In Vitro and In Vivo Characterization of a Novel Nonsteroidal, Species-Specific Progesterone Receptor Modulator, PRA-910

摘要: 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 identifying more receptor-specific and tissue-selective modulators, we discovered a novel nonsteroidal, 6-aryl benzoxazinone compound, PRA-910, that displays unique vitro vivo activities. PR/PRE reporter assay COS-7 cells, PRA-910 shows potent antagonist activity with IC50 value approximately 20 nM. alkaline phosphatase human breast cancer cell line T47D, partial at low concentrations also effective agonist higher (EC50 700 nM). binds to high affinity (K d=4 nM) was previously shown exhibit greater than 100-fold selectivity for versus other steroid receptors. adult ovariectomized rat, antagonist. It inhibits progesterone-induced uterine decidual response ED50 0.4 mg/kg, p.o., reverses suppression estradiol-induced complement C3 expression potency similar RU-486. nonhuman primate, however, agonist. effect on endometrial histology strongly resembles progesterone. This compound suppresses epithelial proliferation both estrogen endometrium as would. summary, structurally biologically selective modulator either or activity, depending context, concentration, species.