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

4-((1 R,2 R)-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.