Synthesis, structure-activity relationships, and biological evaluation of fatty alcohol phosphates as lysophosphatidic acid receptor ligands, activators of PPARgamma, and inhibitors of autotaxin.
We previously reported that fatty alcohol phosphates (FAP) represent a minimal pharmacophore required to interact with lysophosphatidic acid (LPA) receptors. To improve the activity of the first-generation saturated FAP series, a structure-activity relationship (SAR) study was carried out that includes modifications to the headgroup and alkyl side chain of the FAP pharmacophore. A series of unsaturated (C(10)-C(18)) FAP, headgroup-modified hydrolytically stable saturated (C(10)-C(18)) alkyl phosphonates, and saturated and unsaturated (C(10)-C(18)) thiophosphate analogues were synthesized and evaluated for activity in RH7777 cells transfected with individual LPA(1)(-3) receptors, in PC-3 cells and in human platelets that endogenously express all three isoforms. In this series we identified several LPA(1)- and LPA(3)-selective antagonists with IC(50) values in the nanomolar range. Oleoyl-thiophosphate (15g) was shown to be a pan-agonist, whereas tetradecyl-phosphonate (16c) was identified as a pan-antagonist. These compounds were also tested for the ability to activate the transcription factor PPARgamma, an intracellular receptor for LPA, in CV1 cells transfected with the PPRE-Acox-Rluc reporter gene. All the FAP tested, along with the previously reported LPA GPCR antagonists dioctanoyl glycerol pyrophosphate (2), Ki16425 (6), and the agonist OMPT (3), were activators of PPARgamma. The pan-agonist oleoyl-thiophosphate (15g) and pan-antagonist tetradecyl-phosphonate (16c) mimicked LPA in inhibiting autotaxin, a secreted lysophospholipase D that produces LPA in biological fluids.
Durgam
Gangadhar G
GG
Department of Pharmaceutical Sciences, College of Pharmacy and Department of Physiology, College of Medicine, University of Tennessee Health Science Center, 847 Monroe Avenue, Room 227C, Memphis, Tennessee 38163, USA.
Virag
Tamas
T
Walker
Michelle D
MD
Tsukahara
Ryoko
R
Yasuda
Satoshi
S
Liliom
Karoly
K
van Meeteren
Laurens A
LA
Moolenaar
Wouter H
WH
Wilke
Nicole
N
Siess
Wolfgang
W
Tigyi
Gabor
G
Miller
Duane D
DD
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D005233:Fatty Alcohols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D066298:In Vitro Techniques; D008024:Ligands; D010755:Organophosphates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D047495:PPAR gamma / Q000819:agonists*; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D051381:Rats; D049368:Receptors, Lysophosphatidic Acid / Q000819:agonists* / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D000099189:Lysophospholipase D
D002118:Calcium; D005233:Fatty Alcohols; D008024:Ligands; D010755:Organophosphates; D063065:Organophosphonates; D047495:PPAR gamma; D010726:Phosphodiesterase Inhibitors; D010727:Phosphoric Diester Hydrolases; D049368:Receptors, Lysophosphatidic Acid; D000099189:Lysophospholipase D; C502989:oleoyl thiophosphate; C502990:tetradecyl phosphonate