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  • The reductase family is composed of

    2024-04-18

    The 5α-reductase family is composed of three known isozymes, with the types I and II being the most known. Type I isozyme, which is the dominant form, can be found in the skin, liver, kidney, brain and lung. Furthermore, it has been evidenced that type I activity is several times higher in PC than in BPH. Type II isozyme predominates in the prostate and other genital tissues and plays a major role in BPH. It was observed that T (9) have higher affinity to this isozyme than to type I isoform [9], [11]. More recently, type III isozyme was identified in CRPC cells as well as in other tissues such as pancreas, brain, skin and adipose tissues [29], [30]. A recent study suggested that, in addition to its potential role in synthesizing DHT (10) in both androgen-stimulated and androgen-deprived human PC, this isozyme can also be considered a biomarker of malignancy in several tumors [31], [32]. 5α-Reductases are microsomal membrane bound enzymes containing a high content of hydrophobic aminoacids distributed throughout their structures suggesting that they are intrinsic membrane proteins. Due to the fact that they are membrane bound enzymes and has not been purified due to its unstable nature, their crystal structure is still not known. For this reason, the design of 5α-reductase inhibitors has been mainly based on the knowledge on the structure of the substrates, on the enzyme mechanism and on previous structure–activity relationships (SAR) information [9], [31]. In this context, the Kumar group recently published a series of works on ligand-based 3D-QSAR studies using self-organizing molecular field analysis on several steroidal 5α-reductase inhibitors to rationalize the molecular properties and their human 5α-reductase inhibitory activities [33], [34], [35], [36]. The results of these works can provide useful information for the design and optimization of Capsaicin receptor steroidal structures as 5α-reductase inhibitors that are being used nowadays.
    Steroidal inhibitors of 5α-reductase One of the most common consequences of BPH is urinary retention and strain on the bladder, which can favor urinary tract infections, Capsaicin receptor or kidney damage, bladder stones, and even incontinence [5], [10]. The most known therapeutic strategies aiming LUTS reduction include the use of α1-adrenergic receptor antagonists, e.g. alfuzosin (11) and tamsulosin (12), phytotherapy (e.g. Serenoa repens extract) and 5α-reductase inhibitors, e.g. finasteride (13) and dutasteride (14), either in monotherapy or in combination regimens (Fig. 1) [5], [10]. Structurally, 5α-reductase inhibitors can be broadly grouped as steroidal and non-steroidal, with the steroidal class being larger than the non-steroidal class. Several nonsteroidal compounds with human 5α-reductase inhibitory properties have been developed aiming to overcome the undesired hormonal side effects of steroidal compounds. The majority of the nonsteroidal 5α-reductase inhibitors are azasteroidal analogues, prepared by removing one or more rings from the azasteroidal parental structure. A relevant example is the compound LY-191,704 (bexlosteride) (15) (Fig. 2), which is a 4-azasteroid analogue with potent type I 5α-reductase inhibitory properties [37]. Other relevant non-steroidal 5α-reductase inhibitors include, for example, several triterpenoids isolated from the fungus Ganoderma lucidum, e.g. ganoderic acid (16) (Fig. 2) [38], [39]. The ideal 5α-reductase inhibitor should bind the enzyme and have little or no affinity for the androgen or other steroidal receptors or enzymes. For this reason, in several biological and pharmacological studies, in addition to the in vitro enzymatic inhibitory activities and the in vivo effects on T (9) serum levels it is also common to evaluate the AR binding and activation capacities of the developed compounds [31]. Steroidal 5α-reductase inhibitors can be structurally classified in three main types: azasteroids, 3-carboxylic acids and other pregnane/androstane derivatives. The most important of these groups are the azasteroids, which were developed intending to mimic the enzyme-bound enolate intermediate by isosteric change between a carbon and nitrogen. This group includes the 4-azasteroids finasteride (13) and dutasteride (14) (Fig. 1), the only two steroidal 5α-reductase inhibitors that are being clinically used in the treatment of BHP. Of these two drugs, the first to enter the market and the most known 5α-reductase inhibitor is finasteride (13). This 4-azasteroid has been shown to be a mechanism-based inhibitor of 5α-reductase-type II acting as an alternate substrate [40]. Subsequent to inhibitor binding, there is hydride transfer from the NADPH cofactor to the Δ1 double bond of finasteride (13). The intermediate enolate tautomerizes at the enzyme active site to form a bisubstrate analogue in which dihydrofinasteride is covalently bound to NADP+ (Scheme 2). Thus, this drug forms an extremely stable but non-covalently enzyme-bound NADP-dihydrofinasteride adduct, which is ultimately processed to dihydrofinasteride [40]. Finasteride (13) is also a 5α-reductase-type I inhibitor, however the NADP-dihydrofinasteride adduct is formed with a much smaller rate constant compared to 5α-reductase-type II.