Affinity and kinetics study of anthranilic acids as HCA2 receptor agonists. Issue 14 (15th July 2015)

• Record Type: Journal Article
• Authors: van Veldhoven, Jacobus P.D.; Liu, Rongfang; Thee, Stephanie A.; Wouters, Yessica; Verhoork, Sanne J.M.; Mooiman, Christiaan; Louvel, Julien; IJzerman, Adriaan P.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 23:Issue 14(2015)
• Page Start: 4013
• Page End: 4025
• Publication Date: 2015-07-15
• Subjects: GPR109A/HCA2 receptor -- Kinetics -- Residence time -- Biphenyl anthranilic acid derivatives -- Nicotinic acid; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2015.02.018
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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 = 75 nM) and6z (IC50 = 108 nM) 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 23 nM 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.