Synthesis and pharmacological evaluation of second-generation phosphatidic acid derivatives as lysophosphatidic acid receptor ligands
Short-chain phosphatidic acid derivatives, dioctanoyl glycerol pyrophosphate (DGPP 8:0, 1) and phosphatidic acid 8:0 (PA 8:0, 2), were previously identified as subtype-selective LPA1 and LPA3 receptor antagonists. Recently, we reported that the replacement of the phosphate headgroup by thiophosphate in a series of fatty alcohol phosphates (FAP) improves agonist as well as antagonist activities at LPA GPCR. Here, we report the synthesis of stereoisomers of PA 8:0 analogs and their biological evaluation at LPA GPCR, PPARγ, and ATX. The results indicate that LPA receptors stereoselectively interact with glycerol backbone modified ligands. We observed entirely stereospecific responses by dioctyl PA 8:0 compounds, in which (R)-isomers were found to be agonists and (S)-isomers were antagonists of LPA GPCR. From this series, we identified compound 13b as the most potent LPA3 receptor subtype-selective agonist (EC50 = 3 nM), and 8b as a potent and selective LPA3 receptor antagonist (Ki = 5 nM) and inhibitor of ATX (IC50 = 600 nM). Serinediamide phosphate 19b was identified as an LPA3 receptor specific antagonist with no effect on LPA1, LPA2, and PPARγ. © 2005 Elsevier Ltd. All rights reserved.
Bioorganic and Medicinal Chemistry Letters
Durgam, G., Tsukahara, R., Makarova, N., Walker, M., Fujiwara, Y., Pigg, K., Baker, D., & Sardar, V. (2006). Synthesis and pharmacological evaluation of second-generation phosphatidic acid derivatives as lysophosphatidic acid receptor ligands. Bioorganic and Medicinal Chemistry Letters, 16 (3), 633-640. https://doi.org/10.1016/j.bmcl.2005.10.031