Design, Synthesis, and Biological Characterization of Metabolically Stable Selective Androgen Receptor Modulators

Craig A. Marhefka, Wenqing Gao, Kiwon Chung, Juhyun Kim, Yali He, Donghua Yin, Casey Bohl, James T. Dalton, Duane Miller

Research output: Contribution to journalArticle

106 Citations (Scopus)

Abstract

A series of nonsteroidal ligands were synthesized as second-generation agonists for the androgen receptor (AR). These ligands were designed to eliminate metabolic sites identified in one of our first-generation AR agonists, which was inactive in vivo due to its rapid metabolism to inactive constituents. The binding affinity of these compounds was evaluated using AR isolated from rat ventral prostate. These second-generation compounds bound the AR in a high affinity and stereoselective manner, with Ki values ranging from about 4 to 130 nM. The ability of these ligands to stimulate AR-mediated transcriptional activation was examined in cells transfected with the human AR and a hormone-dependent luciferase reporter gene. Although some compounds were unable to stimulate AR-mediated transcription, several demonstrated activity similar to that of dihydrotestosterone (DHT, an endogenous steroidal ligand for the AR). We also evaluated the in vivo pharmacologic activity of selected compounds in castrated male rats. Three compounds were identified as selective androgen receptor modulators (SARMs), exhibiting significant anabolic activity while having only moderate to minimal androgenic activity in vivo.

Original languageEnglish (US)
Pages (from-to)993-998
Number of pages6
JournalJournal of Medicinal Chemistry
Volume47
Issue number4
DOIs
StatePublished - Feb 12 2004

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Androgen Receptors
Ligands
Androgens
Dihydrotestosterone
Luciferases
Reporter Genes
Transcriptional Activation
Prostate
Hormones

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

Design, Synthesis, and Biological Characterization of Metabolically Stable Selective Androgen Receptor Modulators. / Marhefka, Craig A.; Gao, Wenqing; Chung, Kiwon; Kim, Juhyun; He, Yali; Yin, Donghua; Bohl, Casey; Dalton, James T.; Miller, Duane.

In: Journal of Medicinal Chemistry, Vol. 47, No. 4, 12.02.2004, p. 993-998.

Research output: Contribution to journalArticle

Marhefka, Craig A. ; Gao, Wenqing ; Chung, Kiwon ; Kim, Juhyun ; He, Yali ; Yin, Donghua ; Bohl, Casey ; Dalton, James T. ; Miller, Duane. / Design, Synthesis, and Biological Characterization of Metabolically Stable Selective Androgen Receptor Modulators. In: Journal of Medicinal Chemistry. 2004 ; Vol. 47, No. 4. pp. 993-998.
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