A TRPA1 inhibitor suppresses neurogenic inflammation and airway contraction for asthma treatment
| Autor: | Jun Chen, Justin Elstrott, Lan Wang, Simon S. Gao, Richard A.D. Carano, Jose E. Heredia, Elisia Villemure, Daniel G. Shore, Wyne P. Lee, Bobby Brillantes, Joseph H. Lin, Liling Liu, David H. Hackos, Jens Kortmann, Matthew Volgraf, Daniel D. Bravo, Christine Tam, Lorena Riol-Blanco, Steven Magnuson, Lionel Rouge, Chris Bjornson, Baihua Hu, Tania Chernov-Rogan, Rebecca M. Reese, Christopher P. Arthur, Min Jung, Michelle Dourado, Xiumin Wu, Victory Joseph, Alberto Estevez, John Liu, Alvin Gogineni, Juan Zhang, Laurie Leong, Jian Payandeh, Vishal Verma, Shannon D. Shields, Han Ting Ding, Brian Safina, Alessia Balestrini, Yong Chen, Vineela D. Gandham, Eric Suto, Jianyong Wang, Justin Ly, Rebecca N. Bauer, Jonas Doerr, Alexis Rohou, Cary D. Austin, Jason A. Vander Heiden, Xiaoying Yang, Ryan L. Wong, Lucinda Tam, Liuxi Chen, Kathy Hötzel, Kai H. Barck, Merone Roose-Girma, Claudio Ciferri, Huifen Chen, Bianca M. Liederer |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Neurogenic inflammation Contraction (grammar) business.industry Immunology Antagonist Airway inflammation food and beverages medicine.disease 03 medical and health sciences Transient receptor potential channel 030104 developmental biology 0302 clinical medicine Edema medicine Immunology and Allergy medicine.symptom Airway business psychological phenomena and processes 030217 neurology & neurosurgery Asthma |
| Zdroj: | Journal of Experimental Medicine. 218 |
| ISSN: | 1540-9538 0022-1007 |
| Popis: | Despite the development of effective therapies, a substantial proportion of asthmatics continue to have uncontrolled symptoms, airflow limitation, and exacerbations. Transient receptor potential cation channel member A1 (TRPA1) agonists are elevated in human asthmatic airways, and in rodents, TRPA1 is involved in the induction of airway inflammation and hyperreactivity. Here, the discovery and early clinical development of GDC-0334, a highly potent, selective, and orally bioavailable TRPA1 antagonist, is described. GDC-0334 inhibited TRPA1 function on airway smooth muscle and sensory neurons, decreasing edema, dermal blood flow (DBF), cough, and allergic airway inflammation in several preclinical species. In a healthy volunteer Phase 1 study, treatment with GDC-0334 reduced TRPA1 agonist-induced DBF, pain, and itch, demonstrating GDC-0334 target engagement in humans. These data provide therapeutic rationale for evaluating TRPA1 inhibition as a clinical therapy for asthma. |
| Databáze: | OpenAIRE |
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