2. Academic Validation
  3. Discovery of N-(3-Carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-lH-pyrazole-5-carboxamide (GLPG1837), a Novel Potentiator Which Can Open Class III Mutant Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Channels to a High Extent

Discovery of N-(3-Carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-lH-pyrazole-5-carboxamide (GLPG1837), a Novel Potentiator Which Can Open Class III Mutant Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Channels to a High Extent

  • J Med Chem. 2018 Feb 22;61(4):1425-1435. doi: 10.1021/acs.jmedchem.7b01288.
Steven E Van der Plas 1,  Hans Kelgtermans 1,  Tom De Munck 1,  Sébastien L X Martina 1,  Sébastien Dropsit 1,  Evelyne Quinton 1,  Ann De Blieck 1,  Caroline Joannesse 1,  Linda Tomaskovic 2,  Mia Jans 1,  Thierry Christophe 1,  Ellen van der Aar 1,  Monica Borgonovi 3,  Luc Nelles 1,  Maarten Gees 1,  Pieter Stouten 1,  Jan Van Der Schueren 1,  Oscar Mammoliti 1,  Katja Conrath 1,  Martin Andrews 1
Affiliations

Affiliations

  • 1 Galapagos NV , Generaal De Wittelaan L11 A3, 2800 Mechelen, Belgium.
  • 2 Fidelta Ltd. , Prilaz Baruna Filipovića 29, Zagreb HR-10000, Croatia.
  • 3 Galapagos SASU , 102 Avenue Gaston Roussel, 93230 Romainville, France.
PMID: 29148763 DOI: 10.1021/acs.jmedchem.7b01288
Abstract

Cystic fibrosis (CF) is caused by mutations in the gene for the cystic fibrosis transmembrane conductance regulator (CFTR). With the discovery of Ivacaftor and Orkambi, it has been shown that CFTR function can be partially restored by administering one or more small molecules. These molecules aim at either enhancing the amount of CFTR on the cell surface (correctors) or at improving the gating function of the CFTR channel (potentiators). Here we describe the discovery of a novel potentiator GLPG1837, which shows enhanced efficacy on CFTR mutants harboring class III mutations compared to Ivacaftor, the first marketed potentiator. The optimization of potency, efficacy, and pharmacokinetic profile will be described.

Figures
Products