The Galapagos S1PR2 antagonist GLPG2938 is a preclinical candidate intended for the treatment of idiopathic pulmonary fibrosis (IPF). Though several S1PR1 modulators have been approved, no selective S1PR2 antagonist has entered clinical development yet. The Galapagos team attempted to find a new starting point with two consecutive HTS campaigns, but did not find any advanceable starting points, but were able to develop a literature starting point to a candidate. A hydrazine motif in the starting point was replaced with a benzylic amine in a surprisingly large property change for a central motif. Improving lipophilic efficiency was key to reducing CYP inhibition. GLPG2938 does not appear to have entered development yet, but should be a useful tool to understand S1PR2 biology.