The death of a cell is an inevitable part of its biology. During homeostasis, most cells die through apoptosis. If homeostasis is disturbed, cell death can switch to proinflammatory forms of death, such as necroptosis, pyroptosis, or NETosis. We demonstrate that the formation of neutrophil extracellular traps (NETs), a special form of neutrophil cell death that releases chromatin structures to the extracellular space, is dependent on gasdermin D (GSDMD). GSDMD is a pore-forming protein and an executor of pyroptosis. We screened a chemical library and found a small molecule based on the pyrazolo-oxazepine scaffold that efficiently blocks NET formation and GSDMD-mediated pyroptotic cell death in human cells. During NETosis, GSDMD is proteolytically activated by neutrophil proteases and, in turn, affects protease activation and nuclear expansion in a feed-forward loop. In addition to the central role of GSDMD in pyroptosis, we propose that GSDMD also plays an essential function in NETosis.

Gasdermin D plays a vital role in the generation of neutrophil extracellular traps

The present invention relates to dihydropyrazole compounds that are useful for treating cellular proliferative diseases, for treating disorders associated with KSP kinesin activity, and for inhibiting KSP kinesin. The invention also related to compositions which comprise these compounds, and methods of using them to treat cancer in mammals.

Mitotic kinesin inhibitors

The invention is directed to methods to inhibit TGF-β and/or p38-α kinase using compounds of formula (1) or the pharmaceutically acceptable salts thereof wherein R3 is a noninterfering substituent; each Z is CR2 or N, wherein no more than two Z positions in ring A are N, and wherein two adjacent Z positions in ring A cannot be N; each R2 is independently a noninterfering substituent; L is a linker; n is 0 or 1; and Ar' is the residue of a cyclic aliphatic, cyclic heteroaliphatic, aromatic or heteroaromatic moiety optionally substituted with 1-3 noninterfering substituents.

Quinazoline derivatives as medicaments

There is provided small molecule anti-human immunodeficiency virus (anti-HIV) compounds as well as a phenotypic cell-based high throughput screening (HTS) assay for their identification.

Anti viral compounds

The invention relates to the field of blood coagulation. Novel oxazolidinone derivatives of the general formula (I) 
processes for their preparation and their use as medicinally active compounds for the prophylaxis and/or treatment of disorders are described.

Substituted oxazolidinones and their use in the field of blood coagulation

Human neutrophil elastase (HNE) is a key protease for matrix degradation. High HNE activity is observed in inflammatory diseases. Accordingly, HNE is a potential target for the treatment of pulmonary diseases such as chronic obstructive pulmonary disease (COPD), acute lung injury (ALI), acute respiratory distress syndrome (ARDS), bronchiectasis (BE), and pulmonary hypertension (PH). HNE inhibitors should reestablish the protease–anti-protease balance. By means of medicinal chemistry a novel dihydropyrimidinone lead-structure class was identified. Further chemical optimization yielded orally active compounds with favorable pharmacokinetics such as the chemical probe BAY-678. While maintaining outstanding target selectivity, picomolar potency was achieved by locking the bioactive conformation of these inhibitors with a strategically positioned methyl sulfone substituent. An induced-fit binding mode allowed tight interactions with the S2 and S1 pockets of HNE. BAY 85-8501 ((4S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile) was shown to be efficacious in a rodent animal model related to ALI. BAY 85-8501 is currently being tested in clinical studies for the treatment of pulmonary diseases.

Freezing the Bioactive Conformation to Boost Potency: The Identification of BAY 85-8501, a Selective and Potent Inhibitor of Human Neutrophil Elastase for Pulmonary Diseases.

The invention relates to compounds of formula (I), to a method for their production and to the use of said compounds as medicaments.

Substituted 2-thio-3, 5-dicyano-4-phenyl-6-aminopyridines and their use as adenosine receptor-selective ligands

The use of compounds of formula (I) as medicaments, novel compounds of formula (I) and a method for production thereof are disclosed. Compounds of formula (I) are effective as adenosine receptor ligands.

Substituted 2-oxy-3,5-dicyano-4-aryl-6-aminopyridines and use thereof

The invention relates to the compounds of formula (I), to a method for producing the same and to the use thereof as medicaments.

Adenosine receptor selective modulators

The invention relates to compounds of formula (I), a method for the production thereof and the use of the same as pharmaceuticals.

Ulrich Rosentreter

Papers

Freezing the Bioactive Conformation to Boost Potency: The Identification of BAY 85-8501, a Selective and Potent Inhibitor of Human Neutrophil Elastase for Pulmonary Diseases.

Substituted 2-thio-3, 5-dicyano-4-phenyl-6-aminopyridines and their use as adenosine receptor-selective ligands

Substituted 2-oxy-3,5-dicyano-4-aryl-6-aminopyridines and use thereof

Adenosine receptor selective modulators

Substituted 2-carba-3,5-dicyano-4-aryl-6-aminopyridines and the use of the same as selective ligands of the adenosine receptor