Optimization of amide-based EP3 receptor antagonists

Bioorg Med Chem Lett. 2016 Jun 1;26(11):2670-5. doi: 10.1016/j.bmcl.2016.04.009. Epub 2016 Apr 9.

Abstract

Prostaglandin E receptor subtype 3 (EP3) antagonism may treat a variety of symptoms from inflammation to cardiovascular and metabolic diseases. Previously, most EP3 antagonists were large acidic ligands that mimic the substrate, prostaglandin E2 (PGE2). This manuscript describes the optimization of a neutral small molecule amide series with improved lipophilic efficiency (LipE) also known as lipophilic ligand efficiency (LLE) ((a) Nat. Rev. Drug Disc.2007, 6, 881; (b) Annu. Rep. Med. Chem.2010, 45, 380).

Keywords: EP3 receptor; GPCR; Indazole; LipE; Metabolites; P-gp; PGE2.

MeSH terms

  • Amides / chemical synthesis
  • Amides / chemistry
  • Amides / pharmacology*
  • Dose-Response Relationship, Drug
  • Humans
  • Molecular Structure
  • Receptors, Prostaglandin E, EP3 Subtype / antagonists & inhibitors*
  • Structure-Activity Relationship

Substances

  • Amides
  • PTGER3 protein, human
  • Receptors, Prostaglandin E, EP3 Subtype