Antiandrogens

Antiandrogens Prostate cancer Benign prostatic hypertrophy Acnc 

The remainder of the discussion in this section is concerned with antiandrogens and antioestrogens to exemplify the pharmacology of steroid antagonists. 

The order in which the steps are performed is quite flexible. The synthesis of the antiandrogen dutasteride thus starts with the construction of the side chain at 17. The reaction of acid (44-1) with the aniline (46-1) poceeds to afford the amide (46-2). Ring A of the steroid is then opened to the corresponding keto-acid (46-3) with a concomitant loss of carbon 4 by means of the permanganate-periodate combination. Reductive alkylation with ammonia then affords the saturated lactam (46-4). 

Treatment of this last intermediate with DDQ leads to the dehydrogenation of the lactam ring to form the 1-dehydro derivative dutasteride (46-5) [45]. 

An analogue in which a carboxylic acid attached to the 3 position takes the place of the polar pyridone ring in the previous examples also exhibits antiandrogenic activity. The synthesis starts by reaction of the intermediate (44-1) common to the preceding antiandrogens with phosphorus tribromide. This reagent converts the 

In early sixties eyprotemone acetate was first discovered to possess antiandrogen activity. A few other compounds were found to exhibit similar properties. 

Pregna-4, 6-diene-3, 20-dione, 17-(aeetyloxy)-6-chloro- Chlormadinone acetate BP (1968)  

It is used in the treatment of functional uterine bleeding. It also exerts very slight oestrogenic activity. 

Mechanism of Action. Chlormadinone acetate is an orally active progestogen having distinct and potent antiandrogenie aetivity, which has been used in eombination as an oral contraceptive. It serves as a hormonal antineoplastic agent. 

The mineralocorticoid-aldosterone essentially monitors the eleetrolyte balance in the body by enhaneing the excretion of and the retention of Na. Thus, aldosterone antagonists are usually employed for the effective treatment of edematous ailments and hypertension. 

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Environmental antiandrogens Vinclozolin Procymidone Kraft mill effluent... 

A highly modified methyl testosterone derivative also exhibits antiandrogenic activity. One synthesis of this compound Involves initial alkylation of methyl testosterone (3 ) by means of strong base and methyl iodide to afford the 4,4-dimethyl derivative Formylation with alkoxide and... 

ACE inhibitors do not completely block aldosterone synthesis. Since this steroid hormone is a potent inducer of fibrosis in the heart, specific antagonists, such as spironolactone and eplerenone, have recently been very successfully used in clinical trials in addition to ACE inhibitors to treat congestive heart failure [5]. Formerly, these drugs have only been applied as potassium-saving diuretics in oedematous diseases, hypertension, and hypokalemia as well as in primary hyperaldosteronism. Possible side effects of aldosterone antagonists include hyperkalemia and, in case of spironolactone, which is less specific for the mineralocorticoid receptor than eplerenone, also antiandrogenic and progestational actions. 

SARMs are AR ligands that display tissue-specific androgenic/antiandrogenic activities. 

ATC G03H L02BB02 Use non-steroidal antiandrogen (for treatment of prostatic carcinoma)... 

Cyproterone acetate (CPA) is a progestational antiandrogen that blocks the androgen receptors. It is combined with ethinyl estradiol in an oral contraceptive formulation, which is indicated in female acne patients with a high level of seborrhea, therapy resistant papulo-pustular acne or acne conglobata not responding to other treatments. 

Spironolactone is an antiandrogen which blocks androgen-receptors, alters steroidogenesis by adrenals and gonads and inhibits 5-a reductase. In doses of 100-200 mg daily it reduces sebum production and improves inflammatory acne in women. During treatment, birth control measures are required due to the risk of male fetus feminization. 

Chemicals with antiandrogenic activity inclnde pharmacenticals developed as anticancer agents (e.g., flntamide, Neri and Monahan 1972 Neri et al. 1972, in Lntsky et al. 1975) and 179-methyltestosterone nsed to treat testosterone deficiency (Katsiadaki et al. 2006). Other antiandrogens inclnde varions pesticides snch as the... 

Baatrup, E. and Junge, M. (2001). Antiandrogenic pesticides disrupt sexual characteristics in the adult male guppy (Poecilia reticulata). Environmental Health Perspectives 109, 1063-1070. 

Gray, L.E. (1998). Tiered screening and testing strategy for xenoestrogens and antiandrogens. Toxicology Letters 103, 677-680. 

Gray, L.E., Ostby, J.S., and Kelce, W.R. (1994). Developmental effects of an environmental antiandrogen—the fungicide vinclozolin alters sex differentiation of the male rat. Toxicology and Applied Pharmacology 129,46-52. 

Gray, L.E., Ostby, J., and Wolf, C. et al. (1996). Effects of estrogenic, antiandrogenic and dioxin-like synthetic chemicals on mammalian sexual differentiation. Abstracts of Papers of the American Chemical Society 212,4—TOXI. 

Katsiadaki, I., Morris, S., and Squires, C. et al. (2006). Use of the three-spined stickleback (Gasterosteus aculeatus) as a sensitive in vivo test for detection of environmental antiandrogens. Environmental Health Perspectives 114, 115-121. 

Kelce, W.R., Monosson, E., and Gamcsik, M.P. et al. (1994). Environmental hormone disrupters—evidence that Vinclozolin developmental toxicity is mediated by antiandrogenic metabolites. Toxicology and Applied Pharmacology 126, 276-285. 

Lutsky, B.N., Budak, M., and Koziol, P. (1975). The effects of a nonsteroid antiandrogen, flut-amide, on sebaceous gland activity. Journal Investigative Dermatology 64, 412 17. 

Neri, R.O. and Monahan, M. (1972). Effects of a novel nonsteroidal antiandrogen on canine prostatic hyperplasia. Investigative Urology 10, 123-130. 

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