Development Of 5aReductase Inhibitors

As discussed, although other approaches to androgen ablation and androgen inhibition (antiandrogens) have been evaluated in the past, these methods produced only a moderate desired impact and had many side effects, thus limiting their use (14). Typical antiandrogen (e.g., flutamide) side effects include onset of erectile dysfunction, impairment in libido and ejaculation, gastrointestinal distress, nausea, flatulence, gynecomastia, breast pain, diminished energy levels, impairment in spermatogenesis, and decreased muscle mass. In contrast, because mature (postpubertal) patients with 5 a-reductase deficiency did not appear to have impaired sexual function or diminished external mascu-linization, the 5 a-reductase enzyme was a logical target for treating men with clinically significant BPH. The potential blockade of 5a-reductase seemed to provide hope for decreasing prostate growth and minimizing side effects.

Investigators began to work to create an effective 5 a-reductase inhibitor to treat BPH. Early research included the development of 3-oxosteroid compounds. Unfortunately, these agents were rapidly inactivated or metabolized, thus limiting their clinical usefulness (15). Subsequently, 4-aza-3-oxosteroid derivatives of testosterone were developed. However, in addition to their effective 5 a-reductase inhibition properties, many of the early agents also demonstrated partial antiandrogenic effects such as those described previously, thus diminishing their clinical usefulness. In 1994 researchers developed finasteride (MK-906), a 4-azasteroid compound that showed great promise for clinical efficacy with minimal side effects. A critical feature of finasteride was its stable A-ring that resembled the transition state between T and DHT (Fig. 3). This stable A-ring permits finasteride to bind with high affinity to the active site of the 5a-reductase enzyme, thus preventing the enzyme from acting on T. Finasteride treatment was subsequently found to decrease 5a-reductase activity in prostate tissue by 100-fold in comparison to tissue from placebo-treated control patients (16). Furthermore, finasteride was shown to be capable of

Fig. 3. Molecular formula of finasteride. Permission obtained from ProscarĀ® product monograph. Rahway, NJ: Merck & Co, 1993.

blocking 5a-reductase without affecting the binding of T to the androgen receptor (17). These features are critical to the potential maintenance of fertility, libido, erectile function, and secondary sexual characteristics.

Stoner reported in 1992 that men taking finasteride 5 mg/day had a 25% decrease in ejaculate volume, but no changes were noted in total sperm count, motility, or sperm morphology (18). Other studies have shown that finasteride at doses 543 times human exposure did not negatively affect fertility, sperm concentration, or ejaculate volume in sexually mature male rabbits (19). Finally, finasteride was found not to exert any estrogenic or other steroid hormone effects, which had been a problem with some of the earlier investigational compounds (17).

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