Structure-activity relationships of 1,5-biaryl pyrroles as EP1 receptor antagonists

Bioorg Med Chem Lett. 2006 Jul 15;16(14):3657-62. doi: 10.1016/j.bmcl.2006.04.073. Epub 2006 May 11.

Abstract

The preliminary SAR of a series of novel 1,5-biaryl pyrrole EP1 receptor antagonists derived from compound 1 is described. Replacement of the benzyl group of 1 with isosteric groups was investigated. The most effective replacement was found to be the isobutyl group. The cyclopentylmethyl and cyclohexylmethyl groups were also effective benzyl replacements. The cyclohexylmethyl derivative 19 demonstrated the lowest metabolic clearance within this series. In addition, several high affinity substituted benzyl analogues were also identified. Compound 39 was found to have good bioavailability in rats and demonstrated efficacy in the established FCA preclinical model of inflammatory pain with a calculated ED50 of 9.2mg/kg.

MeSH terms

  • Analgesics / pharmacology*
  • Animals
  • Benzoates / chemical synthesis
  • Benzoates / pharmacology*
  • Biological Availability
  • Cyclohexanes / chemistry
  • Cyclopentanes / chemistry
  • Inflammation / drug therapy
  • Inflammation / pathology
  • Ligands
  • Pain / drug therapy
  • Pain / pathology
  • Pyrroles / chemistry
  • Pyrroles / pharmacology*
  • Rats
  • Receptors, Prostaglandin E / antagonists & inhibitors*
  • Receptors, Prostaglandin E, EP1 Subtype
  • Structure-Activity Relationship

Substances

  • Analgesics
  • Benzoates
  • Cyclohexanes
  • Cyclopentanes
  • Ligands
  • Pyrroles
  • Receptors, Prostaglandin E
  • Receptors, Prostaglandin E, EP1 Subtype