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Endocrine Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Flutamide was the first NSAA to be introduced in 1983, and this was followed by nilutamide and bicalutamide in 1989 and 1995, respectively. These agents, often known as first-generation inhibitors, are interesting from a medicinal chemistry standpoint in that bicalutamide and the active metabolite of flutamide (hydroxyflutamide) both contain a pseudo five-membered ring stabilized by a cyclic NH–O hydrogen bond. However, nilutamide contains a fully formed bioisosterically equivalent imidazolidinedione ring of similar three-dimensional shape. Another analog of this generation, topilutamide (also known as fluridil), has a similar structure and three-dimensional shape but is used exclusively as a topical anti-androgen for the treatment of pattern hair loss and is not further described here.
Androgen receptor modulators: a review of recent patents and reports (2012-2018)
Published in Expert Opinion on Therapeutic Patents, 2019
Shinya Fujii, Hiroyuki Kagechika
Since AR activation is closely related to aggravation of prostate cancer, AR antagonists are used clinically for the treatment of prostate cancer [18–21]. Cyproterone acetate (7) is a steroidal AR antagonist used in the treatment of androgen-dependent disorders including prostate cancer (Figure 3) [22,23]. Oxendolone (8) is used in the treatment of enlarged prostate in Japan [24]. However, steroidal antagonists exhibit side effects due to cross-activity with other steroid hormone receptors, and therefore various nonsteroidal AR antagonists (nonsteroidal antiandrogens, NSAAs) have been developed. Flutamide (9) is one of the first-generation nonsteroidal AR antagonists; it was discovered in 1967 and has been in clinical use since the 1980s [25,26]. Flutamide (9) has also been a lead compound for the development of various novel nonsteroidal AR antagonists. Two other first-generation NSAAs, the hydantoin derivative nilutamide (10) [27,28] and the sulfone derivative bicalutamide (11) [29,30], have been in clinical use since the 1990s. Bicalutamide (11) is the most potent of the three, having the highest receptor affinity and a superior ADMET profile [31], and is, therefore, the most widely used first-generation NSAA for prostate cancer. Topilutamide (12) is also a first-generation NSAA used for the treatment of pattern hair loss in the Czech Republic and Slovakia [32].