Discovery of Vilaprisan (BAY 1002670): A Highly Potent and Selective Progesterone Receptor Modulator Optimized for Gynecologic Therapies.

Progesterone plays an important role in the female reproductive system. However, there is also evidence that gynecologic disorders/diseases such as uterine fibroids and endometriosis are progesterone-dependent. Steroidal and non-steroidal selective progesterone receptor modulators (SPRMs) have shown potential for the treatment of such diseases. Steroidal SPRMs, including mifepristone and ulipristal acetate, have proven effective in clinical trials. However, several steroidal SPRMs containing a dimethylamino substituent have been associated with elevated liver enzymes in patients. An earlier drug discovery program identified lonaprisan as a highly selective SPRM that did not show drug-related change in liver enzyme activity. Building on data obtained from that work, here we describe the research program that culminated in the discovery of a novel steroidal SPRM, vilaprisan, which combines an extremely high potency with very favorable drug metabolism and pharmacokinetic properties. Vilaprisan has entered clinical development and is currently undergoing phase 3 clinical trials.

Gaze Behavior of Gymnastics Judges: Where Do Experienced Judges and Gymnasts Look While Judging?

Gymnastics judges and former gymnasts have been shown to be quite accurate in detecting errors and accurately judging performance. PURPOSE: The purpose of the current study was to examine if this superior judging performance is reflected in judges' gaze behavior. METHOD: Thirty-five judges were asked to judge 21 gymnasts who performed a skill on the vault in a video-based test. Classifying 1 sample on 2 different criteria, judging performance and gaze behavior were compared between judges with a higher license level and judges with a lower license level and between judges who were able to perform the skill (specific motor experience [SME]) and those who were not. RESULTS: The results revealed better judging performance among judges with a higher license level compared with judges with a lower license level and more fixations on the gymnast during the whole skill and the landing phase, specifically on the head and arms of the gymnast. Specific motor experience did not result in any differences in judging performance; however, judges with SME showed similar gaze patterns to those of judges with a high license level, with 1 difference in their increased focus on the gymnasts' feet. CONCLUSION: Superior judging performance seems to be reflected in a specific gaze behavior. This gaze behavior appears to partly stem from judges' own sensorimotor experiences for this skill and reflects the gymnasts' perspective onto the skill.

HMGA proteins regulate the expression of FGF2 in uterine fibroids.

In human fibroids genes encoding the high-mobility proteins containing the 'AT-hook' DNA-binding motif (HMGA) are frequently affected by non-random chromosomal rearrangements. Thus, the different proteins and their derivatives resulting from these genomic rearrangements can be assumed to be involved in the genesis of these tumors by activation of largely identical downstream pathways. Constructs encoding HMGA proteins and their relevant derivatives were overexpressed in human myometrial cells, and RNA isolated from these cells was hybridized to filter arrays. Four genes were either up- or down-regulated at least 2-fold after overexpression of either of the HMGA genes and their derivatives. FGF2 (fibroblast growth factor 2) was one of these genes, and we were then able to show by microarray analyses that tumors with rearrangements of the HMGA2 locus (n = 8) expressed significantly higher levels of FGF2 than those with an apparently normal karyotype (n = 47). Accordingly, by quantitative real-time PCR uterine leiomyomas with rearrangements of the HMGA2 locus were found to express significantly higher levels of FGF2 than those with an apparently normal karyotype with a linear relationship between the expression of FGF2 and the level of HMGA2 overexpression as well as the tumor size. The results of western blot analyses confirmed these findings. Moreover, stimulation of myometrial tissue by FGF1, a strong inducer of HMGA2, leads to an increase of HMGA2 as well as FGF2 expression. In conclusion, the results contribute to the understanding of the association between the overexpression of HMGA proteins, the regulation of FGF2 expression and the size of fibroids.

In vitro characterization of ZK 230211--A type III progesterone receptor antagonist with enhanced antiproliferative properties.

The progesterone receptor (PR) is a key regulator of female reproductive functions. Compounds with progesterone inhibiting effects (PR antagonists) have found numerous utilities in female reproductive health, ranging from contraception to potential treatment of progesterone-dependent diseases like uterine leiomyomas. Based on in vitro characteristics such as DNA binding activity and partial agonistic transcriptional behavior in the presence of protein kinase A activators (cyclic-AMP), three types of PR modulators with antagonistic properties have been defined. In this study, we analyzed the in vitro characteristics of the PR antagonist ZK 230211 in comparison to the classical antagonists onapristone and mifepristone. We focused on PR actions in genomic signaling pathways, including DNA binding activity, nuclear localization and association with the nuclear receptor corepressor (NCoR) as well as actions in non-genomic signaling, such as the activation of c-Src kinase signaling and cyclin D1 gene promoter activity. ZK 230211 represents a type of PR antagonist with increased inhibitory properties in comparison to mifepristone and onapristone. When liganded to the progesterone receptor, ZK 230211 induces a strong and persistent binding to its target response element (PRE) and increases NCoR recruitment in CV-1 cells. Furthermore, ZK 230211 displays less agonistic properties with regard to the association of PR isoform B and the cytoplasmic c-Src kinase in HeLa cells. It represses T47D cell cycle progression, in particular estradiol-induced S phase entry. In summary, our studies demonstrate ZK 230211 to be a type III progesterone receptor antagonist which is characterized by very strong DNA binding activity and strong antiproliferative effects in the cancer cell lines HeLa and T47D.

Global gene expression profiling of progesterone receptor modulators in T47D cells provides a new classification system.

Progesterone receptor modulators (PRMs) play an important role in women's health. They are widely used in oral contraception or hormone therapy, and provide an attractive treatment approach for gynecological disorders such as uterine leiomyomas, endometriosis or breast cancer. Due to the broad range of activities, various studies were conducted to assess progesterone receptor antagonists (PAs) and selective progesterone receptor modulators (SPRMs) with respect to progesterone receptor (PR) agonistic and antagonistic activities in vivo. These properties are not always adequately reflected in classical in vitro models, especially differences in the agonistic potential of SPRMs, such as asoprisnil, J1042, and J912, and mixed antagonists, such as mifepristone, are not sufficiently substantiated. The effects of PRMs upon gene expression in progesterone target tissues such as breast epithelium and uterus are poorly understood. This study compares the properties of PR ligands using mammalian two-hybrid assays and gene expression profiling. The protein-protein interaction analyses in HeLa cells provide for specific ligand-induced PR conformations, whereas Affymetrix GeneChip HG-U133Plus2.0 analyses in T47D breast cancer cells indicate the transcriptional activity on the level of target genes. The analyses comprise the pure agonist R5020, the non-steroidal PR modulator PRA-910, SPRMs (J1042, asoprisnil, J912), the mixed antagonist mifepristone, classical antagonists (onapristone, ZK 137316) and the pure antagonist lonaprisan to consider all types of ligands described before. Marginal differences were identified in coactivator interaction profiles at all, but significant differences between SPRMs and PR antagonists (PAs) were observed in recruiting the LXXLL-motif containing peptide (LX-H10), very similar to in vivo activities in endometrial transformation in the rabbit (McPhail test). Global gene expression profiles demonstrated progesterone-independent effects for all PR modulators examined and emphasised similarities of asoprisnil and J1042 compared to J912 and all types of PR antagonists. In summary, the data support the popular concept of PR modulator classification in agonists, selective progesterone receptor modulators, mixed and pure antagonists. It further refines previous classification models and accentuates unique effects for each PR modulator.

Changes in maximum muscle strength and rapid muscle force characteristics after long-term special support and reconnaissance missions: a preliminary report.

PURPOSE: The purpose of the present study was to examine the impact of 8 days of immobilization during a Special Support and Reconnaissance mission (SSR) on muscle mass, contraction dynamics, maximum jump height/power, and body composition. METHODS: Unilateral maximal voluntary contraction, rate of force development, and maximal jump height were tested to assess muscle strength/power along with whole-body impedance analysis before and after SSR. RESULTS: Body weight, fat-free mass, and total body water decreased (4-5%) after SSR, along with impairments in maximal jump height (-8%) and knee extensor maximal voluntary contraction (-10%). Furthermore, rate of force development was severely affected (-15-30%). CONCLUSIONS: Eight days of immobilization during a covert SSR mission by Special Forces soldiers led to substantial decrements in maximal muscle force and especially in rapid muscle force capacity. This may negatively influence the ability for rapid exfiltration and redeployment, respectively.

Investigational developments for the treatment of progesterone-dependent diseases.

BACKGROUND: Clinical evidence has shown that conditions such as uterine fibroids, endometriosis and breast cancer are progesterone-dependent diseases. Therefore, progesterone receptor (PR) antagonists and selective PR modulators (SPRMs) are under development for the treatment of these conditions. However, the first PR antagonists that became available exhibit insufficient selectivity or tolerability for the chronic administration required to treat these conditions. Despite initial setbacks, development of second-generation PR antagonists with better selectivity continues forward. OBJECTIVE: In this review we would like to summarise prospects for using PR antagonists for the treatment of uterine fibroids, endometriosis and breast cancer, and to give an overview of the development of new steroidal and non-steroidal PR antagonists. METHOD: Available preclinical and clinical data and publications have been reviewed with the focus on scientific background and use in the three mentioned indications. RESULTS/CONCLUSION: Preclinical and clinical evidence demonstrated that PR antagonists and SPRMs are effective for the treatment of progesterone-dependent diseases. Future development will demonstrate if they can become important drugs.