2. Academic Validation
  3. Discovery of the S1P2 Antagonist GLPG2938 (1-[2-Ethoxy-6-(trifluoromethyl)-4-pyridyl]-3-[[5-methyl-6-[1-methyl-3-(trifluoromethyl)pyrazol-4-yl]pyridazin-3-yl]methyl]urea), a Preclinical Candidate for the Treatment of Idiopathic Pulmonary Fibrosis

Discovery of the S1P2 Antagonist GLPG2938 (1-[2-Ethoxy-6-(trifluoromethyl)-4-pyridyl]-3-[[5-methyl-6-[1-methyl-3-(trifluoromethyl)pyrazol-4-yl]pyridazin-3-yl]methyl]urea), a Preclinical Candidate for the Treatment of Idiopathic Pulmonary Fibrosis

  • J Med Chem. 2021 May 13;64(9):6037-6058. doi: 10.1021/acs.jmedchem.1c00138.
Oscar Mammoliti 1,  Adeline Palisse 1,  Caroline Joannesse 1,  Sandy El Bkassiny 1,  Brigitte Allart 1,  Alex Jaunet 1,  Christel Menet 1,  Beatrice Coornaert 1,  Kathleen Sonck 1,  Inge Duys 1,  Philippe Clément-Lacroix 2,  Line Oste 1,  Monica Borgonovi 2,  Emanuelle Wakselman 2,  Thierry Christophe 1,  Nicolas Houvenaghel 1,  Mia Jans 1,  Bertrand Heckmann 2,  Laurent Sanière 2,  Reginald Brys 1
Affiliations

Affiliations

  • 1 Galapagos NV, Generaal De Wittelaan L11 A3, 2800 Mechelen, Belgium.
  • 2 Galapagos SASU, 102 avenue Gaston Roussel, 93230 Romainville, France.
PMID: 33939425 DOI: 10.1021/acs.jmedchem.1c00138
Abstract

Mounting evidence from the literature suggests that blocking S1P2 receptor (S1PR2) signaling could be effective for the treatment of idiopathic pulmonary fibrosis (IPF). However, only a few antagonists have been so far disclosed. A chemical enablement strategy led to the discovery of a pyridine series with good antagonist activity. A pyridazine series with improved lipophilic efficiency and with no CYP inhibition liability was identified by scaffold hopping. Further optimization led to the discovery of 40 (GLPG2938), a compound with exquisite potency on a phenotypic IL8 release assay, good pharmacokinetics, and good activity in a bleomycin-induced model of pulmonary fibrosis.

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