Rational Design and Synthesis of 4-((1R,2R)-2-Hydroxycyclohexyl)-2(trifluoromethyl)benzonitrile (PF-998425), a Novel, Nonsteroidal Androgen Receptor Antagonist Devoid of Phototoxicity for Dermatological Indications

Li, Jie Jack; Iula, Donna M.; Nguyen, Maria N.; Hu, Lain-Yen; Dettling, Danielle; Johnson, Theodore R.; Du, Daniel Y.; Shanmugasundaram, Veerabahu; A. Van Camp, Jennifer; Wang, Zhi; Harter, William G.; Yue, Wen-Song; Boys, Mark L.; Wade, Kimberly J.; Drummond, Elena M.; Samas, Brian M.; Lefker, Bruce A.; Hoge, Garrett S.; Lovdahl, Mark J.; Asbill, Jeffrey; Carroll, Matthew; Meade, Mary Ann; Ciotti, Susan M.; Krieger-Burke, Theresa

doi:10.1021/jm8009316.s001

jm8009316_si_001.pdf (1.65 MB)

Rational Design and Synthesis of 4-((1R,2R)-2-Hydroxycyclohexyl)-2(trifluoromethyl)benzonitrile (PF-998425), a Novel, Nonsteroidal Androgen Receptor Antagonist Devoid of Phototoxicity for Dermatological Indications

journal contribution

posted on 2008-11-13, 00:00 authored by Jie Jack Li, Donna M. Iula, Maria N. Nguyen, Lain-Yen Hu, Danielle Dettling, Theodore R. Johnson, Daniel Y. Du, Veerabahu Shanmugasundaram, Jennifer A. Van Camp, Zhi Wang, William G. Harter, Wen-Song Yue, Mark L. Boys, Kimberly J. Wade, Elena M. Drummond, Brian M. Samas, Bruce A. Lefker, Garrett S. Hoge, Mark J. Lovdahl, Jeffrey Asbill, Matthew Carroll, Mary Ann Meade, Susan M. Ciotti, Theresa Krieger-Burke

4-((1R,2R)-2-Hydroxycyclohexyl)-2(trifluoromethyl)benzonitrile [PF-0998425, (−)-6a] is a novel, nonsteroidal androgen receptor antagonist for sebum control and treatment of androgenetic alopecia. It is potent, selective, and active in vivo. The compound is rapidly metabolized systemically, thereby reducing the risk of unwanted systemic side effects due to its primary pharmacology. (−)-6a was tested negative in the 3T3 NRU assay, validating our rationale that reduction of conjugation might reduce potential phototoxicity.