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    • Finasteride was the first steroidal reductase inhibitor

    2023-05-24

    Finasteride (13) was the first steroidal 5α-reductase inhibitor approved by the US Food and Drug Administration (FDA) in 1992 for treatment of BPH. In fact, long term clinical studies with this drug demonstrated a sustained reduction of the prostatic specific antigen and an overall improvement in BHP [6], [31], [41]. In addition to finasteride (13), several other azasteroids with 5α-reductase inhibitory properties have been developed aiming not only to overcome the side effects of finasteride (13) but also to improve their inhibitory potency and selectivity and to perform structure–activity relationship studies. In this context, the structural modifications performed were mainly based on the structural scaffold of finasteride (13) and usually involved changes in the lateral chain bound to C17, functionalizations at N4 and C7 and the reduction of the Δ1-double bond (examples in Fig. 3 and Table 1) [5], [9], [11]. A significant advance in this field was the development of dual inhibitors of both isozymes (types I and II), such as dutasteride (14), allowing a more general blockage of DHT (10) synthesis. In fact, this drug is a potent irreversible competitive inhibitor of human 5α-reductases-type I and type-II, forming a stable complex with both isoenzymes which has a slow rate of dissociation. Dutasteride (14) is approximately 60 times more potent than finasteride (13), reduces the DHT (10) circulating levels by more than 90%, and also improves clinical outcomes in BPH. In addition, this drug has the advantages of being well tolerated and having only transient side effects. Due to all these reasons, in 2002, FDA approved its use in the symptomatic treatment of BPH [44]. As can be seen in Fig. 1, Fig. 3, the chemical structures of the two most successful 4-azasteroids, finasteride (13) and dutasteride (14) only differ in their lateral chain bond to C17. Consequently, it is not surprising that a range of modifications in this part of the structure of 4-azasteroids have been further explored allowing the development of other interesting inhibitors such as YK-4-279 25 (Fig. 3), which potently inhibits type I and II isozymes [45]. Recent studies involving the preparation of 4-azasteroids with potential 5α-reductase inhibitory properties includes, for example, the works of Kim et al. which prepared a series of pregnane derivatives functionalized at their A- and B-rings with or without 20-oximes [46], [47]. Structure–activity studies revealed that 4-azasteroids with a 20-oxime group (e.g. compounds 26, 27 and 29, Fig. 3) as well as 20-hydroximineprogesterone have interesting inhibitory activities of prostatic rat 5α-reductases, however lesser than that observed with finasteride (13) [46]. In another research work, aiming the development of 17β-hydroxysteroid dehydrogenase type 7 (17β-HSD7) inhibitors, several 4-methyl-4-aza-5α-androstane derivatives differing in their C17 substituent were prepared. In the selectivity studies performed it was observed that compounds 30 and 31 (Fig. 3) also significantly inhibited 5α-reductases type I and II at 0.3μM. In this work it was observed that 4-azasteroids have lesser 5α-reductase inhibitory activity than their 4-methyl-4-aza analogues [48]. Recently, the synthesis of a conjugate between finasteride and polimod (compound 32, Fig. 3), an orally bioactive immune enhancer, has been reported and it was demonstrated that this new derivative have stronger 5α-reductase inhibition than finasteride (13). In addition, results from in vivo studies suggested that this compound has an improved toxicity profile than finasteride (13) [49]. The insertion of the nitrogen atom in other positions of the steroid backbone was also investigated. In fact, almost all positions have been explored, including 6-azasteroids [50], [51], [52] and 19-nor-10-azasteroids [53], [54] (relevant examples in Fig. 4). One of the most successful groups is 6-azasteroids with a Δ4-3-ketone group, developed to mimic the structural and charge polarization features of the transition state for the enzyme catalyzed transfer of the hydride from NADPH to T (9). Some 6-azasteroids exhibited potent dual enzyme inhibitory activity namely compounds 35–39 (Fig. 4 and Table 2) [50], [51], [52].