| Autor: |
Sachin Sundarlal Chaudhari, Abraham Thomas, Daisy Manish Shah, Satyawan Jadhav, Malini Bajpai, Srinivasa Honnegowda, Neelima Khairatkar-Joshi, Sanjib Das, Abhay Kulkarni, Girish S. Gudi, Indrani Sarkar |
| Rok vydání: |
2015 |
| Předmět: |
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| Zdroj: |
5.1 Airway Pharmacology and Treatment. |
| DOI: |
10.1183/13993003.congress-2015.pa4367 |
| Popis: |
Background: Antibody mediated IL-17 blockade is remarkably successful in autoimmune disease treatment. Recent studies implicate IL-17 in airway diseases. Increased IL-17 immuno-reactivity and Th17 cells in lung tissue and IL-17 level in bronchoalveolar lavage fluid (BALF) is reported in human COPD patients and tobacco-smoke-exposed rats. Anti-IL-17 Ab attenuates airway inflammation in these animals. In human COPD patients, lung IL-17 immuno-reactivity correlates with disease severity. Recent studies also implicate IL-17 in COPD exacerbations. Hence IL-17 blockade seems a very attractive approach in potentially addressing the anti-inflammatory treatment gap in COPD management. IL-17 production is modulated by RORγt / RORc receptor in mice / man and offers a novel mechanism for IL-17 blockade. Objective: We synthesized several novel, potent, selective RORc blockers and evaluated efficacy of the series lead called “Compound A” in animal model of COPD. Results: Compound A is highly selective and potent preclinical lead with IC 50 ofless than 40 nM in RORc binding and PBMC- IL-17 release assay. In vivo, it produced ∼ 75 % inhibition of IL-17 release induced by LPS and anti-CD3. Its efficacy in a COPD was evaluated in cigarette smoke mouse model under acute (7 days) and chronic (3 months) conditions. Compound A showed promising efficacy in suppressing lung cellular infiltration by 50-70% upon intranasal administration. In chronic model, the compound showed significant decrease of lung emphysema, epithelial IL-17 immuno-reactivity and RORgt/IL-17 positive lung cells. Conclusion: Our RORc antagonist is a novel, inhalable IL-17 blocker for potential treatment of COPD. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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