Novel Pyrrolidine Derivatives of Budesonide as Long Acting Inhaled Corticosteroids for the Treatment of Pulmonary Inflammatory Diseases
| Autor: | Alessandro Fioni, Anna Maria Capelli, Chiara Carnini, Gessica Marchini, Fabio Rancati, Valentina Cenacchi, Eleonora Ghidini, Fabrizio Facchinetti |
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| Rok vydání: | 2018 |
| Předmět: |
Agonist
Budesonide medicine.drug_class Protein Conformation Drug design CHO Cells Pharmacology 01 natural sciences 03 medical and health sciences Mice 0302 clinical medicine Cricetulus Receptors Glucocorticoid In vivo Adrenal Cortex Hormones Drug Discovery Administration Inhalation medicine Animals Humans Tissue Distribution Receptor Asthma Lung Inhalation 010405 organic chemistry Chemistry Pneumonia medicine.disease 0104 chemical sciences Molecular Docking Simulation medicine.anatomical_structure RAW 264.7 Cells 030220 oncology & carcinogenesis Drug Design Molecular Medicine medicine.drug |
| Zdroj: | Journal of medicinal chemistry. 61(11) |
| ISSN: | 1520-4804 |
| Popis: | Inhaled corticosteroids (ICSs) represent the first line therapy for the treatment of asthma and are also extensively utilized in chronic obstructive pulmonary disease. Our goal was to develop a new ICS with a basic group, which can allow solid state feature modulation, achieving at the same time high local anti-inflammatory effect and low systemic exposure. Through a rational drug design approach, a new series of pyrrolidine derivatives of budesonide was identified. Within the series, several compounds showed nanomolar binding affinity (Ki) with GR that mostly correlated with the effect in inducing GR nuclear translocation in CHO cells and anti-inflammatory effects in macrophagic cell lines. Binding and functional cell-based assays allowed identifying compound 17 as a potent ICS agonist with a PK profile showing an adequate lung retention and low systemic exposure in vivo. Finally, compound 17 proved to be more potent than budesonide in a rat model of acute pulmonary inflammation. |
| Databáze: | OpenAIRE |
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