Lactams as prostanoid receptor ligands. Part 4: 2-Piperidones as selective EP4 receptor agonists

2-Piperidones were prepared bearing heptanoic acid or a thioether heptanoic acid at the 1-position as well as appropriately substituted at the 6-position to mimic the structure of prostaglandins. The stereochemical purity at the 6-position was determined to be ⩾95% ee for an advanced synthetic intermediate. The 2-piperidones were identified as potent agonists at the EP4 prostanoid receptor. They displayed a high affinity (Ki 5–130 nM) at EP4 and subtype selectivity.

Graphical abstract2-Piperidones were prepared bearing heptanoic acid or a thioether heptanoic acid at the 1-position and appropriately substituted at the 6-position to mimic the structure of prostaglandins. The stereochemical purity at the 6-position was determined to be ⩾95% ee. The 2-piperidone ligands were identified as potent agonists at the EP4 prostanoid receptor and also displayed subtype selectivity.Figure optionsDownload full-size imageDownload as PowerPoint slide