Structure-activity relationships (SAR) and structure-kinetic relationships (SKR) of bicyclic heteroaromatic acetic acids as potent CRTh2 antagonists II: lead optimization

Bioorg Med Chem Lett. 2014 Nov 1;24(21):5123-6. doi: 10.1016/j.bmcl.2014.08.029. Epub 2014 Aug 19.

Abstract

Extensive structure-activity relationship (SAR) and structure-kinetic relationship (SKR) studies in the bicyclic heteroaromatic series of CRTh2 antagonists led to the identification of several molecules that possessed both excellent binding and cellular potencies along with long receptor residence times. A small substituent in the bicyclic core provided an order of magnitude jump in dissociation half-lives. Selected optimized compounds demonstrated suitable pharmacokinetic profiles.

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

MeSH terms

  • Acetates / chemical synthesis
  • Acetates / chemistry*
  • Acetates / pharmacokinetics
  • Animals
  • Bridged Bicyclo Compounds / chemistry*
  • Half-Life
  • Humans
  • Indoles / chemistry
  • Injections, Intravenous
  • Rats
  • Rats, Wistar
  • Receptors, Immunologic / antagonists & inhibitors*
  • Receptors, Immunologic / metabolism
  • Receptors, Prostaglandin / antagonists & inhibitors*
  • Receptors, Prostaglandin / metabolism
  • Structure-Activity Relationship

Substances

  • Acetates
  • Bridged Bicyclo Compounds
  • Indoles
  • Receptors, Immunologic
  • Receptors, Prostaglandin
  • indole
  • prostaglandin D2 receptor