1. In vitro and in vivo characterization of a novel nonsteroidal, species-specific progesterone receptor modulator, PRA-910.
- Author
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Zhang Z, Lundeen SG, Slayden O, Zhu Y, Cohen J, Berrodin TJ, Bretz J, Chippari S, Wrobel J, Zhang P, Fensome A, Winneker RC, and Yudt MR
- Subjects
- Animals, COS Cells, Cell Line, Tumor, Chlorocebus aethiops, Female, Heterocyclic Compounds, 2-Ring metabolism, Humans, In Vitro Techniques, Male, Nitriles metabolism, Rats, Rats, Sprague-Dawley, Receptors, Progesterone metabolism, Species Specificity, Two-Hybrid System Techniques, Heterocyclic Compounds, 2-Ring pharmacology, Nitriles pharmacology, Receptors, Progesterone drug effects
- Abstract
The progesterone receptor (PR) is an important regulator of female reproduction. Consequently, PR modulators have found numerous pharmaceutical utilities in women's reproductive health. In the process of identifying more receptor-specific and tissue-selective PR modulators, we discovered a novel nonsteroidal, 6-aryl benzoxazinone compound, PRA-910, that displays unique in vitro and in vivo activities. In a PR/PRE reporter assay in COS-7 cells, PRA-910 shows potent PR antagonist activity with an IC50 value of approximately 20 nM. In the alkaline phosphatase assay in the human breast cancer cell line T47D, PRA-910 is a partial progesterone antagonist at low concentrations and is also an effective PR agonist at higher concentrations (EC50 value of approximately 700 nM). PRA-910 binds to the human PR with high affinity (Kd = 4 nM) and was previously shown to exhibit greater than 100-fold selectivity for the PR versus other steroid receptors. In the adult ovariectomized rat, PRA-910 is a potent PR antagonist. It inhibits progesterone-induced uterine decidual response with an ED50 value of 0.4 mg/kg, p.o., and reverses progesterone suppression of estradiol-induced complement C3 expression with potency similar to RU-486. In the nonhuman primate, however, PRA-910 is a PR agonist. The effect on endometrial histology strongly resembles that of progesterone. This unique compound also suppresses estradiol-induced epithelial cell proliferation and both estrogen and progesterone receptor expression in the uterine endometrium as a PR agonist would. In summary, PRA-910 is a structurally and biologically novel selective PR modulator with either PR agonist or antagonist activity, depending on context, concentration, and species.
- Published
- 2007