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.