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  • A rational approach for the

    2024-05-15

    A rational approach for the design of new steroid compounds as possible competitive inhibitors of CYP17 include chemical modification at C17 of the enzyme's natural substrates, pregnenolone (1) and progesterone (2), introducing groups with moderate to strong dipole properties at C20, such as oxime and hydroxyl, among others (Fig. 13 and Table 9) [146], [147], [148], [149]. In this context, a set of Δ4-3-ketone- and Δ5-3β-hydroxypregnanes (e.g. 182–185, Fig. 13) has been prepared and evaluated by Li et al., which were thought as type I CYP17 inhibitors [148]. Pregnenolone-based compounds were generally more potent than the corresponding progesterone derivatives, which is in accordance with the fact that pregnenolone is the preferred substrate of human CYP17. The importance of the Δ16-double bond (compound 183) and the orientation at C20 (20β-ols being more potent than 20α-ols) for the enzyme inhibition was also evidenced in this study [148]. However, another study revealed that the presence of double bond at C16 decreases the importance of the orientation at C20, since similar activities have been observed for both the 20β-hydroxy- and 20α-hydroxy-Δ16 compounds 186 and 187[150]. Later, Hartmann and co-workers prepared different pregnene oximes that showed important CYP17 inhibitory activities with a type II binding (188–198, Fig. 13) [151]. Compound 188 was effective in vivo and suppressed plasma concentrations of T (9) more potently than ketoconazole (155), whereas no inhibition of CYP17 activity was found when an hydroxamic KU-0060648 function was added to the C17-side chain [152]. A difference in the inhibitory potential of rat CYP17 of the aziridinyl pregnanes 199–202 was observed between the S- and R-isomers, the S-isomers 199 and 201 being 162 and 30-fold more potent than the R-isomers, respectively [153]. However, this finding was not corroborated by later studies that used the human enzyme [154]. The activity of the aziridinyl compounds 203–205 was also reported [154]. Other steroidal molecules evaluated as inhibitors of CYP17 are also depicted in Fig. 13. The 17-aza derivative 206 inhibited human CYP17 with an IC50 value of 4.9μM [155]. Compound 207 inhibited both 5α-reductase and CYP17 with Ki values of 27 and 14nM, respectively [156]. The oxime 208 was also a dual inhibitor with the ability to reduce serum and prostatic T (9) and DHT (10) concentrations in vivo [157]. A landmark in the discovery and development of steroidal CYP17 inhibitors have been achieved in 1995, when Jarman et al. reported the synthesis of abiraterone (157) (Fig. 10), a 17-(3-pyridyl)androstane derivative which is a potent irreversible inhibitor of human testicular CYP17 [158]. When compared with ketoconazole (155), abiraterone (157) showed about 16- and 9-fold more potency for the inhibition of both 17α-hydroxylase and C17,20-lyase activities of CYP17, respectively, with IC50 values in the low nM range [18], [75], [129], [158]. An expected type II inhibition by direct coordination of the nitrogen lone pair of the pyridyl ring at C17 with the heme Fe is probably responsible for the observed activity of abiraterone (157) [158], [159]. However, abiraterone (157) causes irreversible inhibition of the CYP17 activity, which seems to be due to the presence of the C16–17 double bond [160]. Preclinical studies performed with abiraterone (157) showed that this compound is not only a more potent CYP17 inhibitor than ketoconazole (155), but also is less effective inhibitor of other CYP450 enzymes, responsible for the significant side effects and potential pharmacological interactions of ketoconazole, in PC therapy [125], [128]. Accordingly, preclinical studies in mice demonstrated that abiraterone (157) reduced serum T (9) to castrate levels, in spite of a compensatory significant increase in luteinizing hormone (LH) [161], however in human PC patients, sustained suppression of T (9) production was not observed [162]. For this reason, abiraterone (157) was developed to be concomitantly used with GnRH analogues in mCRPC [163].