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

  • J Med Chem. 2008 Nov 13;51(21):7010-4. doi: 10.1021/jm8009316.
Jie Jack Li  1 ,  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
Affiliations
  • 1. Department of Chemistry, Michigan Laboratories, Pfizer Global Research & Development, 2800 Plymouth Road, Ann Arbor, Michigan 48105, USA. [email protected]
PMID: 18921992 DOI: 10.1021/jm8009316
Abstract

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.

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