Structure-activity relationships (SAR) and structure-kinetic relationships (SKR) of pyrrolopiperidinone acetic acids as CRTh2 antagonists

Bioorg Med Chem Lett. 2014 Nov 1;24(21):5111-7. doi: 10.1016/j.bmcl.2014.08.026. Epub 2014 Aug 18.

Abstract

Pyrrolopiperidinone acetic acids (PPAs) were identified as highly potent CRTh2 receptor antagonists. In addition, many of these compounds displayed slow-dissociation kinetics from the receptor. Structure-kinetic relationship (SKR) studies allowed optimisation of the kinetics to give potent analogues with long receptor residence half-lives of up to 23 h. Low permeability was a general feature of this series, however oral bioavailability could be achieved through the use of ester prodrugs.

Keywords: CRTh2 antagonist; Permeability; Prodrug; Receptor residence time; Structure–activity relationship (SAR); Structure–kinetic relationship (SKR).

MeSH terms

  • Acetates / chemical synthesis
  • Acetates / chemistry*
  • Acetates / pharmacokinetics
  • Acetates / pharmacology*
  • Administration, Oral
  • Animals
  • Caco-2 Cells
  • Cell Membrane Permeability / drug effects
  • Half-Life
  • Humans
  • Piperidines / chemistry*
  • Pyrazoles / chemistry*
  • Rats
  • Receptors, Immunologic / antagonists & inhibitors*
  • Receptors, Immunologic / metabolism
  • Receptors, Prostaglandin / antagonists & inhibitors*
  • Receptors, Prostaglandin / metabolism
  • Structure-Activity Relationship

Substances

  • Acetates
  • Piperidines
  • Pyrazoles
  • Receptors, Immunologic
  • Receptors, Prostaglandin
  • pyrazole
  • prostaglandin D2 receptor