Synthesis and biological evaluation of phosphonic and thiophosphoric acid derivatives of lysophosphatidic acid.
Using 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). Additionally, thiophosphate 19 bears an isosteric phosphate mimetic that confers agonism at the LPA1 receptor but not LPA2.
Santos
Webster L
WL
Department of Chemistry and Chemical Biology, 12 Oxford Street, Cambridge, MA 02138, USA.
Heasley
Brian H
BH
Jarosz
Renata
R
Carter
Karen M
KM
Lynch
Kevin R
KR
Macdonald
Timothy L
TL
D000577:Amides / Q000737:chemistry; D000818:Animals; D002478:Cells, Cultured; D008246:Lysophospholipids / Q000138:chemical synthesis* / Q000494:pharmacology; D009829:Oleic Acids / Q000737:chemistry; D010710:Phosphates / Q000737:chemistry*; D010756:Phosphoric Acids / Q000737:chemistry*; D011869:Radioligand Assay / Q000379:methods; D049368:Receptors, Lysophosphatidic Acid / Q000819:agonists* / Q000378:metabolism; D013229:Stearic Acids / Q000737:chemistry
D000577:Amides; D008246:Lysophospholipids; D009829:Oleic Acids; D010710:Phosphates; D010756:Phosphoric Acids; D049368:Receptors, Lysophosphatidic Acid; D013229:Stearic Acids; C030242:phosphoric acid; C035638:thiophosphoric acid; C040995:isostearic acid