![cdock 1.12 cdock 1.12](https://i.ytimg.com/vi/Ss6cZuclFFc/maxresdefault.jpg)
It was found that combination of dutasteride and enzalutamide synergistically inhibited tumour cell proliferation 15. It is currently being studied as a chemopreventive agent and in combination with other androgen-reducing agents in PCa treatment. Dutasteride blocks both type 1and type 2 isoenzymes and has an inhibitory effect in PCa 13, 14. Therefore, the inhibition of 5α-reductase could potentially reduce the risk of PCa development, prevent disease progression, and treat existing disease.ĥα-reductase inhibitors, like finasteride and dutasteride ( Figure 1), were used in the clinic for the treatment of BPH and were also proposed for chemoprevention and treatment of PCa. The 5α-reductase levels, particularly type 1, appear to increase during the disease course of prostatic intraepithelial neoplasia and PCa, with greater expression occurring as the disease progresses 12.
![cdock 1.12 cdock 1.12](https://i.redd.it/pdt5vzi977451.jpg)
More recently, type 3 isozyme was identified in castration-resistant PCa cells as well as in other tissues such as the pancreas, brain, skin and adipose tissues 11. Type 1 5α-reductase (5αR-1) is mainly expressed in prostate epithelial cells as well as in skin and liver at an optimal pH range of 6.0–8.5, while the type 2 5α-reductase (5αR-2) at an optimal pH 5.5, is mainly found in prostatestromal compartment and other genital tissues 10. The 5α-reductase family is composed of three isozymes, with the types 1 and 2 being the most known. 5α-reductases, which are NADPH-dependent enzymes, are responsible for the reduction of T to DHT. Recently, it has been shown that the low levels of DHT in the prostate after ADT is a result of intratumoral androgen synthesis 9. Therefore, the exploration of developing new anti-PCa agents with increased activity and fewer side effects is still in urgent. Although AR antagonists shown great benefits in treating PCa, drug resistances caused by AR mutation occur spontaneously in PCa 6, 7 as well as altered steroidogenesis 8 underlies the emergence of castration-resistant prostate cancer (CRPC) within 2–3 years after starting ADT. Newly approved enzalutamide ( Figure 1) is a new generation AR antagonist which is effective for bicalutamide-resistant tumours and has been used in CRPC patients 5. A number of small molecular AR antagonists, such as bicalutamide and flutamide ( Figure 1) have been shown good therapeutic effects in clinic 4. Thereafter, androgen ablation therapy has been shown to produce the most beneficial responses in multiple settings in PCA patients.Īs the substantial clinical efficacy with AR blockade in PCa patients, AR has been recognized as an attractive target for the treatment of PCa. 3 introduced androgen deprivation therapy (ADT) for advanced and metastatic PCa in 1941. Androgens, including testosterone (T) and dihydrotestosterone (DHT), and androgen receptor (AR) signalling pathway are essential for prostate development and homeostasis 2. In China, that number was 60,300 and has increased rapidly over the last 10 years 1. It was estimated that around 220,800 cases were diagnosed in the United States in 2015 alone. Prostate cancer (PCa) is the second leading cause of death in men only less than lung cancer. Overall, compound 9d can be identified as a potential dual 5α-reductase inhibitor and AR antagonist, which might be of therapeutic importance for PCa treatment. The docking result of 9d-AR indicated that AR was forced to expands its binding cavity and maintain an antagonistic conformation since the steric hindrance of 9d impeded H12 transposition. Moreover, most of the synthesized compounds displayed good 5α-reductase inhibitory activities with IC 50 lower than 1 μM. Among all the compounds, androstpyrazole derivatives (9a–9d) displayed the best inhibition activity comparable with flutamide. The results indicated that most of the synthesized compounds inhibited the testosterone-stimulated cell proliferation with good selectivity and safety. Their anti-proliferation activities were evaluated in AR + cell line 22RV1 and AR − cell line PC-3. In this study, a series of androst-17β-amide compounds have been designed and synthesized targeting both AR and 5α-reductase. Apart from androgen receptor, 5α-reductase has also been recognized as a potential target.
![cdock 1.12 cdock 1.12](https://www.harburnhobbies.co.uk/acatalog/202lg.png)
Prostate cancer (PCa) is the second leading cause of death in men.