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 LPA(1) and LPA(3) 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, PPARgamma, 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 LPA(3) receptor subtype-selective agonist (EC(50)=3 nM), and 8b as a potent and selective LPA(3) receptor antagonist (K(i)=5 nM) and inhibitor of ATX (IC(50)=600 nM). Serinediamide phosphate 19b was identified as an LPA(3) receptor specific antagonist with no effect on LPA(1), LPA(2), and PPARgamma.
Durgam
Gangadhar G
GG
Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Tsukahara
Ryoko
R
Makarova
Natalia
N
Walker
Michelle D
MD
Fujiwara
Yuko
Y
Pigg
Kathryn R
KR
Baker
Daniel L
DL
Sardar
Vineet M
VM
Parrill
Abby L
AL
Tigyi
Gabor
G
Miller
Duane D
DD
D000818:Animals; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D008024:Ligands; D008958:Models, Molecular; D009097:Multienzyme Complexes / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D010710:Phosphates / Q000737:chemistry; D010712:Phosphatidic Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D049368:Receptors, Lysophosphatidic Acid / Q000819:agonists* / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism
D008024:Ligands; D009097:Multienzyme Complexes; D047495:PPAR gamma; D010710:Phosphates; D010712:Phosphatidic Acids; D010726:Phosphodiesterase Inhibitors; D043562:Receptors, G-Protein-Coupled; D049368:Receptors, Lysophosphatidic Acid