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J. Biol. Chem., Vol. 280, Issue 31, 28468-28475, August 5, 2005

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Molecular and Pharmacological Properties of a Potent and Selective Novel Nonsteroidal Progesterone Receptor Agonist Tanaproget^*

Zhiming Zhang, Andrea M. Olland¶||, Yuan Zhu, Jeff Cohen, Tom Berrodin, Susan Chippari, Chandrasekaran Appavu**, Shen Li**, James Wilhem¶||, Raj Chopra¶||, Andrew Fensome¶, Puwen Zhang¶, Jay Wrobel¶, Rayomand J. Unwalla¶, C. Richard Lyttle, and Richard C. Winneker

From the Women's Health Research Institute and the Departments of ^¶Chemical and Screening Sciences and ^**Drug Safety and Metabolism, Wyeth Research, Collegeville, Pennsylvania 19426 and ^||Wyeth Research, Cambridge, Massachusetts 02140

Progesterone receptor (PR) agonists have several important applications in women's health, such as in oral contraception and post-menopausal hormone therapy. Currently, all PR agonists used clinically are steroids. Because of their interactions with other steroid receptors, steroid-metabolizing enzymes, or other steroid-signaling pathways, these drugs can pose significant side effects in some women. Efforts to discover novel nonsteroidal PR agonists with improved biological properties led to the discovery of tanaproget (TNPR). TNPR binds to the PR from various species with a higher relative affinity than reference steroidal progestins. In T47D cells, TNPR induces alkaline phosphatase activity with an EC₅₀ value of 0.1 nM, comparable with potent steroidal progestins such as medroxyprogesterone acetate (MPA) and trimegestone (TMG), albeit with a reduced efficacy (60%). In a mammalian two-hybrid assay to measure PR agonist-induced interaction between steroid receptor co-activator-1 and PR, TNPR showed similar potency (EC₅₀ value of 0.02 nM) and efficacy to MPA and TMG. Importantly, in key animal models such as the rat ovulation inhibition assay, TNPR demonstrates full efficacy and an enhanced progestational potency (30-fold) when compared with MPA and TMG. Furthermore, TNPR has relatively weak interactions with other steroid receptors and binding proteins and little effect on cytochrome P450 metabolic pathways. Finally, the three-dimensional crystal structure of the PR ligand binding domain with TNPR has been delineated to demonstrate how this nonsteroidal ligand achieves its high binding affinity. Therefore, TNPR is a structurally novel and very selective PR agonist with an improved preclinical pharmacological profile.

Received for publication, April 15, 2005 , and in revised form, May 27, 2005.

The atomic coordinates and structure factors (code 1ZUC) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Division of Endocrinology and Reproductive Disorders, Women's Health Research Inst., Wyeth Research, 500 Arcola Rd., Collegeville, PA 19355. Tel.: 484-865-5627; Fax: 484-865-9389; E-mail: zhangz{at}wyeth.com.

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