Identification of novel pyrazole acid antagonists for the EP1 receptor

Bioorg Med Chem Lett. 2006 Sep 15;16(18):4767-71. doi: 10.1016/j.bmcl.2006.06.086. Epub 2006 Jul 14.

Abstract

The discovery, synthesis and structure-activity relationship (SAR) of a novel series of EP1 receptor antagonists is described. Pyrazole acid 4, identified from a chemical array, had desirable physicochemical properties, an excellent in vitro microsomal inhibition and cytochrome P450 (CYP450) profile and good exposure levels in blood. This compound had an ED50 of 1.3 mg/kg in a rat pain model. A range of more potent analogues in the in vitro assay was identified using efficient array chemistry. These EP1 antagonists have potential as agents in the treatment of PGE2 mediated pain.

MeSH terms

  • Animals
  • Chemical Phenomena
  • Chemistry, Physical
  • Cytochrome P-450 Enzyme System / metabolism
  • Molecular Structure
  • Pyrazoles / chemical synthesis*
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacokinetics
  • Pyrazoles / pharmacology*
  • Rats
  • Receptors, Prostaglandin E / antagonists & inhibitors*
  • Receptors, Prostaglandin E / metabolism
  • Receptors, Prostaglandin E, EP1 Subtype
  • Structure-Activity Relationship

Substances

  • Ptger1 protein, rat
  • Pyrazoles
  • Receptors, Prostaglandin E
  • Receptors, Prostaglandin E, EP1 Subtype
  • pyrazole
  • Cytochrome P-450 Enzyme System