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

Magee-Womens Hospital, Pittsburgh, Pennsylvania, United States
Journal of Biological Chemistry (Impact Factor: 4.57). 09/2005; 280(31):28468-75. DOI: 10.1074/jbc.M504144200
Source: PubMed


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 EC(50) value of 0.1 nm, comparable with potent steroidal progestins such as medroxyprogesterone acetate (MPA) and trimegestone (TMG), albeit with a reduced efficacy ( approximately 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 (EC(50) 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.

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    • "For rat studies, the MPA dosage used was based on the IC50 of ovulation-inhibition in rats (0,1 mg kg−1 day−1) [36], to guarantee physiologically active concentrations, this concentration was multiplied tenfold (1 mg kg−1 day−1). Rats received a 90 day slow release pellet to ensure stable release. "
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    • "tures of the LBD of MR, GR, and AR complexed with an agonist ligand have been solved, and the contacts involved in activating these receptors have been identified (Matias et al., 2000; Bledsoe et al., 2002, 2005). The crystal structures of the human PRLBD associated with various progestins have also been solved (Williams and Sigler, 1998; Madauss et al., 2004; Zhang et al., 2005). Nevertheless, the contact(s) between progestins and the ligand-binding cavity that are required to trigger PR activation remained to be identified, as well as the structural elements that modulate progestin activity. "
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