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  • YK-4-279 Another significant group of reductase

    2023-05-24

    Another significant group of 5α-reductase inhibitors is the steroidal 3-carboxylic YK-4-279 derivatives (relevant examples in Fig. 5), which were designed to mimic the putative enzyme-bound enolate intermediate. This was achieved by introducing sp2-hybridized centers at C3 and C4 and an anionic carboxylic acid at C3 to replace the enolate oxyanion. Additionally, it was evidenced that the introduction of Δ3- and Δ5-double bonds as well as C17 di-isopropyl and tert-butyl amides are also important for the enzyme inhibitory potency [9], [11]. The most representative member of this group is epristeride (48) (Fig. 5), which potently inhibits 5α-reductase type II and is a weak inhibitor of the type I isozyme [55] and has entered clinical trials for treatment of BPH. Other relevant compounds of this class include, for example, several estratriene-3-carboxylates containing an aromatic A-ring and 3-nitro, 3-sulphonic and 3-phosphinic acid steroids (e.g. compounds 49–56, Fig. 5 and Table 3) [5], [9], [11], [56]. Interestingly, in a recent study the combination of the relevant structural features of finasteride (13) and epristeride (48) in a hybrid steroidal derivative was successfully explored. In fact, compound 60 (Fig. 5) was prepared and inhibitory studies using human prostatic 5α-reductase evidenced that this compound is a powerful inhibitor, with low IC50 (71nM), however less potent than finasteride (13) (IC50=35nM). Similar compounds prepared from estrone, with an aromatic A-ring and a 3-OH or 3-sulfamic acid revealed lower inhibitory properties [57]. Very recently, Aggarwal et al., prepared several novel steroidal 17a-substituted 3-cyano-17a-aza-D-homo-3,5-androstadien-17-ones (e.g. compounds 61–66), 17a-substituted 17-oxo-17a-aza-D-homo-3,5-androstadien-3-oic acids (e.g. compounds 67–70) and 17-oxo-19-nor-3,5-androstadien-3-oic acid (71) (Fig. 5) and evaluated their 5α-reductase inhibitory activity by in vitro and in vivo studies [58]. In this study it was observed that the carboxysteroids 67–70 (Fig. 5, Table 4) not only potently inhibited 5α-reductase II enzyme but also significantly reduced rat prostate weights [58]. Considering that progesterone and deoxycorticosterone competes with T (9) for the 5α-reductase enzyme, the pregnane nucleus has also been providing a representative template for the development of 5α-reductase inhibitors. The first studies involving this scaffold explored the positions 4 and/or 6 of progesterone and analogues frequently combined with D-ring functionalizations, allowing the preparation of interesting enzyme inhibitors. In addition, 16- and 17-substituted 17a-oxo-D-homosteroids were also synthesized and evaluated as 5α-reductase inhibitors [9], [11]. More recently, several studies in this context in which A-, B- and D-ring functionalizations of pregnane derivatives (Fig. 6, Fig. 7) successfully led to the development of new and potent 5α-reductase inhibitors that in several cases are even better than finasteride (13) [9], [11], [64], [65]. Taking into account that several progesterone derivatives with an ester moiety at C-17 have high activity as 5α-reductase inhibitors and inhibit prostate cell growth, Bratoeff et al. prepared similar compounds but with arylcarbamates at C-17 (e.g. compounds 72 and 73, Fig. 6), which revealed to be not only inhibitors of the human 5α-reductases (Table 5, entries 1 and 2), but also significantly reduced the diameter of the pigmented spot of hamster flank organs [66]. The same research group developed 4,5-epoxyprogesterone derivatives with an C-17 ester (e.g. compounds 76 and 77, Fig. 6) and compared their biological activities with the non-epoxidized analogues 74 and 75. In this study, it was observed that the introduction of a 4α,5α-epoxide led to human 5α-reductase inhibitory activities higher than that observed for the corresponding unsaturated derivatives (Table 5, entries 3–6). In addition, these epoxides decreased the weight of the prostate from hamsters treated with T (9) in a similar way as finasteride (13) [67]. Later, Bratoeff et al. also prepared 17α-hydroxyprogesterone (79), 17α-hydroxy-4α,5α-epoxypregnan-3,20-dione (80), as well as 4-chloro- and 4-bromopregn-4-ene-3,20-diones with a free 17α-hydroxyl group or its 4-ethylbenzoate ester (compounds 81–84) from 17α-acetoxyprogesterone (78) and concluded that the 4-halo-17-hydroxyl derivatives were the best 5α-reductase inhibitors within this group and that the epoxysteroid 80 selectively inhibits 5α-reductase-type I. The aromatic esters only have a low 5α-reductase-type II inhibitory activity [68]. Progesterone derivatives with an additional double bond at C6C7 also revealed interesting results in this context [9], [11], [64], [65]. These include, for example, compounds with 16β-methyl and 17α-ester groups (e.g. compounds 85–90, Table 5, entries 7–12) [69], [70] as well as D-homo derivatives (e.g. steroids 91–93, Table 5, entries 13–15) [69]. In other studies several similar progesterone derivatives with or without C-6-halogens and having an ester side chain at C-17 (e.g. benzoate ester bearing a Cl, F or Br atom at C-4 position of the phenyl ring) (Compounds 94–107, Fig. 6) were prepared aiming structure–activity relationship studies for the inhibition of 5α-reductase enzyme and to evaluate its effect on hamster flank organs diameter size. In these works, it was observed that, generally, steroidal derivatives lacking the chlorine substituent at C-6 exhibited a higher 5α-reductase inhibitory activity (Table 5, entries 16–25) as compared to the series of compounds having a chlorine atom at C-6 [71], [72].