Discovery of a novel EP2/EP4 dual agonist with high subtype-selectivity

Bioorg Med Chem Lett. 2012 Jan 1;22(1):396-401. doi: 10.1016/j.bmcl.2011.10.109. Epub 2011 Nov 7.

Abstract

A series of γ-lactam prostaglandin E(1) analogs bearing a 16-phenyl moiety in the ω-chain and aryl moiety in the α-chain were synthesized and biologically evaluated. Among the tested compounds, γ-lactam PGE analog 3 designed as a structural hybrid of 1 and 2 was discovered as the most optimized EP2/EP4 dual agonist with excellent subtype-selectivity (K(i) values: mEP2=9.3 nM, mEP4=0.41 nM). A structure-activity relationship study is presented.

MeSH terms

  • Alprostadil / analogs & derivatives*
  • Animals
  • Carboxylic Acids / chemistry
  • Chemistry, Pharmaceutical / methods
  • Drug Design
  • Humans
  • Kinetics
  • Lactams / chemistry*
  • Models, Chemical
  • Molecular Conformation
  • Rats
  • Receptors, Prostaglandin E, EP2 Subtype / chemistry*
  • Receptors, Prostaglandin E, EP4 Subtype / chemistry*

Substances

  • Carboxylic Acids
  • Lactams
  • Receptors, Prostaglandin E, EP2 Subtype
  • Receptors, Prostaglandin E, EP4 Subtype
  • Alprostadil