In order to increase the
In order to increase the oral bioavailability, abiraterone (157) is being used in the form of its 3β-acetoxy prodrug, abiraterone acetate (156). In spite of the fact that high-fat meals increase the oral THZ1 of abiraterone acetate (156), it is recommended that this drug should be taken on an empty stomach. After intestinal absorption, the 3β-acetoxy derivative is quickly deacetylated to the active drug abiraterone (157) , . Several Phase I clinical trials revealed that abiraterone acetate (156) is safe and effective on lowering serum androgen levels, being the most common side effects due to the increase of adrenocorticotrophic hormone (ACTH) levels, that led to hypokalemia and hypertension , . Phase II clinical trials show that a significant decrease in hyperaldosteronism-related symptoms was observed when a corticosteroid is used concomitantly , , . Therefore, prednisone 5mg b.i.d. was included in all subsequent studies, as well as in the FDA label indication. A Phase III study established the benefit of this drug in the overall survival of men with mCRPC showing disease progression during or after therapy with docetaxel. Another Phase III study set to be completed in 2014 is evaluating the use of abiraterone acetate (156) and prednisone versus prednisone alone in CRPC prior to chemotherapy . Due to its pharmacotherapeutical properties, abiraterone acetate (156) was approved by the US Food and Drug Administration (FDA), in April 2012, for the treatment of metastatic CRPC after chemotherapy . In 2001, Hartmann et al. reported that the introduction of a pyrimidyl substituent at C17 originated compounds such as 209 and 210 (Fig. 14), which were more potent inhibitors of the human enzyme than both abiraterone acetate (156) and abiraterone (157) (Table 10, entries 1–4), under the same assay conditions. These authors also demonstrated that compound 210 effectively lowered T (9) plasma concentrations to castrate levels after administration to mice , . The thiazole and furan derivatives 211 and 212 were also synthesized and tested on the monkey cynomolgous enzyme (Fig. 14) , . A series of interesting effects on PC cells other than just CYP17 inhibition was reported by Brodie et al. for the imidazolyl, pyrazolyl, and isoxazolyl androstane derivatives 213–219 (Fig. 14 and Table 10, entries 5–11). The isoxazolyl compound 219 was not only a non-competitive inhibitor of human CYP17 but also a competitive inhibitor of 5α-reductase, with a potency similar to finasteride, while in addition bearing antiandrogenic activity , , , , . Its effects were confirmed using PC xenograft models, however, its short half-life and relatively low bioavailability were reasoned to limit its efficacy in vivo , , . In 2006, Wolfling et al. reported the synthesis of a series of dihydrooxazine derivatives 221–232 (Fig. 14). The low inhibitory activity of CYP17 showed by this set of coumpounds was most likely due to the bulkiness of the C17 moieties and the absence of a double bond at C16 . Later, the same group reported the synthesis of the oxazolidone derivative 233 (Fig. 14), which inhibited the activity of rat testicular C17,20-lyase with an IC50 value of 3μM . Similar inhibition of the enzyme was observed with the halogenated oxazoline derivatives 234 and 143, and with the D-ring fused arylpyrazoline 237 (Fig. 14) . The N-phenylpyrazolyl derivatives 235 and 236 were however much less active, with IC50 values in the high μM range , as was the steroidal D-ring fused oxazolidine 238 (Fig. 14) . In 1996, Njar et al. reported the first steroidal inhibitors of CYP17 bearing a heterocyclic moiety bound to C17 by a nitrogen atom . Azole heterocycles such as imidazole, pyrazole, triazole and tetrazole, were attached to C17 by the N1 of the heterocycle leading to very interesting compounds, among which the imidazolyl derivatives 239 and 240 and the tetrazolyl derivative 241 were found to be the most promising (Fig. 15 and Table 11, entries 1–3) , , , . In this series, progesterone derivatives were more potent CYP17 inhibitors than the corresponding pregnenolone steroids . In vitro results with compounds 239–241 revealed a high inhibitory potential of the human enzyme expressed in LNCaP cells. In addition, compounds 239 and 240 completely suppressed T (9) and DHT (10) stimulated growth of LNCaP cells below 5μM, and displayed antiandrogenic activity , . In vivo experiments confirmed these results and showed that the compounds were however less effective than castration .