Lactams as EP4 prostanoid receptor agonists. 3. Discovery of N-ethylbenzoic acid 2-pyrrolidinones as subtype selective agents

J Med Chem. 2004 Dec 2;47(25):6124-7. doi: 10.1021/jm049290a.

Abstract

Two distinct synthetic schemes were applied to access heteroatom-containing alpha-chain lactams or lactams terminated as aryl acids. The latter lactams were devised using a pharmacophore for EP(4) receptor activity. gamma-Lactams were characterized for their prostanoid EP receptor affinities and EP(4) activity and found to be selective for the EP(2) and EP(4) receptors or selective for the EP(4) subtype. Benzoic acid 17 displayed enhanced in vivo exposure relative to 3.

MeSH terms

  • Animals
  • Benzoates / chemical synthesis*
  • Benzoates / pharmacokinetics
  • Benzoates / pharmacology
  • Blood Proteins / metabolism
  • Half-Life
  • Humans
  • Lactams / chemical synthesis*
  • Lactams / pharmacokinetics
  • Lactams / pharmacology
  • Models, Molecular
  • Molecular Conformation
  • Monte Carlo Method
  • Oxidation-Reduction
  • Protein Binding
  • Pyrrolidines / chemical synthesis*
  • Pyrrolidines / pharmacokinetics
  • Pyrrolidines / pharmacology
  • Rats
  • Receptors, Prostaglandin E / agonists*
  • Receptors, Prostaglandin E / metabolism
  • Receptors, Prostaglandin E, EP2 Subtype
  • Receptors, Prostaglandin E, EP4 Subtype
  • Structure-Activity Relationship

Substances

  • Benzoates
  • Blood Proteins
  • Lactams
  • PTGER2 protein, human
  • PTGER4 protein, human
  • Pyrrolidines
  • Receptors, Prostaglandin E
  • Receptors, Prostaglandin E, EP2 Subtype
  • Receptors, Prostaglandin E, EP4 Subtype