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.

Autor:	Pizzonero M; Galapagos SASU, 102 Avenue Gaston Roussel, 93230 Romainville, France., Akkari R; Galapagos SASU, 102 Avenue Gaston Roussel, 93230 Romainville, France., Bock X; Galapagos SASU, 102 Avenue Gaston Roussel, 93230 Romainville, France., Gosmini R; Galapagos SASU, 102 Avenue Gaston Roussel, 93230 Romainville, France., De Lemos E; Galapagos SASU, 102 Avenue Gaston Roussel, 93230 Romainville, France., Duthion B; Galapagos SASU, 102 Avenue Gaston Roussel, 93230 Romainville, France., Newsome G; Galapagos SASU, 102 Avenue Gaston Roussel, 93230 Romainville, France., Mai TT; Galapagos SASU, 102 Avenue Gaston Roussel, 93230 Romainville, France., Roques V; Galapagos SASU, 102 Avenue Gaston Roussel, 93230 Romainville, France., Jary H; Galapagos SASU, 102 Avenue Gaston Roussel, 93230 Romainville, France., Lefrancois JM; Galapagos SASU, 102 Avenue Gaston Roussel, 93230 Romainville, France., Cherel L; Galapagos SASU, 102 Avenue Gaston Roussel, 93230 Romainville, France., Quenehen V; Galapagos SASU, 102 Avenue Gaston Roussel, 93230 Romainville, France., Babel M; Galapagos SASU, 102 Avenue Gaston Roussel, 93230 Romainville, France., Merayo N; Galapagos SASU, 102 Avenue Gaston Roussel, 93230 Romainville, France., Bienvenu N; Galapagos SASU, 102 Avenue Gaston Roussel, 93230 Romainville, France., Mammoliti O; Galapagos NV, Generaal De Wittelaan L11, A3, 2800 Mechelen, Belgium., Coti G; Galapagos NV, Generaal De Wittelaan L11, A3, 2800 Mechelen, Belgium., Palisse A; Galapagos NV, Generaal De Wittelaan L11, A3, 2800 Mechelen, Belgium., Cowart M; AbbVie, Inc., 1 North Waukegan Road, North Chicago, Illinois 60064-1802, United States., Shrestha A; AbbVie, Inc., 1 North Waukegan Road, North Chicago, Illinois 60064-1802, United States., Greszler S; AbbVie, Inc., 1 North Waukegan Road, North Chicago, Illinois 60064-1802, United States., Van Der Plas S; Galapagos NV, Generaal De Wittelaan L11, A3, 2800 Mechelen, Belgium., Jansen K; Galapagos NV, Generaal De Wittelaan L11, A3, 2800 Mechelen, Belgium., Claes P; Galapagos NV, Generaal De Wittelaan L11, A3, 2800 Mechelen, Belgium., Jans M; Galapagos NV, Generaal De Wittelaan L11, A3, 2800 Mechelen, Belgium., Gees M; Galapagos NV, Generaal De Wittelaan L11, A3, 2800 Mechelen, Belgium., Borgonovi M; Galapagos SASU, 102 Avenue Gaston Roussel, 93230 Romainville, France., De Wilde G; Galapagos NV, Generaal De Wittelaan L11, A3, 2800 Mechelen, Belgium., Conrath K; Galapagos NV, Generaal De Wittelaan L11, A3, 2800 Mechelen, Belgium.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2024 Apr 11; Vol. 67 (7), pp. 5216-5232. Date of Electronic Publication: 2024 Mar 25.
DOI:	10.1021/acs.jmedchem.3c01790
Abstrakt:	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.
Databáze:	MEDLINE
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