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
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journal contribution
posted on 2021-05-04, 12:35authored byOscar Mammoliti, Adeline Palisse, Caroline Joannesse, Sandy El Bkassiny, Brigitte Allart, Alex Jaunet, Christel Menet, Beatrice Coornaert, Kathleen Sonck, Inge Duys, Philippe Clément-Lacroix, Line Oste, Monica Borgonovi, Emanuelle Wakselman, Thierry Christophe, Nicolas Houvenaghel, Mia Jans, Bertrand Heckmann, Laurent Sanière, Reginald Brys
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.