ACTIVITY OF 17-BETA-(N-ALKYL ARYLFORMAMIDO) AND 17-BETA-[(N-ALKYL/ARYL) ARYLAMIDO]-4-METHYL-4-AZA-5-ALPHA-ANDROSTAN-3-ONES AS 5-ALPHA-REDUCTASE INHIBITORS IN THE HAMSTER FLANK ORGAN AND EAR/

Skin disorders such as acne, seborrhea, hirsutism, and androgenic alop ecia are secondary to excess local androgenic activity. Because the mo st potent androgen, dihydrotestosterone, is formed from testosterone b y 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 serie s of 17 beta-(N-alkyl/arylformamido)- and 17 a-[(N-alkyl/aryl)alkyl/ar ylamido]-4-methyl-4-aza-5 alpha-androstan-3-one derivatives as 5a-redu ctase inhibitors following their topical application on the flank orga ns and ears of Golden Syrian hamsters, The parameters measured were ma inly the size of the underlying sebaceous glands and 5a-reductase acti vity in the flank organs and ears, We found that 17 beta-(N-amylformam ido)-4-methyl-4-aza-5 alpha-androstan-3-one (EM-401), 17 beta-(N-hexyl formamido)-4-methyl-4-aza-5 alpha-androstan-3-one (EM-402), and 17 bet a-(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) a fter topical application at the doses of 30, 100, and 300 mu g, respec tively, twice daily for 4 wk, EM-402 also reduced the size of underlyi ng sebaceous glands by 38%, 42%, and 59% of intact control values at t he same doses. Comparable results were observed on the size of the seb aceous glands of the ears. In addition, we have observed a concentrati on-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, respecti vely, using topical EM-402, EM-402 had no significant effect on the sa me parameters in the left contralateral flank organs or ears. In addit ion, EM-402 had no effect on prostatic and seminal vesicle weights whe reas EM-401 and EM-540 showed some systemic effects. These data illust rate that EM-402 applied topically, at the concentrations used, exerts a potent local anti-androgenic effect without any systemic action in the hamster.