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Karen E Sexton,
Stephen Barrett,
Katy Bridgwood, Matthew Carroll,
Danielle Dettling,
Daniel Du,
Stephen Fakhoury,
Victor Fedij,
Lain-Yen Hu,
Catherine Kostlan,
David Pocalyko,
Neil Raheja,
Yvonne Smith,
Veerabahu Shanmugasundaram,
Kimberly Wade
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ABSTRACT: A series of pantolactam based compounds were identified as potent antagonists for the androgen receptor (AR). Those that possessed properties suitable for topical delivery were evaluated in the validated Hamster Ear Model. Several compounds were found to be efficacious in reducing wax esters, a major component of sebum, initiating further preclinical work on these compounds.
Bioorganic & medicinal chemistry letters 09/2011; 21(18):5230-3. · 2.65 Impact Factor
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Lorna H Mitchell,
Lain-Yen Hu,
Maria Nguyen,
Stephen Fakhoury,
Yvonne Smith,
Donna Iula,
Catherine Kostlan, Matthew Carroll,
Danielle Dettling,
Daniel Du,
David Pocalyko,
Kimberly Wade,
Bruce Lefker
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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.
Bioorganic & medicinal chemistry letters 05/2009; 19(8):2176-8. · 2.65 Impact Factor
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ABSTRACT: 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.
Bioorganic & medicinal chemistry letters 02/2009; 19(5):1310-3. · 2.65 Impact Factor
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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, [......],
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
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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.
Journal of Medicinal Chemistry 11/2008; 51(21):7010-4. · 4.80 Impact Factor
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Jennifer A Van Camp,
Lain-Yen Hu,
Catherine Kostlan,
Bruce Lefker,
Jie Li,
Lorna Mitchell,
Zhi Wang,
Wen-Song Yue, Matthew Carroll,
Danielle Dettling,
Daniel Du,
David Pocalyko,
Kimberly Wade
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ABSTRACT: A series of substituted 4-aryl-2-trifluoromethylbenzonitrile analogs were evaluated in the human androgen receptor binding and cellular functional assays. Analogs with sufficient in vitro binding and cellular potency (IC(50)<200 nM) were tested in the progesterone receptor binding assay for selectivity and in the Golden Syrian hamster ear model for in vivo efficacy. Within the series, compound 4 e was identified to be the most active analog in vivo (wax ester inhibition=86%).
Bioorganic & Medicinal Chemistry Letters 11/2007; 17(20):5529-32. · 2.55 Impact Factor
