Discovery of Icenticaftor (QBW251), a Cystic Fibrosis Transmembrane Conductance Regulator Potentiator with Clinical Efficacy in Cystic Fibrosis and Chronic Obstructive Pulmonary Disease

Darren Le Grand, Martin Gosling, Urs Baettig, Parmjit Bahra, Kamlesh Bala, Cara Brocklehurst, Emma Budd, Rebecca Butler, Atwood K Cheung, Hedaythul Choudhury, Stephen P Collingwood, Brian Cox, Henry Danahay, Lee Edwards, Brian Everatt, Ulrike Glaenzel, Anne-Lise Glotin, Paul Groot-Kormelink, Edward Hall, Julia HattoCatherine Howsham, Glyn Hughes, Anna King, Julia Koehler, Swarupa Kulkarni, Megan Lightfoot, Ian Nicholls, Christopher Page, Giles Pergl-Wilson, Mariana Oana Popa, Richard Robinson, David Rowlands, Tom Sharp, Matthew Spendiff, Emily Stanley, Oliver Steward, Roger J Taylor, Pamela Tranter, Trixie Wagner, Hazel Watson, Gareth Williams, Penny Wright, Alice Young, David A Sandham

Research output: Contribution to journalArticlepeer-review

16 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)7241-7260
Number of pages20
JournalJournal of Medicinal Chemistry
Volume64
Issue number11
Early online date24 May 2021
DOIs
Publication statusPublished - 10 Jun 2021
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2021 American Chemical Society.

Keywords

  • Administration, Oral
  • Aminopyridines/chemistry
  • Animals
  • Cystic Fibrosis/drug therapy
  • Cystic Fibrosis Transmembrane Conductance Regulator/antagonists & inhibitors
  • Disease Models, Animal
  • Drug Evaluation, Preclinical
  • Gene Deletion
  • Half-Life
  • Humans
  • Protein Binding
  • Pulmonary Disease, Chronic Obstructive/drug therapy
  • Rats
  • Rats, Sprague-Dawley
  • Solubility
  • Structure-Activity Relationship

ASJC Scopus subject areas

  • Drug Discovery
  • Molecular Medicine

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