PTGER4 antagonist with novel scaffold for pain

An antagonist of the prostaglandin E2 receptor, PTGER4, that is smaller and more polar than previous PTGER4 antagonists, could help treat pain by specifically blocking pro-inflammatory prostaglandin signaling without disrupting prostaglandin synthesis.

In binding competition assays in vitro, 71 potential hits from a docking screen of over 400 million compounds were tested for ability to bind PTGER4, with ten hits further screened in cell-based assays for the ability to inhibit PTGER4, six of which showed inhibitory activity. Two compounds with low similarity to previously described PTGER4 ligands underwent structure-based optimization, resulting in one optimized lead compound which inhibited PTGER4 with a Ki of 15.6 nM. The compound, which has a spiro-ring system that supports a warhead carboxylate, showed no inhibitory activity against the prostaglandin synthesizing enzymes COX-1 or COX-2, which are commonly targeted by NSAIDs, or against other PTGER family members. ...