Lysophosphatidic acid (LPA) is a bioactive compound that has gained attention due to its role in neoplastic diseases. Our group has developed a potent dual LPA1/LPA3 receptor antagonist, VPC51098 (LPA1 IC(50) = 84 nM, LPA1 IC(50) = 48 nM) that contained a labile phosphate head group. This lability has impaired our evaluation of our scaffold of LPA receptor antagonists in vivo.
View Article and Find Full Text PDFPhosphatidic acid and lysophosphatidic acid are minor but important anionic bioactive lipids involved in a number of key cellular processes, yet these molecules have a simple phosphate headgroup. To find out what is so special about these lipids, we determined the ionization behavior of phosphatidic acid (PA) and lysophosphatidic acid (LPA) in extended (flat) mixed lipid bilayers using magic angle spinning 31P NMR. Our data show two surprising results.
View Article and Find Full Text PDFA recently reported dual LPA(1)/LPA(3) receptor antagonist (1) has been modified so as to modulate the basicity, sterics, and dipole moment of the 2-pyridyl moiety. Additionally, the implications of installing nonhydrolyzable phosphate head group isosteres with regard to antagonist potency and selectivity at LPA receptors is described. This study has resulted in the development of the first nonhydrolyzable and presumably phosphatase-resistant LPA(3)-selective antagonist reported to date.
View Article and Find Full Text PDFUsing an N-oleoyl ethanolamide scaffold, a series of phosphate polar head group analogues of LPA comprised of various alpha-substituted phosphonates and thiophosphates was prepared. In a broken cell GTP[gamma35S] binding assay, agonist activity was evaluated at the three LPA receptors of the endothelial differentiation gene (Edg) family. This study has resulted in the discovery of a nonhydrolyzable LPA1-selective agonist (11).
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