2. Academic Validation
  3. Affinity and kinetics study of anthranilic acids as HCA2 receptor agonists

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.
Jacobus P D van Veldhoven 1,  Rongfang Liu 1,  Stephanie A Thee 1,  Yessica Wouters 1,  Sanne J M Verhoork 1,  Christiaan Mooiman 1,  Julien Louvel 1,  Adriaan P IJzerman 2
Affiliations

Affiliations

  • 1 Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, PO Box 9502, 2300 RA Leiden, The Netherlands.
  • 2 Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, PO Box 9502, 2300 RA Leiden, The Netherlands. Electronic address: ijzerman@lacdr.leidenuniv.nl.
PMID: 25737085 DOI: 10.1016/j.bmc.2015.02.018
Abstract

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.

Figures