Chen C, Li X, Singh S M, Labrie F
MRC Group in Molecular Endocrinology, CHUL Research Center and Laval University, Québec, Canada.
J Invest Dermatol. 1998 Aug;111(2):273-8. doi: 10.1046/j.1523-1747.1998.00271.x.
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 5alpha-reductase, the inhibition of 5alpha-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 17beta-(N-alkyl/arylformamido)-and 17beta-[(N-alkyl/aryl)alkyl/arylamido]-4-methyl-4-aza-5alpha -androstan-3-one derivatives as 5alpha-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 5alpha-reductase activity in the flank organs and ears. We found that 17beta-(N-amylformamido)-4-methyl-4-aza-5alpha-androstan+ ++-3-one (EM-401), 17beta-(N-hexylformamido)-4-methyl-4-aza-5alpha-androstan -3-one (EM-402), and 17beta-(N-heptylformamido)-4-methyl-4-aza-5alpha-andro -stan-3-one (EM-540) are potent inhibitors of 5alpha-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 microg, 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 5alpha-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.
痤疮、脂溢性皮炎、多毛症和雄激素性脱发等皮肤疾病是局部雄激素活性过高所致。由于最有效的雄激素双氢睾酮是由睾酮经5α-还原酶作用形成的，抑制5α-还原酶是干扰皮肤中雄激素作用的合理方法。在本研究中，我们研究了一系列17β-（N-烷基/芳基甲酰胺基）-和17β-[(N-烷基/芳基)烷基/芳基酰胺基]-4-甲基-4-氮杂-5α-雄甾烷-3-酮衍生物作为5α-还原酶抑制剂，在局部应用于金黄叙利亚仓鼠的胁腹器官和耳朵后的抑制作用。所测量的参数主要是胁腹器官和耳朵中皮脂腺的大小以及5α-还原酶活性。我们发现17β-（N-戊基甲酰胺基）-4-甲基-4-氮杂-5α-雄甾烷-3-酮（EM-401）、17β-（N-己基甲酰胺基）-4-甲基-4-氮杂-5α-雄甾烷-3-酮（EM-402）和17β-（N-庚基甲酰胺基）-4-甲基-4-氮杂-5α-雄甾烷-3-酮（EM-540）是5α-还原酶活性的有效抑制剂。EM-402分别以30、100和300μg的剂量每日两次局部应用4周后，使处理后的胁腹器官大小分别降低22%、31%和32%（所有p均<0.01）。在相同剂量下，EM-402还使基础皮脂腺的大小分别降低至完整对照值的38%、42%和59%。在耳朵皮脂腺大小方面观察到了类似结果。此外，使用局部应用的EM-402，我们分别在右侧胁腹器官和耳朵中观察到5α-还原酶活性呈浓度依赖性抑制47%-80%（p<0.01）和46%-80%（p<0.01）。EM-402对左侧对侧胁腹器官或耳朵中的相同参数无显著影响。此外，EM-402对前列腺和精囊重量无影响，而EM-401和EM-540显示出一些全身作用。这些数据表明，以所用浓度局部应用的EM-402在仓鼠中发挥了强大的局部抗雄激素作用，而无任何全身作用。
