Affinity and kinetics study of anthranilic acids as HCA2 receptor agonists

Bioorg Med Chem. 2015 Jul 15;23(14):4013-25. doi: 10.1016/j.bmc.2015.02.018. Epub 2015 Feb 17.


Structure-affinity relationship (SAR) and structure-kinetics relationship (SKR) studies were combined to investigate a series of biphenyl anthranilic acid agonists for the HCA2 receptor. In total, 27 compounds were synthesized and twelve of them showed higher affinity than nicotinic acid. Two compounds, 6g (IC50=75nM) and 6z (IC50=108nM) showed a longer residence time profile compared to nicotinic acid, exemplified by their kinetic rate index (KRI) values of 1.31 and 1.23, respectively. The SAR study resulted in the novel 2-F, 4-OH derivative (6x) with an IC50 value of 23nM as the highest affinity HCA2 agonist of the biphenyl series, although it showed a similar residence time as nicotinic acid. The SAR and SKR data suggest that an early compound selection based on binding kinetics is a promising addition to the lead optimization process.

Keywords: Biphenyl anthranilic acid derivatives; GPR109A/HCA(2) receptor; Kinetics; Nicotinic acid; Residence time.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding, Competitive
  • Chemistry Techniques, Synthetic
  • Drug Evaluation, Preclinical / methods
  • HEK293 Cells / drug effects
  • Humans
  • Inhibitory Concentration 50
  • Kinetics
  • Niacin / metabolism
  • Nicotinic Agonists / chemistry*
  • Nicotinic Agonists / metabolism
  • Nicotinic Agonists / pharmacology
  • Receptors, G-Protein-Coupled / agonists*
  • Receptors, G-Protein-Coupled / metabolism
  • Receptors, Nicotinic / metabolism
  • Structure-Activity Relationship*
  • ortho-Aminobenzoates / chemistry*


  • HCAR2 protein, human
  • Nicotinic Agonists
  • Receptors, G-Protein-Coupled
  • Receptors, Nicotinic
  • ortho-Aminobenzoates
  • anthranilic acid
  • Niacin