New progesterone esters as 5alpha-reductase inhibitors.

Area of Science:

• Medicinal Chemistry
• Endocrinology
• Pharmacology

Background:

• Androgens play a crucial role in male sexual development and function.
• 5alpha-reductase is a key enzyme in androgen metabolism, converting testosterone to dihydrotestosterone.
• Inhibitors of 5alpha-reductase are valuable for treating conditions like benign prostatic hyperplasia and androgenetic alopecia.

Purpose of the Study:

• To synthesize and evaluate novel progesterone derivatives as potential 5alpha-reductase inhibitors.
• To assess the antiandrogenic activity of these compounds in preclinical models.

Main Methods:

• Synthesis of four new progesterone derivatives: compounds 7, 8, 9, and 10.
• Pharmacological evaluation using gonadectomized hamster seminal vesicles and flank organs.
• Measurement of seminal vesicle weight and flank organ diameter as indicators of antiandrogenic effect.
• Assessment of inhibition of testosterone (T) to dihydrotestosterone (DHT) conversion.

Main Results:

• Compounds 7 (4-bromo-17alpha-(p-fluorobenzoyloxy)-4-pregnene-3,20-dione) and 9 (4-bromo-17alpha-(p-chlorobenzoyloxy)-pregnene-3,20-dione) exhibited the highest antiandrogenic effects.
• Compounds 7 and 9 showed greater inhibition of 5alpha-reductase activity compared to finasteride in the flank organ model.
• Steroid 7 demonstrated superior inhibitory activity on T to DHT conversion than finasteride.

Conclusions:

• The novel progesterone derivatives, particularly compounds 7 and 9, possess significant antiandrogenic properties.
• These compounds represent promising candidates for the development of new therapies targeting androgen-dependent conditions.
• The p-fluorobenzoyloxy and p-chlorobenzoyloxy substitutions at C-17 are crucial for enhanced antiandrogenic activity.