FCE 28260: A Forgotten 5α-Reductase Inhibitor

nkrata · August 22, 2024, 6:27pm

FCE 28260: A Forgotten 5α-Reductase Inhibition

So we’re all familiar with 5alpha reductase inhibitors: we know they block 5AR and prevent Testosterone from turning into DHT. The two that have been on the market for decades now are Finasteride and Dutasteride.

However, did you know there are other 5-alpha-reductase inhibitors? I made a video on Epristeride nearly a year ago and how it’s been available for decades in China to treat BPH and also used off-label for AGA.

Well, there are a bunch of 5AR inhibitors that never made it to market: some for being liver toxic and others, from what it seems, simply due to funding. Today, we are going to be looking at one in particular: FCE 28260 also known as PNU 156765

Giudici, D., Briatico, G., Cominato, C., Zaccheo, T., Iehlé, C., Nesi, M., Panzeri, A., & Di Salle, E. (1996). FCE 28260, a new 5α-reductase inhibitor: In vitro and in vivo effects. Journal of Steroid Biochemistry and Molecular Biology, 58(3), 299–305. Redirecting

Giudici, D., Briatico, G., Cominato, C., Zaccheo, T., Iehlé, C., Nesi, M., Panzeri, A., & Di Salle, E. (1996). FCE 28260, a new 5α-reductase inhibitor: In vitro and in vivo effects. Journal of Steroid Biochemistry and Molecular Biology, 58(3), 299–305. https://doi.org/10.1016/0960-0760(96)00040-4

Study Overview of FCE 28260

In the study titled, "FCE 28260, a New 5 -Reductase Inhibitor: In Vitro and In Vivo Effects’’ by Giudici et al. focuses on FCE 28260, a novel 5α-reductase inhibitor. The study meticulously compares the inhibitory effects of FCE 28260 and finasteride on 5αR activity both in vitro and in vivo.

Source: https://www.researchgate.net/publication/361521671_Androgens_aging_and_prostate_health

The study involved using enzyme extracts from rat and human prostate tissue. Prostatic tissue is rich in 5α-reductase, making it a relevant source for studying the enzyme’s activity and its inhibition by drugs like FCE 28260. This comparison allows for the evaluation of the drug’s effect across species, which is important for understanding its potential therapeutic effects in humans based on animal models.

In addition to natural enzyme sources, the researchers used human recombinant 5αR type 1 and 2 isozymes. Recombinant DNA technology enables the production of human enzymes in other organisms, providing pure enzyme forms for research. The 5α-reductase enzyme exists in at least two main isoforms: type 1 and type 2, which differ in their amino acid sequences, regulation, tissue distribution, and physiological roles. By studying both isoforms, the researchers could assess the drug’s inhibitory effects more specifically and determine whether it selectively inhibits one type over the other or if it’s a broad-spectrum inhibitor affecting both isoforms equally.

Comparative Efficacy: FCE 28260 vs. Finasteride

The IC50 value, representing the concentration of a substance required to inhibit a specific biological function—here, enzyme activity—by 50%, is a pivotal measure of a drug’s potency.

The comparative analysis of FCE 28260 and finasteride, a previously established 5αR inhibitor, in terms of IC50 values, reveals the former’s superior inhibitory efficacy on 5αR activity, thereby indicating its potential as a more effective treatment for DHT-related disorders.

When it comes to looking at FCE 28260’s IC50 values for blocking the natural sources of rat and human prostatic 5αR, the respective values are 15 nM and 16 nM.

These figures stand in contrast to those of finasteride, which in the natural sources of rat and human prostatic 5aR displays IC50 values of 30 nM for rats and 52 nM for human prostatic 5αR.

Now, there needs to be a distinction that is to be made here as the paper mentions that the researchers also obtained IC50 values for Human Recombinant 5αR Type 1 and Type 2 Isozymes. Now what does “human recombinant” mean in this context and why is it important, you may ask? “Human recombinant” refers to 5α-reductase (5αR) isozymes—specifically type 1 and type 2—that have been produced using recombinant DNA technology. This method involves inserting the human gene that codes for the 5αR enzyme into a host cell, such as bacteria or yeast, which then expresses the enzyme. These recombinant enzymes are essentially identical to their naturally occurring counterparts in the human body but are produced in a controlled laboratory setting. This allows for the production of pure, isolated enzymes free from other human proteins or interfering substances, providing a clear and focused tool for scientific study.

Grinding up human and rat prostates in a blender isn’t exactly the cleanest or best way of assessing FCE and Finasteride’ respective IC50 scores on the 5aR that may be found in those tissue samples. Plus, the researchers are now able to effectively assess what is going on with the different types of 5AR in regards to FCE and Finasteride’s inhibitory capabilities.

So, what did the researchers find? When looking closely at the breakdown for the IC50 Values for Human Recombinant 5αR Type 1 and Type 2 Isozymes, FCE 28260’s heightened potency in reducing the enzymatic conversion of testosterone to DHT achieved IC50 values of 3.3 nM for type 2 and 36 nM for type 1.

Giudici, D., Briatico, G., Cominato, C., Zaccheo, T., Iehlé, C., Nesi, M., Panzeri, A., & Di Salle, E. (1996). FCE 28260, a new 5α-reductase inhibitor: In vitro and in vivo effects. Journal of Steroid Biochemistry and Molecular Biology, 58(3), 299–305. https://doi.org/10.1016/0960-0760(96)00040-4

For finasteride, when it came to the human recombinant 5AR types, for type 2 Finasteride obtained 8.5nM IC50. For type 1, 470 nM. This makes FCE 13 times more potent than Finasteride.

This dual inhibitory capacity not only speaks to the compound’s efficacy but also to its potential applicability across a range of DHT-related conditions, given the distinct tissue localizations and physiological roles of the two 5αR isozymes.

Giudici, D., Briatico, G., Cominato, C., Zaccheo, T., Iehlé, C., Nesi, M., Panzeri, A., & Di Salle, E. (1996). FCE 28260, a new 5α-reductase inhibitor: In vitro and in vivo effects. Journal of Steroid Biochemistry and Molecular Biology, 58(3), 299–305. https://doi.org/10.1016/0960-0760(96)00040-4

The superiority of FCE 28260 over finasteride is further highlighted by its broader inhibitory spectrum and longer duration of action. The compound’s ability to achieve lower IC50 values against both the rat and human forms of 5αR, as well as its more potent and extensive inhibition of the human recombinant 5αR type 1 and 2 isozymes, positions FCE 28260 as a notably more effective therapeutic option.

Molecular Weight Assessment

When comparing the 5α-reductase (5AR) inhibitory effects of FCE 28260 (PNU 156765) and dutasteride, several key factors distinguish their therapeutic potential and pharmacokinetic profiles.

Dutasteride is renowned for its potent inhibition of all three isoforms of 5α-reductase, achieving up to a 98% reduction in circulating DHT levels. This broad-spectrum inhibition is facilitated by its competitive and mechanism-based (irreversible) inhibitory action, with IC50 values of 3.9 nM for type I and 1.8 nM for type II 5α-reductase.

This potency underscores dutasteride’s effectiveness in significantly lowering DHT levels, offering a robust therapeutic option for conditions like benign prostatic hyperplasia (BPH) and androgenic alopecia.

Conclusion

The real shame here is that FCE 28260 could have been a very effective treatment and perhaps had a better side effect profile than Finasteride. Topically, it may have been more permeable than Dutasteride. I couldn’t find much on its half life, so if anyone knows feel free to comment.