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

• Published in: Bioorganic & medicinal chemistry letters Vol. 15; no. 10; pp. 2523 - 2526
• Main Authors: Elworthy, Todd R., Brill, Emma R., Caires, Christopher C., Kim, Woongki, Lach, Leang K., Tracy, Jahari Laurant, Chiou, San-San
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 16.05.2005; Elsevier
• Subjects: 2-Piperidone; Biological and medical sciences; EP4 agonist; Lactams - chemistry; Lactams - pharmacology; Ligands; Medical sciences; Miscellaneous; Pharmacology. Drug treatments; Piperidones - chemistry; Piperidones - pharmacology; Receptors, Prostaglandin E - agonists; Receptors, Prostaglandin E, EP4 Subtype; Selective EP4 ligands; δ-Lactams as prostanoids; 2-Piperidone; EP4 agonist; δ-Lactams as prostanoids; Selective EP4 ligands; Agonist; Prostaglandin; Ligand; Lactam; Purity; Selectivity; Organic sulfide; Structure activity relation; Biphenyl derivatives; Piperidine derivatives; Prostanoid; Affinity; Chemical synthesis; EP4 prostanoid receptor
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2005.03.059

2-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. 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 5–130nM) at EP4 and subtype selectivity.