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This version published online on July 7, 2005
Endocrinology, doi:10.1210/en.2005-0024
A more recent version of this article appeared on October 1, 2005
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Submitted on January 10, 2005
Accepted on June 29, 2005

A New Selective Estrogen Receptor Modulator (SERM) with Potent Uterine Antagonist Activity, Agonist Activity in Bone, and Minimal Ovarian Stimulation

Andrew G. Geiser*, Conrad W. Hummel, Michael W. Draper, Judith W. Henck, Ilene R. Cohen, Daniel G. Rudmann, Kevin B Donnelly, Mary D. Adrian, Timothy A. Shepherd, Owen B. Wallace, Denis J. McCann, Samuel W. Oldham, Henry U. Bryant, Masahiko Sato, and Jeffrey A. Dodge

Affiliations: Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana, 46285; Array Biopharma, 3200 Walnut Street, Boulder, Colorado 80301

* To whom correspondence should be addressed. E-mail: geiser_andrew_g{at}lilly.com.

The use of selective estrogen receptor modulators (SERMs) for the treatment of estrogen-dependent diseases in pre-menopausal women has been hindered by undesirable ovarian stimulation and associated risks of ovarian cysts. We have identified a SERM compound (LY2066948) that is a strong estrogen antagonist in the uterus yet has minimal effects on the ovaries of rats. LY2066948 binds with high affinity to both estrogen receptors, and has potent estrogen antagonist activity in human uterine and breast cancer cells. Oral administration of LY2066948 to immature rats blocked uterine weight gain induced by ethynyl estradiol with an ED50 of 0.07 mg/kg. Studies in mature rats demonstrated that LY2066948 decreases uterine weight by 51% after 35 days treatment, confirming potent uterine antagonist activity over several estrous cycles. This strong uterine response contrasted with the minimal effects on the ovaries: serum estradiol levels remained within the normal range, while histologic evaluation showed granulosa cell hyperplasia in few of the rats. Bone studies demonstrated that LY2066948 prevented ovariectomy-induced bone loss and treatment of ovary-intact rats caused no bone loss, confirming estrogen receptor agonist skeletal effects. Collectively, these data show that LY2066948 exhibits a tissue specific profile consistent with strong antagonist activity in the uterus, agonist activity in bone, and minimal effects in the ovaries.
Key words: SERM • uterine leiomyoma • uterine fibroid • ovary • bone




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