Activity of 17β-(N-alkyl/arylformamido) and 17β-[(N-alkyl/aryl) alkyl/arylamido]-4-methyl-4-aza-5α-androstan-3-ones as 5α-reductase inhibitors in the hamster flank organ and ear

Skin disorders such as acne, seborrhea, hirsutism, and androgenic alopecia are secondary to excess local androgenic activity. Because the most potent androgen, dihydrotestosterone, is formed from testosterone by the action of 5 alpha-reductase, the inhibition of 5 alpha-reductase is a logical approach to interfere with androgenic action in the skin. In this study, we have investigated the inhibitory effect of a series of 17 beta-(N-alkyl/arylformamido)- and 17 beta-[(N-alkyl/aryl)alkyl/arylamido]-4-methyl-4-aza-5 alpha-androstan-3-one derivatives as 5a-reductase inhibitors following their topical application on the flank organs and ears of Golden Syrian hamsters, The parameters measured were mainly the size of the underlying sebaceous glands and 5a-reductase activity in the flank organs and ears, We found that 17 beta-(N-amylformamido)-4-methyl-4-aza-5 alpha-androstan-3-one (EM-401), 17 beta-(N-hexylformamido)-4-methyl-4-aza-5 alpha-androstan-3-one (EM-402), and 17 beta-(N-heptylformamido)-4-methyl-4-aza-5 alpha-andro-stan-3-one (EM-540) are potent inhibitors of 5a-reductase activity. EM-402 decreases the size of treated flank organs by 22%, 31%, and 32% (p < 0.01 for all) after topical application at the doses of 30, 100, and 300 mu g, respectively, twice daily for 4 wk, EM-402 also reduced the size of underlying sebaceous glands by 38%, 42%, and 59% of intact control values at the same doses. Comparable results were observed on the size of the sebaceous glands of the ears. In addition, we have observed a concentration-dependent 47%-80% (p < 0.01) and 46%-80% (p < 0.01) inhibition of 5 alpha-reductase activity in the right flank organs and ears, respectively, using topical EM-402, EM-402 had no significant effect on the same parameters in the left contralateral flank organs or ears. In addition, EM-402 had no effect on prostatic and seminal vesicle weights whereas EM-401 and EM-540 showed some systemic effects. These data illustrate that EM-402 applied topically, at the concentrations used, exerts a potent local anti-androgenic effect without any systemic action in the hamster.