2. Academic Validation
  3. Discovery of GLPG2737, a Potent Type 2 Corrector of CFTR for the Treatment of Cystic Fibrosis in Combination with a Potentiator and a Type 1 Co-corrector

Discovery of GLPG2737, a Potent Type 2 Corrector of CFTR for the Treatment of Cystic Fibrosis in Combination with a Potentiator and a Type 1 Co-corrector

  • J Med Chem. 2024 Apr 11;67(7):5216-5232. doi: 10.1021/acs.jmedchem.3c01790.
Mathieu Pizzonero 1,  Rhalid Akkari 1,  Xavier Bock 1,  Romain Gosmini 1,  Elsa De Lemos 1,  Béranger Duthion 1,  Gregory Newsome 1,  Thi-Thu-Trang Mai 1,  Virginie Roques 1,  Hélène Jary 1,  Jean-Michel Lefrancois 1,  Laetitia Cherel 1,  Vanessa Quenehen 1,  Marielle Babel 1,  Nuria Merayo 1,  Natacha Bienvenu 1,  Oscar Mammoliti 2,  Ghjuvanni Coti 2,  Adeline Palisse 2,  Marlon Cowart 3,  Anurupa Shrestha 3,  Stephen Greszler 3,  Steven Van Der Plas 2,  Koen Jansen 2,  Pieter Claes 2,  Mia Jans 2,  Maarten Gees 2,  Monica Borgonovi 1,  Gert De Wilde 2,  Katja Conrath 2
Affiliations

Affiliations

  • 1 Galapagos SASU, 102 Avenue Gaston Roussel, 93230 Romainville, France.
  • 2 Galapagos NV, Generaal De Wittelaan L11, A3, 2800 Mechelen, Belgium.
  • 3 AbbVie, Inc., 1 North Waukegan Road, North Chicago, Illinois 60064-1802, United States.
PMID: 38527911 DOI: 10.1021/acs.jmedchem.3c01790
Abstract

Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) protein. This epithelial anion channel regulates the active transport of chloride and bicarbonate ions across membranes. Mutations result in reduced surface expression of CFTR channels with impaired functionality. Correctors are small molecules that support the trafficking of CFTR to increase its membrane expression. Such correctors can have different mechanisms of action. Combinations may result in a further improved therapeutic benefit. We describe the identification and optimization of a new pyrazolol3,4-bl pyridine-6-carboxylic acid series with high potency and efficacy in rescuing CFTR from the cell surface. Investigations showed that carboxylic acid group replacement with acylsulfonamides and acylsulfonylureas improved ADMET and PK properties, leading to the discovery of the structurally novel co-corrector GLPG2737. The addition of GLPG2737 to the combination of the potentiator GLPG1837 and C1 corrector 4 led to an 8-fold increase in the F508del CFTR activity.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-158144
    CFTR Corrector