| Autor: |
Giles Pergl-Wilson, Anna King, Julia Hatto, Henry Danahay, David Andrew Sandham, Mariana Oana Popa, Emily Stanley, Parmjit Bahra, Urs Baettig, Rebecca Butler, Brian Cox, Lightfoot Megan, Christopher J. Page, Alice Young, Paul J. Groot-Kormelink, Trixie Wagner, Swarupa Kulkarni, Glyn Hughes, Edward Charles Hall, David J. Rowlands, Lee Edwards, Atwood K. Cheung, Matthew Spendiff, Tom Sharp, Kamlesh Bala, Stephen Paul Collingwood, Hazel Watson, Julia Koehler, Oliver Ross Steward, Anne-Lise Glotin, Penny Wright, Cara E. Brocklehurst, Ulrike Glaenzel, Ian Nicholls, Richard I. Robinson, Roger J. Taylor, Catherine Howsham, Brian Everatt, Darren Le Grand, Hedaythul Choudhury, Gareth Williams, Emma Budd, Martin Gosling, Pamela Tranter |
| Rok vydání: |
2021 |
| Předmět: |
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| Zdroj: |
Journal of Medicinal Chemistry. 64:7241-7260 |
| ISSN: |
1520-4804
0022-2623 |
| DOI: |
10.1021/acs.jmedchem.1c00343 |
| Popis: |
Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel are established as the primary causative factor in the devastating lung disease cystic fibrosis (CF). More recently, cigarette smoke exposure has been shown to be associated with dysfunctional airway epithelial ion transport, suggesting a role for CFTR in the pathogenesis of chronic obstructive pulmonary disease (COPD). Here, the identification and characterization of a high throughput screening hit 6 as a potentiator of mutant human F508del and wild-type CFTR channels is reported. The design, synthesis, and biological evaluation of compounds 7-33 to establish structure-activity relationships of the scaffold are described, leading to the identification of clinical development compound icenticaftor (QBW251) 33, which has subsequently progressed to deliver two positive clinical proofs of concept in patients with CF and COPD and is now being further developed as a novel therapeutic approach for COPD patients. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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