No abstract

P, ec~ived 25 January 1991Thirteen point mutations of human interleakin-6 at the C-terminus were constructed at the eDNA.level, Two degenerate oliBonucleotid¢ primers were used for PCR synthesis of two groups or point mutations at positions 182 and 1114. The mutated cDNAs were in vitro transcribed and transla.ted and subsequently assayed for biological activity in the B9 cell proliferation test. Our results confirm our fornter findinlls obtained with deletion mutants on the importance of the C.terminus of IL-6 for biological activity, In additiotl, we now present ~videnc¢ for the importance of an a.hdis at the C.tern'finus of IL-6 and the presence of the positive charlle at position 1112 for biololtical activity.

Development of muscle collagen cross-linkage was investigated by determining hydroxylysylpyridinoline and lysylpyridinoline contents of longissimus dorsi, semitendinosus and extensor carpi ulnaris muscles. These were removed from male, female and castrated German Simmental cattle (150-620 days old) fattened on different energy levels and related to possible influences of sex, feeding intensity and type of muscle. In intramuscular collagen, an age-related increase in pyridinoline content was found. Cross-link formation was also influenced by sex and feeding intensity. Epimysia exhibited differences in pyridinoline content which were probably due to differences in physical strain of the muscles.

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 secondgeneration 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 progesteronedependent diseases. Future development will demonstrate if they can become important drugs.

No abstract

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.

Sex steroid receptors are ligand-triggered transcription factors. Oestrogen, progesterone and androgen receptors form, together with the glucocorticoid and mineralocorticoid receptors, a subgroup of the superfamily of nuclear receptors. They share a common mode of action, namely translating a hormone-i.e. a small-molecule signal-from outside to changes in gene expression and cell fate, and thereby represent "natural" pharmacological targets.For pharmacological therapy, these receptors have originally been addressed by hormones and synthetic hormone analogues in order to overcome pathologies related to deficiencies in the natural ligands. Another major use for female sex hormone receptor modulators is oral contraception, i.e. birth control.On the other side, blocking the activity of sex steroid receptors has become an established way to treat hormone-dependent malignancies, such as breast and prostate cancer.In this review, we will discuss how the experience gained from the classical pharmacology of these receptors and their molecular similarities led to new options for the treatment of gender-specific diseases and highlight recent progress in medicinal chemistry of sex hormone-modulating drugs.

C-terminally deleted analogs of human interleukin-6 (IL-6) have been constructed at the cDNA level, and after cell-free transcription and translation their biological activity was analyzed. Removal of only 4 amino acids resulted in complete loss of biological activity as determined by the B9 cell proliferation assay. Secondary structure prediction of human IL-6 resulted in 58% helix, 14% ~-structure, and 28% turn and coil (average of 3 inde pendent methods). The circular dichroism of recombinant human IL-6 was measured in the near and far W. Evaluation of the latter in terms of secondary structures gave 67% helix, 15% /?-structure, and 18% turn and coil.