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

• Published in: Endocrinology (Philadelphia) Vol. 146; no. 10; pp. 4524 - 4535
• Main Authors: Geiser, Andrew G., Hummel, Conrad W., Draper, Michael W., Henck, Judith W., Cohen, Ilene R., Rudmann, Daniel G., Donnelly, Kevin B, Adrian, Mary D., Shepherd, Timothy A., Wallace, Owen B., McCann, Denis J., Oldham, Samuel W., Bryant, Henry U., Sato, Masahiko, Dodge, Jeffrey A.
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Endocrine Society 01.10.2005; Oxford University Press
• Subjects: 17β-Estradiol; Agonists; Animals; Biological and medical sciences; Bone and Bones - drug effects; Bone and Bones - physiology; Bone loss; Cell Line, Tumor; Estrogen receptors; Estrogens; Ethinyl Estradiol - pharmacology; Ethinylestradiol; Female; Fundamental and applied biological sciences. Psychology; Humans; Hyperplasia; Kinetics; Naphthalenes - pharmacology; Oral administration; Ovarian cancer; Ovariectomy; Ovaries; Ovulation Induction; Piperidines - pharmacology; Rats; Receptors; Receptors, Estrogen - agonists; Receptors, Estrogen - antagonists & inhibitors; Receptors, Estrogen - drug effects; Receptors, Estrogen - physiology; Selective estrogen receptor modulators; Sex hormones; Sexual Maturation; Stimulation; Uterine cancer; Uterus; Uterus - drug effects; Uterus - physiology; Vertebrates: endocrinology; Weight; Osteoarticular system; Ovary; Agonist; Selective estrogen receptor modulator; Uterus; Female genital system; Antagonist; Bone
• DOI: 10.1210/en.2005-0024
• ISSN: 0013-7227

The use of selective estrogen receptor modulators for the treatment of estrogen-dependent diseases in premenopausal women has been hindered by undesirable ovarian stimulation and associated risks of ovarian cysts. We have identified a selective estrogen receptor modulator 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 d 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, whereas 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.