1,5-Biaryl pyrrole derivatives as EP1 receptor antagonists. Structure-activity relationships of 6-substituted and 5,6-disubstituted benzoic acid derivatives

Bioorg Med Chem Lett. 2007 Feb 15;17(4):916-20. doi: 10.1016/j.bmcl.2006.11.059. Epub 2006 Nov 22.

Abstract

Herein we describe the SAR of 1,5-biaryl pyrrole derivatives, with substituents in the 6-position of the benzoic acid moiety, as EP(1) receptor antagonists. Substitution at this position was well tolerated and led to the identification of several analogues with high affinity for the EP(1) receptor that displayed good efficacy in the established FCA model of inflammatory pain. Furthermore, several analogues were prepared which combined substitution at the 5- and 6-positions as well as derivatives with an aromatic ring fused to the 5- and 6-positions.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / chemical synthesis
  • Anti-Inflammatory Agents / pharmacokinetics
  • Anti-Inflammatory Agents / pharmacology
  • Area Under Curve
  • Benzoates / chemical synthesis*
  • Benzoates / pharmacology*
  • Brain / metabolism
  • CHO Cells
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Cricetinae
  • Cricetulus
  • Cytochrome P-450 Enzyme System / metabolism
  • Dose-Response Relationship, Drug
  • Half-Life
  • Humans
  • Indicators and Reagents
  • Pain / drug therapy
  • Pain Measurement / drug effects
  • Pyrroles / chemical synthesis*
  • Pyrroles / pharmacology*
  • Rats
  • Receptors, Prostaglandin E / antagonists & inhibitors*
  • Receptors, Prostaglandin E, EP1 Subtype
  • Structure-Activity Relationship

Substances

  • Anti-Inflammatory Agents
  • Benzoates
  • Indicators and Reagents
  • PTGER1 protein, human
  • Pyrroles
  • Receptors, Prostaglandin E
  • Receptors, Prostaglandin E, EP1 Subtype
  • Cytochrome P-450 Enzyme System