Structural modulation of oxidative metabolism in design of improved benzothiophene selective estrogen receptor modulators

Zhihui Qin, Irida Kastrati, Rezene T. Ashgodom, Daniel D. Lantvit, Cassia R. Overk, Yongsoo Choi, Richard B. Van Breemen, Judy L. Bolton, Gregory R.J. Thatcher

Research output: Contribution to journalArticlepeer-review

16 Scopus citations


Raloxifene and arzoxifene are benzothiophene selective estrogen receptor modulators (SERMs) of clinical use in postmenopausal osteoporosis and treatment of breast cancer and potentially in hormone replacement therapy. The benefits of arzoxifene are attributed to improved bioavailability over raloxifene, whereas the arzoxifene metabolite, desmethylarzoxifene (DMA) is a more potent antiestrogen. As polyaromatic phenolics, benzothiophene SERMs undergo oxidative metabolism to electrophilic quinoids. The long-term clinical use of SERMs demands increased understanding of correlations between structure and toxicity, with metabolism being a key component. A homologous series of 4′-substituted 4′-desmethoxyarzoxifene derivatives was developed, and metabolism was studied in liver and intestinal microsomes. Formation of glutathione conjugates was assayed in rat liver microsomes and novel adducts were characterized by liquid chromatography-tandem mass spectrometry. Formation of glucuronide conjugates was assayed in human intestine and liver microsomes, demonstrating formation of glucuronides ranging from 5 to 100% for the benzothiophene SERMs: this trend was inversely correlated with the loss of parent SERM in rat liver microsomal incubations. Molecular orbital calculations generated thermodynamic parameters for oxidation that correlated with Hammett substituent constants; however, metabolism in liver microsomes correlated with a combination of both Hammett and Hansch lipophilicity parameters. The results demonstrate a rich oxidative chemistry for the benzothiophene SERMs, the amplitude of which can be powerfully modulated, in a predictable manner, by structural tuning of the 4′-substituent. The predicted extensive metabolism of DMA was confirmed in vivo and compared with the relatively stable arzoxifene and F-DMA.

Original languageEnglish (US)
Pages (from-to)161-169
Number of pages9
JournalDrug Metabolism and Disposition
Issue number1
StatePublished - Jan 2009
Externally publishedYes

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science


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