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| Title: | Substituted Bicyclic Dihydropyrimidinones and Their Use as Inhibitors of Neutrophil Elastase Activity | ||||||||||||||||||||||||||||||||||||||||||||||||||
| Patent Application Number: | WO 2014/122160 A1 | Publication Date: | 14 August 2014 | ||||||||||||||||||||||||||||||||||||||||||||||||
| Priority Application: | EP 13154256.5 | Priority Date: | 6 February 2013 | ||||||||||||||||||||||||||||||||||||||||||||||||
| Inventors: | Gnamm, C.; Oost, T.; Peters, S.; Hoesch, H.; Ries, U. J. | ||||||||||||||||||||||||||||||||||||||||||||||||||
| Assignee Company: | Boehringer Ingelheim International GMBH; Binger Str. 173, 55216 Ingelheim am Rhein (DE) | ||||||||||||||||||||||||||||||||||||||||||||||||||
| Disease Area: | Pulmonary, gastrointestinal and genitourinary inflammatory diseases, chronic obstructive pulmonary disease, autoimmune and allergic disorders, allograft rejection, and oncological diseases | Biological Target: | Neutrophil Elastase (NE) | ||||||||||||||||||||||||||||||||||||||||||||||||
| Summary: | The invention in this patent application relates to bicyclic dihydropyrimidinone derivatives represented generally by formula (I) that are inhibitors of neutrophil elastase. These compounds may potentially provide treatments for pulmonary and gastrointestinal inflammatory diseases, chronic obstructive pulmonary disease, and other autoimmune and allergic disorders. | ||||||||||||||||||||||||||||||||||||||||||||||||||
| Elastases are serine proteases that hydrolyze elastin and other proteins. Neutrophil elastase (NE) is expressed in the bone marrow precursor cells and stored at high concentrations in the granula of peripheral blood granulocytes until released upon cellular activation. NE plays important roles in the degradation of extracellular matrix (ECM) and in promoting migration and chemotaxis of monocytes and vascular smooth muscle cells. It also affects the components of the coagulation and fibrinolytic pathways. However, the over activity of NE has been linked to the pathologies of several inflammatory diseases including idiopathic pulmonary fibrosis, rheumatoid arthritis, adult respiratory distress syndrome, chronic obstructive pulmonary disease (COPD), and cystic fibrosis. Consequently, the inhibition of NE activities has been a therapeutic target for the treatment of these diseases. Neutrophil elastase inhibitors such as the compounds described in this patent application may potentially treat diseases like COPD, idiopathic pulmonary fibrosis and other fibrotic diseases, cancer, acute lung injury, acute respiratory distress syndrome, bronchiectasis, cystic fibrosis, alpha1-antitrypsin deficiency, and others. | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Important Compound Classes: |  | ||||||||||||||||||||||||||||||||||||||||||||||||||
| Key Structures: | The inventors described the structures of >270 compounds of formula (I) including the four compounds below: | ||||||||||||||||||||||||||||||||||||||||||||||||||
| Biological Assay: | The following assays were used to test all or some of the formula (I) compounds:
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| Biological Data: | The results of the biological assays 1 and 2 obtained from the representative examples highlighted above are listed in the following table: | ||||||||||||||||||||||||||||||||||||||||||||||||||
| Recent Review Articles: | 1. | ||||||||||||||||||||||||||||||||||||||||||||||||||
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Cited By
This article is cited by 2 publications.
- Kayla M. Fantone, Harald Nothaft, Yeongseo Son, Arlene A. Stecenko, Christine M. Szymanski, Balázs Rada. The bacterial serine protease inhibitor ecotin inhibits neutrophil elastase enzymatic activity in cystic fibrosis sputa. Heliyon 2024, 10
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, e38895. https://doi.org/10.1016/j.heliyon.2024.e38895
- Franz von Nussbaum, Volkhart M.-J. Li. Neutrophil elastase inhibitors for the treatment of (cardio)pulmonary diseases: Into clinical testing with pre-adaptive pharmacophores. Bioorganic & Medicinal Chemistry Letters 2015, 25
(20)
, 4370-4381. https://doi.org/10.1016/j.bmcl.2015.08.049
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