Diphenyl ethers as androgen receptor antagonists for the topical suppression of sebum production Lorna H. Mitchell a, * , Lain-Yen Hu b , Maria Nguyen b , Stephen Fakhoury c , Yvonne Smith d , Donna Iula e , Catherine Kostlan f , Matthew Carroll b , Danielle Dettling g , Daniel Du b , David Pocalyko h , Kimberly Wade i , Bruce Lefker b a Pfizer Global Research and Development, Sandwich Laboratories, Ramsgate Road, Sandwich, CT13 9NJ, UK b Pfizer Global Research and Development, Groton Laboratories, CT 06340, USA c Pfizer Global Research and Development, Michigan Laboratories, MI 48105, USA d Decision Informatics, Ltd, Ann Arbor, MI 48104, USA e Cayman Chemical, Ann Arbor, MI 48108, USA f IDSC, LLC, Chelsea MI 48118, USA g Pfizer Global Research and Development, Research Technology Center, MA 02139, USA h Pfizer Global Research and Development, La Jolla Laboratories, CA 92121, USA i Pfizer Global Research and Development, St Louis Laboratories, MO 63141, USA article info Article history: Received 1 February 2009 Revised 25 February 2009 Accepted 26 February 2009 Available online 3 March 2009 Keywords: Androgen receptor Antagonist Sebum Topical Diphenyl ether AR abstract A series of diphenyl ethers was prepared and evaluated for androgen receptor antagonist activity in human androgen receptor binding and cellular functional assays. Analogs with potent in vitro activities were evaluated for topical in vivo efficacy in the Golden Syrian Hamster ear model. Several compounds showed reduction in wax esters in this validated animal model. Ó 2009 Elsevier Ltd. All rights reserved. The androgen receptor (AR) is responsible for the activation of genes involved in the pathogenesis of acne and alopecia. 1 The onset of acne vulgaris infections in the pilosebaceous unit is associated with excess sebum production. The production of sebum is regu- lated by the androgens testosterone and 5a-dihydrotestosterone (5a-DHT). Androgen receptor antagonists, such as cyproterone acetate 2,3 and RU-58841 4 have been shown to suppress sebum pro- duction when applied topically. Mining of data from our AR agonist program identified a number of compounds that bound to the androgen receptor but did not pos- sess agonist activity. A reevaluation showed that some of these were full antagonists, for example diphenyl ethers such as 1, and we have used them as starting points for our program to identify AR antago- nists (Fig. 1) for the topical suppression of sebum production. 5 The chlorine of hit 1 could be relocated from the 2-position to the 3-position (2) with retention of AR binding (ARB) 6 and full antagonist activity in a cellular assay (ARCELL) 7 (Table 1). Unfortu- nately, the chlorobenzonitriles exhibited photoinstability which is not desirable in a topical agent. We therefore examined the 3-trif- luoromethylbenzonitrile template based on precedence of known AR binders. 8 Gratifyingly the initial tolyl analog, 3a, retained AR binding activity, a full antagonist profile, and was photostable but, unfortunately, it lost appreciable cellular activity. The compounds were synthesized by phenol displacement of the desired para-fluorobenzonitrile template under basic condi- tions (Scheme 1). 9 0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2009.02.104 * Corresponding author. Tel.: +44 1304 649599. E-mail address: lorna.mitchell@pfizer.com (L.H. Mitchell). NC O Me Cl 1 Figure 1. Initial AR antagonist lead compound. Bioorganic & Medicinal Chemistry Letters 19 (2009) 2176–2178 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl