1. Development of highly potent glucocorticoids for steroid-resistant severe asthma
- Author
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He, Yuanzheng, Shi, Jingjing, Nguyen, Quang Tam, You, Erli, Liu, Hongbo, Ren, Xin, Wu, Zhongshan, Li, Jianshuang, Qiu, Wenli, Khoo, Sok Kean, Yang, Tao, Yi, Wei, Sun, Feng, Xi, Zhijian, Huang, Xiaozhu, Melcher, Karsten, Min, Booki, and Xu, H Eric
- Subjects
Male ,Animal ,steroid resistant asthma ,Severity of Illness Index ,Asthma ,Mice ,steroid-resistant asthma ,Glucocorticoid ,Drug Development ,5.1 Pharmaceuticals ,Disease Models ,Receptors ,Respiratory ,Animals ,Female ,VSG158 ,glucocorticoid ,Anti-Asthmatic Agents ,Development of treatments and therapeutic interventions ,Glucocorticoids ,Lung ,VSG159 ,high potency - Abstract
Clinical application of inhaled glucocorticoids (GCs) has been hampered in the case of steroid-resistant severe asthma. To overcome this limitation, we have developed a series of highly potent GCs, including VSGC12, VSG158, and VSG159 based on the structural insight into the glucocorticoid receptor (GR). Particularly, VSG158 exhibits a maximal repression of lung inflammation and is 10 times more potent than the currently most potent clinical GC, Fluticasone Furoate (FF), in a murine model of asthma. More importantly, VSG158 displays a unique property to reduce neutrophilic inflammation in a steroid-resistant airway inflammation model, which is refractory to clinically available GCs, including dexamethasone and FF. VSG158 and VSG159 are able to deliver effective treatments with reduced off-target and side effects. In addition, these GCs also display pharmacokinetic properties that are suitable for the inhalation delivery method for asthma treatment. Taken together, the excellent therapeutic and side-effect profile of these highly potent GCs holds promise for treating steroid-resistant severe asthma.
- Published
- 2019