituent of A16-ste-roids, particularly by attachment of nitrogen heterocycles, was a relevant strategy to produce potent inhibitors of the enzyme. Following these considerations, Handratta et al. designed and prepared several A16-steroidal C17 benzoazoles and pyrazines and evaluated their CYP17 and 5a-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). Some of the compounds including 4 and its A4-3-ketone derivative 56 (Fig. 5) were potent CYP17 inhibitors and antagonists of both wild type and mutant AR. These compounds were the first reported examplesbearing such a dual activity. In addition, these steroids inhibited the growth of DHT-stimulated LNCaP and LACP4 PC cells with IC50 values in the low micromolar range. Galeterone 4 and compound 56 were further studied for phar-macokinetic properties and antitumor activities against androgen-dependent LAPC4 human prostate tumor xenografts in severe combined immunodeficient (SCID) mice. Galeterone 4 was more effective than castration in its in vivo antitumor activity [104]. Taking this into account, Vasaitis et al. demonstrated by in vitro and in vivo studies that unlike bicalutamide and castration, galeterone 4 also caused down-regulation of AR protein expression, which appears to contribute to its antitumor efficacy. The authors also evidenced that this compound caused a significant regression of LAPC4 tumors in xenograft models, being more potent than castration, and that treatment with galeterone 4 was also very effective in preventing the formation of LAPC4 tumors [138].

An in vitro study using high-passage LNCaP cells demonstrated that galeterone 4 inhibited the proliferation of these cells that were no longer sensitive to bicalutamide and had increased AR expression. In addition, the combination of galeterone 4with inhibitors of signal transduction pathways such as gefitinib and everolimus, was proven to be syn-ergistic when compared to either agent alone and superior to their combination with bi-calutamide [139]. Later, 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 tumours to anti-androgen therapy. The results observed in this study also indicated that the CYP17 and AR inhibitor galeterone 4 combined with the mTOR inhibitor everolimus may be effective in resistant PC [140].

A very recent in vitro study with LNCaP and LAPC4 cells demonstrated that both galeterone 4 and abiraterone 21 directly down-regulated the expression and activation of the AR via multiple mechanisms, in addition to their CYP17 inhibitory activities [141].

Due to the impressive biological activities observed, galeterone 4 is currently being evaluated in a phase I/II open label clinical trial (ARMOR1 study) as a potential drug for the treatment of castration resistant prostate cancer. 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) [137].

Recently, in a continuing study of the clinical candidate 4 and analogues as potential agents for PC treatment, putative metabolites of 4 and metabolically stable derivatives were prepared. Putative metabolites included compounds with no double bonds at C16, C5, or both as well as their corresponding 3-oxo derivatives. Metabolically stable analogues of 4, developed to optimize its potency and to increase its stability and oral bioa-vailability, included their 3a-azido, 3^-fluoro, 3p-mesylate and 3p-O-sulfamoyl derivatives. Several in vitro studies, including CYP17 inhibitory activity, binding to and transactivation of AR, as well as antiproliferative effects against LNCaP and LAPC4 cell lines, demonstrated that none of the compounds were superior to 4 in the observed effects. The 3^-fluoro analogue was, however, nearly 2-fold more efficacious vs LAPC4 xenografts than 4. Nonetheless, the toxicity observed with this halogenated compound was of concern [142].

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