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.

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.