Journal
CHEMMEDCHEM
Volume 2, Issue 5, Pages 679-690Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.200600280
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Funding
- NCI NIH HHS [R01 CA092160, CA921160, R01 CA092160-09] Funding Source: Medline
- NHLBI NIH HHS [R01 HL061469, R01 HL070231, HL070231, HL61469] Funding Source: Medline
- NINDS NIH HHS [NS29632, R01 NS029632] Funding Source: Medline
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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 alpha-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 Co2+ 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 alpha-hydroxymethylene phosphonate is a selective LPA(3) agonist. Most importantly, the a-bromomethylene and alpha-chloromethylene phosphonates show pan-LPA receptor subtype antagonist activity. The alpha-bromomethylene phosphonates are the first reported antagonists for the LPA(4) GPCR. Each of the alpha-substituted methylene phosphonotes 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 PPAR gamma.
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