Zhang Z, Lundeen S G, Slayden O, Zhu Y, Cohen J, Berrodin T J, Bretz J, Chippari S, Wrobel J, Zhang P, Fensome A, Winneker R C, Yudt M R
Women's Health and Musculoskeletal Biology, Wyeth Research, 500 Arcola Road, 19426 Collegeville, USA
Ernst Schering Found Symp Proc. 2007(1):171-97.
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.
孕激素受体（PR）是女性生殖的重要调节因子。因此，PR调节剂在女性生殖健康领域已发现众多药物用途。在寻找更多受体特异性和组织选择性PR调节剂的过程中，我们发现了一种新型非甾体6-芳基苯并恶嗪酮化合物PRA-910，它具有独特的体外和体内活性。在COS-7细胞的PR/PRE报告基因检测中，PRA-910显示出强效的PR拮抗剂活性，IC50值约为20 nM。在人乳腺癌细胞系T47D的碱性磷酸酶检测中，PRA-910在低浓度时是部分孕激素拮抗剂，在高浓度时也是有效的PR激动剂（EC50值约为700 nM）。PRA-910以高亲和力与人PR结合（Kd = 4 nM），并且先前已证明其对PR相对于其他类固醇受体具有大于100倍的选择性。在成年去卵巢大鼠中，PRA-910是强效的PR拮抗剂。它抑制孕激素诱导的子宫蜕膜反应，口服ED50值为0.4 mg/kg，并逆转孕激素对雌二醇诱导的补体C3表达的抑制作用，效力与RU-486相似。然而，在非人类灵长类动物中，PRA-910是PR激动剂。对子宫内膜组织学的影响与孕激素非常相似。作为PR激动剂，这种独特的化合物还抑制雌二醇诱导的上皮细胞增殖以及子宫内膜中雌激素和孕激素受体的表达。总之，PRA-910是一种结构和生物学上新颖的选择性PR调节剂，根据背景、浓度和物种的不同，具有PR激动剂或拮抗剂活性。
