1,5-Biaryl pyrrole derivatives as EP1 receptor antagonists: Structure-activity relationships of 4- and 5-substituted benzoic acid derivatives

Bioorg Med Chem Lett. 2007 Feb 1;17(3):732-5. doi: 10.1016/j.bmcl.2006.10.078. Epub 2006 Oct 28.

Abstract

This paper details the SAR of 1,5-biaryl pyrrole derivatives with substituents in the 2-, 4-, and 5-positions of the benzoic acid group as EP1 receptor antagonists. Substitution at the 2-position was poorly tolerated, whereas only fluorine was tolerated at the 4-position. In contrast, a range of substituents at the 5-position were discovered which enhanced the in vitro affinity and led to compounds with promising oral exposure. Three derivatives showed efficacy in a preclinical model of inflammatory pain when dosed orally to rats.

MeSH terms

  • Animals
  • Benzoates / chemical synthesis*
  • Benzoates / chemistry
  • Benzoates / pharmacology*
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Inflammation / chemically induced
  • Inflammation / complications
  • Pain / drug therapy
  • Pain / etiology
  • Pyrroles / chemical synthesis*
  • Pyrroles / pharmacology*
  • Rats
  • Receptors, Prostaglandin E / antagonists & inhibitors*
  • Receptors, Prostaglandin E, EP1 Subtype
  • Structure-Activity Relationship

Substances

  • Benzoates
  • Pyrroles
  • Receptors, Prostaglandin E
  • Receptors, Prostaglandin E, EP1 Subtype