Synthesis and evaluation of novel modified γ-lactam prostanoids as EP4 subtype-selective agonists

Bioorg Med Chem. 2012 Jan 15;20(2):702-13. doi: 10.1016/j.bmc.2011.12.009. Epub 2011 Dec 13.

Abstract

To identify chemically and metabolically stable subtype-selective EP4 agonists, design and synthesis of a series of modified γ-lactam prostanoids has been continued. Prostanoids bearing 2-oxo-1,3-oxazolidine, 2-oxo-1,3-thiazolidine and 5-thioxopyrrolidine as a surrogate for the γ-hydroxycyclopentanone without a troublesome 11-hydroxy group were identified as highly subtype-selective EP4 agonists. Among the tested, several representative compounds demonstrated in vivo efficacy after oral dosing in rats. Their pharmacokinetic and structure-activity relationship studies are presented.

MeSH terms

  • Administration, Oral
  • Animals
  • Lactams / chemistry*
  • Prostaglandins / chemical synthesis
  • Prostaglandins / chemistry*
  • Prostaglandins / pharmacokinetics
  • Rats
  • Receptors, Prostaglandin E, EP4 Subtype / agonists*
  • Receptors, Prostaglandin E, EP4 Subtype / metabolism
  • Structure-Activity Relationship
  • Thiazolidines / chemistry
  • Tumor Necrosis Factor-alpha / blood

Substances

  • Lactams
  • Prostaglandins
  • Receptors, Prostaglandin E, EP4 Subtype
  • Thiazolidines
  • Tumor Necrosis Factor-alpha