Discovery of a Potent, Orally Active, Nonsteroidal Androgen Receptor Agonist:  4-Ethyl-1,2,3,4-tetrahydro-6- (trifluoromethyl)-8-pyridono[5,6-g]- quinoline (LG121071)

Deficiencies in circulating levels of the androgens testosterone (T, 1a) and dihydrotestosterone (DHT, 1b) in hypogonadal men can be compensated for by administration of exogenous androgens, which have proven efficacious in hormone replacement therapy, abrogating age-related deterioration of muscle...

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Veröffentlicht in:Journal of medicinal chemistry 1999-01, Vol.42 (2), p.210-212
Hauptverfasser: Hamann, Lawrence G, Mani, Neelakandha S, Davis, Robert L, Wang, Xiao-Ning, Marschke, Keith B, Jones, Todd K
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Sprache:eng
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Zusammenfassung:Deficiencies in circulating levels of the androgens testosterone (T, 1a) and dihydrotestosterone (DHT, 1b) in hypogonadal men can be compensated for by administration of exogenous androgens, which have proven efficacious in hormone replacement therapy, abrogating age-related deterioration of muscle and bone, and regulating plasma lipids. Cancer cachexia, male contraception, and performance enhancement have also been investigated as clinical targets of androgen therapy. The beneficial effects of administered steroidal androgens are often overshadowed by their rapid metabolic conversion to DHT by 5 alpha -reductase and to estrogens by aromatase, resulting in side effects. Circumventing this metabolism through alternate routes of administration, such as intramuscular injection or transdermal patch applied to the scrotal skin, and attempts to improve oral half-life of T using long-chain alkyl esters as prodrugs have met with limited success. Alkylation of androgens at C-17, as in methyltestosterone (1c) and fluoxymesterone (2), has been observed to slow hepatic metabolism, allowing oral administration, but subsequent liver toxicity limits their use for chronic administration.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm9806648