In vitro and in vivo characterization of a novel nonsteroidal, species-specific progesterone receptor modulator, PRA-910.
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.
Zhang
Z
Z
Women's Health and Musculoskeletal Biology, Wyeth Research, 500 Arcola Road, 19426 Collegeville, USA
Lundeen
S G
SG
Slayden
O
O
Zhu
Y
Y
Cohen
J
J
Berrodin
T J
TJ
Bretz
J
J
Chippari
S
S
Wrobel
J
J
Zhang
P
P
Fensome
A
A
Winneker
R C
RC
Yudt
M R
MR
D000818:Animals; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D005260:Female; D006574:Heterocyclic Compounds, 2-Ring / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D009570:Nitriles / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011980:Receptors, Progesterone / Q000187:drug effects* / Q000378:metabolism; D013045:Species Specificity; D020798:Two-Hybrid System Techniques
D006574:Heterocyclic Compounds, 2-Ring; D009570:Nitriles; C488515:PRA-910; D011980:Receptors, Progesterone