α‐Substituted Phosphonate Analogues of Lysophosphatidic Acid (LPA) Selectively Inhibit Production and Action of LPA

Abstract

Isoform-selective agonists and antagonists of the lysophosphatidic acid (LPA) G-protein-coupled receptors (GPCRs) have important potential applications in cell biology and therapy. LPA GPCRs regulate cancer cell proliferation, invasion, angiogenesis, and biochemical resistance to chemotherapy-and radiotherapy-induced apoptosis. LPA and its analogues are also feedback inhibitors of the enzyme lysophospholipase D (lysoPLD, also known as autotaxin), a central regulator of invasion and metastasis. For cancer therapy, the ideal therapeutic profile would be a metabolically stabilized pan-LPA receptor antagonist that also inhibits lysoPLD. Herein we describe the synthesis of a series of novel α-substituted methylene phosphonate analogues of LPA. Each of these analogues contains a hydrolysis-resistant phosphonate mimic of the labile monophosphate of natural LPA. The pharmacological properties of these phosphono-LPA analogues were characterized in terms of LPA receptor subtype-specific agonist and antagonist activity using Ca 2+ mobilization assays in RH7777 and CHO cells expressing the individual LPA GPCRs. In particular, the methylene phosphonate LPA analogue is a selective LPA 2 agonist, whereas the corresponding α-hydroxymethylene phosphonate is a selective LPA 3 agonist. Most importantly, the α-bromomethylene and α-chloromethylene phosphonates show pan-LPA receptor subtype antagonist activity. The α-bromomethylene phosphonates are the first reported antagonists for the LPA 4 GPCR. Each of the α-substituted methylene phosphonates inhibits lysoPLD, with the unsubstituted methylene phosphonate showing the most potent inhibition. Finally, unlike many LPA analogues, none of these compounds activate the intracellular LPA receptor PPARγ.

LPA receptor signaling: pharmacology, physiology, and pathophysiology

“…2, Table 2). Most of these receptor modulators are directed at LPA receptors, particularly against LPA [1][2][3] , although a few compounds have demonstrated some LPA 4 and LPA 5 activity with limited selectivity (182,193,194). Additionally, several compounds target enzymes that regulate the production of LPA, notably ATX and LPPs (195,196).…”

Mechanism of rapid elimination of lysophosphatidic acid and related lipids from the circulation of mice

“…To further investigate the possible role of enzymatic degradation in the elimination of intravenously administered LPA from the plasma, we compared the rate of elimination of intravenously administered C17-LPA to that of two phosphonate-containing LPA analogs, JGW-9 and JGW-10, that are resistant to enzymatic dephosphorylation ( 27,28 ) ( Fig. 3A ).…”

Murine and Human Autotaxin α, β, and γ Isoforms

“…Indeed, apart from compounds issued from lipid chemistry, such as LPA phosphonate analogs (52,53), fatty alcohol phosphates (54), cyclic LPA (55), or Darmstoff analogs of LPA (56), there are no small molecules described as the potent inhibitor of this enzyme. During our screening on autotaxin ␤ partially purified from COS-transfected cells, we identified several compounds that in our hands were good candidates for such a purpose.…”