Discovery of Icenticaftor (QBW251), a Cystic Fibrosis Transmembrane Conductance Regulator Potentiator with Clinical Efficacy in Cystic Fibrosis and Chronic Obstructive Pulmonary Disease
2021; American Chemical Society; Volume: 64; Issue: 11 Linguagem: Inglês
10.1021/acs.jmedchem.1c00343
ISSN1520-4804
AutoresDarren Le Grand, Martin Gosling, Urs Baettig, Parmjit Bahra, Kamlesh Bala, Cara E. Brocklehurst, Emma Budd, Rebecca Butler, Atwood K. Cheung, Hedaythul Choudhury, Stephen P. Collingwood, Brian J. Cox, Henry Danahay, Lee J. Edwards, Brian Everatt, Ulrike Glaenzel, Anne‐Lise Glotin, Paul J. Groot‐Kormelink, Edward J. Hall, Julia Hatto, Catherine Howsham, Glyn A. Hughes, Anna King, Julia Koehler, Swarupa G. Kulkarni, Megan Lightfoot, Ian A. Nicholls, Christopher J. Page, Giles Pergl-Wilson, M. Oana Popa, Richard I. Robinson, David J. Rowlands, Tom Sharp, Matthew Spendiff, Emily Stanley, Oliver Steward, Roger Taylor, Pamela Tranter, Trixie Wagner, Hazel Watson, Gareth Williams, Penny Wright, Alice C. Young, David A. Sandham,
Tópico(s)Inhalation and Respiratory Drug Delivery
ResumoMutations 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.
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