Affinity and kinetics study of anthranilic acids as HCA2 receptor agonists.
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.
Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, PO Box 9502, 2300 RA Leiden, The Netherlands.
Jacobus P D
JP
van Veldhoven
Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, PO Box 9502, 2300 RA Leiden, The Netherlands.
Rongfang
R
Liu
Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, PO Box 9502, 2300 RA Leiden, The Netherlands.
Stephanie A
SA
Thee
Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, PO Box 9502, 2300 RA Leiden, The Netherlands.
Yessica
Y
Wouters
Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, PO Box 9502, 2300 RA Leiden, The Netherlands.
Sanne J M
SJ
Verhoork
Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, PO Box 9502, 2300 RA Leiden, The Netherlands.
Christiaan
C
Mooiman
Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, PO Box 9502, 2300 RA Leiden, The Netherlands.
Julien
J
Louvel
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.
Adriaan P
AP
IJzerman
D001667:Binding, Competitive; D060326:Chemistry Techniques, Synthetic; D004353:Drug Evaluation, Preclinical / Q000379:methods; D057809:HEK293 Cells / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D009525:Niacin / Q000378:metabolism; D018722:Nicotinic Agonists / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000378:metabolism; D013329:Structure-Activity Relationship; D062367:ortho-Aminobenzoates / Q000737:chemistry*
C530636:HCAR2 protein, human; D018722:Nicotinic Agonists; D043562:Receptors, G-Protein-Coupled; D011978:Receptors, Nicotinic; D062367:ortho-Aminobenzoates; C031385:anthranilic acid; D009525:Niacin
Biphenyl anthranilic acid derivatives; GPR109A/HCA(2) receptor; Kinetics; Nicotinic acid; Residence time