Ligand Scientists Discover Tissue-Selective Female Hormone Mimics

June 23, 1998

The Journal of Medicinal Chemistry Highlights Discovery of First Progesterone Mimic To Act Selectively On Uterine Cells And Reproductive Tract With Reduced Impact On Breast Cells

SAN DIEGO, Calif., June 23, 1998--Scientists from Ligand (LYE-gand) Pharmaceuticals Incorporated (Nasdaq: LGND) have discovered "designer" progestins that show a protective activity in the uterus without concomitant stimulation of breast-cell growth. Research surrounding this discovery was released today by the Journal of Medicinal Chemistry, a leading peer-reviewed journal for discoveries in the medicinal chemistry field. Data featured in the journal describe two novel non-steroidal progestin compounds, (S)-LG120746 and (S)-LG120747 that were tested in animal models and demonstrated the ability to selectively stimulate tissues within the body.

Currently available steroidal progestins, which are most often used in hormone replacement therapy and birth control, do not exhibit this ability to discern between tissues or cell types. All progestins used in clinical practice today are steroids, and while they provide a positive benefit, they also carry the potential of enhancing cancer risk in women since they can stimulate cellular proliferation in several types of tissues--most notably breast tissue.

"With this publication, Ligand has revealed the discovery of a completely novel progesterone receptor pharmacophore that may have distinct clinical advantages over currently available steroidal progestin therapies," said Dr. Andrés Negro-Vilar, Ligand Senior Vice President and Chief Scientific Officer. "These compounds should provide a clear benefit when used in hormone replacement therapy and other important female health applications."

Ligand's research team recognized (S)-LG120746's and (S)-LG120747's progestin effect through the application of three in vivo tests or assays. The scientists applied these assays to the Ligand compounds and to medroxyprogesterone acetate (MPA), a commonly prescribed synthetic progestin.

"Two in vivo assays--uterine weight measurements and the ability to maintain pregnancy despite the administration of the progesterone blocker mifepristone--confirmed that the Ligand compounds act like naturally occurring progesterone, but at doses lower than the MPA standard, particularly in the pregnancy maintenance assay," said Todd Jones, Ph.D., Director of Medicinal Chemistry at Ligand. "A third in vivo assay, designed to measure the proliferation of milk-producing buds present in the breast tissue before and after the drug's administration, revealed that the Ligand compounds were six to nine times less stimulating than was MPA." This proliferation of breast cells represents a potential risk for the development of breast cancer.

"The possibilities for these investigations are far-reaching," continued Dr. Jones.

"The opportunity to design specific progestins may one day make hormone replacement therapy (HRT) more appealing and less risky. Tissue-selective estrogens have received a great deal of recent attention. Now Ligand has identified compounds that represent the other side of the HRT coin: Tissue-selective progestins in the future hold hope to offer women significant clinical advances with far fewer side effects."

Ligand discovered (S)-LG120746 and (S)-LG120747 through the application of its proprietary intracellular receptor (IR) technology. Hormones such as progesterone are signaling molecules that influence and regulate certain functions by turning on or off specific genes located in the nucleus of a cell. The Ligand-developed progestins are small enough to enter a cell, and they are selective enough to bind with the specific receptor that will "turn on" the positive responses of progesterone therapy without activating potentially negative progestin effects, such as the proliferation of breast tissue.

Since 1989, Ligand Pharmaceuticals Incorporated has established a leadership position in gene transcription technology, particularly intracellular receptor (IR) technology and Signal Transducers and Activators of Transcription (STATs). Ligand has applied IR and STATs technology to the discovery and development of small molecule drugs to enhance therapeutics and safety profiles and to address unmet patient needs in cancer, women's and men's health and skin diseases, as well as osteoporosis, metabolic, cardiovascular and inflammatory disease.

This document may contain certain forward-looking statements by Ligand and actual results could differ materially from those described as a result of certain risks and uncertainties, including, without limitation (a) studies in animals may not translate to human results; (b) that early in vivo assay results may not be predictive of any results in animals or humans; (c) that these or any potential products under development by Ligand or any of its partners may not receive approval from the U.S. Food and Drug Administration or other authorities to market any of these products; (d) that, there may not be a market for the drugs, if, in fact, the drugs are approved for marketing. The Company undertakes no obligation to update these statements for events or circumstances occurring after the date hereof.
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Ligand Pharmaceuticals Incorporated

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