Novel 17 alpha-chloro-17 beta-sulfinyl steroids as specific inhibitors of sebaceous gland activity: potential antiacne agents.

The preparation and antisebaceous gland activities of a series of 17 alpha-chloro-17 beta-sulfinyl steroids are described. They were obtained from the corresponding 17 alpha-sulfides by chlorination and oxidation with iodobenzene dichloride in aqueous pyridine at -40 degrees C. A single-crystal X-ray structure determination of 17 alpha-chloro-17 beta-(benzylsulfinyl)-1,4-androstadiene-3,11-dione (4) established the absolute configuration at sulfur to be R. From an analysis of their CD spectra, some of the other alpha-chloro sulfoxides were also assigned the same absolute stereochemistry at sulfur. Inhibition of sebaceous gland activity, after topical application of the test compounds, was determined in hamsters and found to reach a maximum with 4. The 17 beta-sulfone and 17 alpha-sulfide corresponding to 4 were less potent. Subcutaneous administration of 4 produced no antiandrogenic effects in either hamsters or rats.

Antiandrogens.

Many antiandrogens, mainly steroidal and some nonsteroidal agents, have been synthesized and tested in several available biological assays. Unfortunately, many of these compounds have other biological activities which make it difficult to ascertain the precise mechanism of antiandrogenic action. The blocking of androgen action can be accomplished by a number of ways: (1) the inhibition of gonadotropin release and/or synthesis, (2) the interference with testosterone and/or dihydrotestosterone biosynthesis, (3) the blocking of protein synthesis, and (4) the competition with androgens at receptor sites. Although the major reason for the development of antiandrogens is to utilize them in certain clinical situations, some have become important tools in studying androgen action, particularly on the molecular level. The clinical effectiveness of some antiandrogens in prostatic hyperplasias, hirsutism, and acne represents an important advance in therapeutics, but the search for more potent antiandrogens with minimal side effects should continue.

The effects of a nonsteroid antiandrogen, flutamide, on sebaceous gland activity.

Flutamide (alpha,alpha,alpha-trifluoro-2-methyl-4'-nitro-m-propionotoluidide), at daily oral doses of 20 mg/day for 24 days, reduced the number and size of skin sebaceous gland cells, and reduced sebum production in ovariectomized, testosterone-stimulated rats. The weight of the preputial glands was also reduced. Unilateral topical application of flutamide (0.1-3.0 mg/day) to flank organs (androgen-sensitive cutaneous sebaceous structures) of testosterone propionate-treated female hamsters for 14 days resulted in bilateral reductions in flank organ weight and in inhibition of in vitro incorporation of 14-C from sodium [1--14C]acetate into lipids. Flutamide inhibition of flank organ weight paralleled the drug effect on lipogenesis. Unilateral topical application of flutamide to flank organs of intact male hamsters for 14 days resulted in significant bilateral reductions of flank organ weight at doses as low as 0.375 mg/day (the lowest dose tested). These weight changes were marked by reduction in sebaceous gland size, accompanied by focal cytoplasmic degeneration, and reductions in cytoplasmic organelles and in the size of the lipid bodies. Flutamide did not, however, seemingly alter the pattern of endogenous total lipids in sebaceous glands, nor did it alter the pattern of 14-C-incorporation into the lipids of male flank organ epidermis and isolated sebaceous glands, when compared to control, untreated preparations.