4-(Alkylthio)- and 4-(arylthio)-benzonitrile derivatives as androgen receptor antagonists for the topical suppression of sebum production

• Published in: Bioorganic & medicinal chemistry letters Vol. 19; no. 5; pp. 1310 - 1313
• Main Authors: Mitchell, Lorna, Wang, Zhi, Hu, Lain-Yen, Kostlan, Catherine, Carroll, Matthew, Dettling, Danielle, Du, Daniel, Pocalyko, David, Wade, Kimberly
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.03.2009
• Subjects: Androgen Antagonists - chemistry; Androgen Antagonists - pharmacology; Androgen receptor; Androgen receptor antagonist; Androgen Receptor Antagonists; Animals; Antiandrogen; Cell Line; Cricetinae; Humans; Insecta; Male; Mesocricetus; Nitriles - chemical synthesis; Nitriles - pharmacology; Protein Binding - drug effects; Protein Binding - physiology; Receptors, Androgen - metabolism; Sebum; Sebum - drug effects; Sebum - secretion; Softdrug; Thioether; Topical; Thioether; Androgen receptor; Antiandrogen; Sebum; Topical; Androgen receptor antagonist; Softdrug
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2009.01.063

The first examples of thioether-substituted benzonitriles as potential soft-drug androgen receptor antagonists are reported. A number of 4-(alkylthio)- and of 4-(arylthio)-benzonitrile analogs were evaluated in human androgen receptor binding and cellular functional assays. Analogs with potent in vitro binding and cellular activities were evaluated for topical in vivo efficacy in the Golden Syrian hamster ear model. Analogs from both the 4-(alkylthio)- and of 4-(arylthio)-benzonitrile series showed moderate reduction of wax esters in vivo.