Synthesis and pharmacological evaluation of second-generation phosphatidic acid derivatives as lysophosphatidic acid receptor ligands

Durgam, Gangadhar G.; Tsukahara, Ryoko; Makarova, Natalia; Walker, Michelle D.; Fujiwara, Yuko; Pigg, Kathryn R.; Baker, Daniel L.; Sardar, Vineet M.; Parrill, Abby L.; Tigyi, Gábor; Miller, Duane D.

doi:10.1016/j.bmcl.2005.10.031

Cited by 48 publications

(65 citation statements)

References 42 publications

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“…In this list of 12 compounds, FMP and FPP stand out as selective agonists of LPA 5 with EC 50 values in the nanomolar range. Although we found several other agonists that activated LPA 5 , these were not full agonists when tested up to 3 M. As the farnesyl phosphates and NAG had not previously been computationally examined at LPA 1-3 , these compounds were docked into both active and inactive models of each receptor as done previously to investigate stereochemical effects on pharmacological profiles (43). The computational results indicated that antagonism is observed for receptor:ligand pairs when either the ligand shows an energetic preference for the inactive receptor model coupled with strong electrostatic interactions with critical ion-pairing residues and good van der Waals contact with hydrophobic residues or an energetic preference for the active receptor model without completely filling the putative hydrophobic binding pocket.…”

Section: Selection Of Mutationmentioning

confidence: 99%

Unique Ligand Selectivity of the GPR92/LPA5 Lysophosphatidate Receptor Indicates Role in Human Platelet Activation

Williams

Khandoga²,

Goyal³

et al. 2009

Journal of Biological Chemistry

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Lysophosphatidic acid (LPA) is a ligand for LPA 1-3 of the endothelial differentiation gene family G-protein-coupled receptors, and LPA 4 -8 is related to the purinergic family G-protein-coupled receptor. Because the structure-activity relationship (SAR) of GPR92/LPA 5 is limited and whether LPA is its preferred endogenous ligand has been questioned in the literature, in this study we applied a combination of computational and experimental site-directed mutagenesis of LPA 5 residues predicted to interact with the headgroup of LPA. Four residues involved in ligand recognition in LPA 5 were identified as follows: R2.60N mutant abolished receptor activation, whereas H4.64E, R6.62A, and R7.32A greatly reduced receptor activation. We also investigated the SAR of LPA 5 using LPA analogs and other non-lysophospholipid ligands. SAR revealed that the rank order of agonists is alkyl glycerol phosphate > LPA > farnesyl phosphates Ͼ Ͼ N-arachidonoylglycine. These results confirm LPA 5 to be a bona fide lysophospholipid receptor. We also evaluated several compounds with previously established selectivity for the endothelial differentiation gene receptors and found several that are LPA 5 agonists. A pharmacophore model of LPA 5 binding requirements was developed for in silico screening, which identified two non-lipid LPA 5 antagonists. Because LPA 5 transcripts are abundant in human platelets, we tested its antagonists on platelet activation and found that these non-lipid LPA 5 antagonists inhibit platelet activation. The present results suggest that selective inhibition of LPA 5 may provide a basis for future anti-thrombotic therapies.Lysophosphatidic acid (LPA, 2 1-radyl-2-hydroxy-sn-3-glycero phosphate) specifically interacts with several protein targets that regulate physiological and pathophysiological processes (1-3). LPA targets include specific G-protein-coupled receptors (GPCRs) that mediate a wide variety of biological effects, including cell proliferation (4), cell survival (5), cell migration (6), and platelet aggregation (7,8). GPCRs are the largest family of transmembrane receptors and represent targets of many therapeutics (9). Eight LPA-specific mammalian GPCRs, LPA 1-8 , have been identified to date (10 -12). Among the eight LPA receptors, LPA 1 , LPA 2 , and LPA 3 are members of the endothelial differentiation gene (EDG) family (13), and the transmembrane domains of human LPA 1-3 show 81% homology with each other (14). The five other members of the EDG family are specific for the related lysophospholipid sphingosine 1-phosphate (S1P). The structural foundation for LPA selectivity over S1P has been linked to a single amino acid at position 3.29, a conserved glutamine in the LPA-specific and glutamate in the S1P-specific members of the EDG family (14 -16). However, the recently identified non-EDG family LPA receptors, LPA 4 /p2y9 (13), LPA 5 /GPR92 (17, 18), LPA 6 /GPR87 (19), LPA 7 /p2y5 (12), and LPA 8 /p2y10 (10), are more closely related to the purinoreceptor gene cluster and share less than 20% amino acid...

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Section: Selection Of Mutationmentioning

confidence: 99%

Unique Ligand Selectivity of the GPR92/LPA5 Lysophosphatidate Receptor Indicates Role in Human Platelet Activation

Williams

Khandoga²,

Goyal³

et al. 2009

Journal of Biological Chemistry

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139

140

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“…Lysophosphatidic acid (18:1) was purchased from Avanti Polar Lipids (Alabaster, AL). OTP was synthesized and provided by RxBio, Inc. (Johnson City, TN) as described previously (Durgam et al, 2006). The test compounds used in the present study were obtained from the following vendors: Genome Research Institute GRI977143 from the University of Cincinnati Drug Discovery Center (Cincinnati, OH), Hit2Lead (http://www.hit2lead.com) H2L5547924, and H2L5828102 from ChemBridge (San Diego, CA), and NSC12404 from the National Cancer Institute Developmental Therapeutics Program Open Chemical Repository.…”

Section: Methodsmentioning

confidence: 99%

“…Stable cell lines expressing the individual LPA 1 , LPA 2 , LPA 3 , LPA 4 , and LPA 5 established receptor subtypes (Tigyi, 2010), as well as putative LPA receptors GPR87 (Tabata et al, 2007) and P2Y10 (Murakami et al, 2008) or appropriate empty vector-transfected controls, have been previously generated and described (Tabata et al, 2007;Murakami et al, 2008;Williams et al, 2009). Assays for ligand-activated mobilization of intracellular Ca 2ϩ were performed using a FlexStation II robotic fluorescent plate reader (Molecular Devices; Sunnyvale, CA) as described previously (Durgam et al, 2006). The appropriate concentrations of the test compounds were either used alone (for agonist testing) or mixed with the respective ϳEC 75 concentration of LPA 18:1 for the LPA receptor being tested (antagonist screen).…”

Section: Methodsmentioning

confidence: 99%

“…A decade ago, we had shown that LPA has profound activity in preventing apoptosis and can also rescue apoptotically condemned cells from the progression of the apoptotic cascade (Deng et al, 2002(Deng et al, , 2003(Deng et al, , 2004(Deng et al, , 2007. We developed an LPA mimic, octadecenyl thiophosphate (OTP) (Durgam et al, 2006), which has efficacy superior to that of LPA in vitro and in vivo in rescuing cells and animals from radiationinduced apoptosis (Deng et al, 2007). Development of LPAbased drug candidates has been limited to the discovery of lipid-like ligands, which is understandable because of the hydrophobic environment of the S1P and LPA G proteincoupled receptor (GPCR) ligand binding pockets (Parrill et al, 2000;Wang et al, 2001;Li et al, 2005;Fujiwara et al, 2007;Valentine et al, 2008;Hanson et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

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Virtual Screening for LPA₂-Specific Agonists Identifies a Nonlipid Compound with Antiapoptotic Actions

et al. 2012

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Lysophosphatidic acid (LPA) is a highly potent endogenous lipid mediator that protects and rescues cells from programmed cell death. Earlier work identified the LPA 2 G proteincoupled receptor subtype as an important molecular target of LPA mediating antiapoptotic signaling. Here we describe the results of a virtual screen using single-reference similarity searching that yielded compounds 2-((9-oxo-9H-fluoren-2-yl) carbamoyl)benzoic acid (NSC12404), 2-((3-(1,3-dioxo-1H-benzo- [de]isoquinolin-2(3H)-yl)propyl)thio)benzoic acid (GRI977143), 4,5-dichloro-2-((9-oxo-9H-fluoren-2-yl)carbamoyl)benzoic acid (H2L55-47924), and 2-((9,10-dioxo-9,10-dihydroanthracen-2-yl)carbamoyl) benzoic acid (H2L5828102), novel nonlipid and drug-like compounds that are specific for the LPA 2 receptor subtype. We characterized the antiapoptotic action of one of these compounds, GRI977143, which was effective in reducing activation of caspases 3, 7, 8, and 9 and inhibited poly(ADP-ribose)polymerase 1 cleavage and DNA fragmentation in different extrinsic and intrinsic models of apoptosis in vitro.Furthermore, GRI977143 promoted carcinoma cell invasion of human umbilical vein endothelial cell monolayers and fibroblast proliferation. The antiapoptotic cellular signaling responses were present selectively in mouse embryonic fibroblast cells derived from LPA 1&2 double-knockout mice reconstituted with the LPA 2 receptor and were absent in vector-transduced control cells. GRI977143 was an effective stimulator of extracellular signal-regulated kinase 1/2 activation and promoted the assembly of a macromolecular signaling complex consisting of LPA 2 , Na ϩ -H ϩ exchange regulatory factor 2, and thyroid receptor interacting protein 6, which has been shown previously to be a required step in LPA-induced antiapoptotic signaling. The present findings indicate that nonlipid LPA 2 -specific agonists represent an excellent starting point for development of lead compounds with potential therapeutic utility for preventing the programmed cell death involved in many types of degenerative and inflammatory diseases.

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“…Recently, metabolically stabilized carba derivatives of CPA (CCPA) were described as a novel inhibitors of metastatic cancer [10,15]. This finding provides the proof of concept for the antimetastatic application of CCPA and led us to develop a second generation of CCPA analogs ( [17], and see Prestwich et al in this issue). CCPA and its analogs could be promising anticancer drug candidates but their anti-metastatic mechanism of action has not been fully elucidated.…”

Section: Introductionmentioning

confidence: 99%

Cyclic phosphatidic acid — A unique bioactive phospholipid

Fujiwara

2008

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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Cyclic phosphatidic acid (CPA) is a naturally occurring analog of the growth factor-like phospholipid mediator, lysophosphatidic acid (LPA). The sn-2 hydroxy group of CPA forms a 5-membered ring with the sn-3 phosphate. CPA affects numerous cellular functions, including antimitogenic regulation of the cell cycle, induction of stress fiber formation, inhibition of tumor cell invasion and metastasis, and regulation of differentiation and survival of neuronal cells. Interestingly, many of these cellular responses caused by CPA oppose those of LPA despite the activation of apparently overlapping receptor populations. Since the early 1990s, studies on CPA actions gradually developed, and we are now beginning to understand the importance of this lipid. In this review, we focus on the current knowledge about CPA, including enzymatic formation of CPA, unique biological activities and biological targets of CPA, and we also explore metabolically stabilized CPA analogs.

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Synthesis and pharmacological evaluation of second-generation phosphatidic acid derivatives as lysophosphatidic acid receptor ligands

Cited by 48 publications

References 42 publications

Unique Ligand Selectivity of the GPR92/LPA5 Lysophosphatidate Receptor Indicates Role in Human Platelet Activation

Unique Ligand Selectivity of the GPR92/LPA5 Lysophosphatidate Receptor Indicates Role in Human Platelet Activation

Virtual Screening for LPA₂-Specific Agonists Identifies a Nonlipid Compound with Antiapoptotic Actions

Cyclic phosphatidic acid — A unique bioactive phospholipid

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Synthesis and pharmacological evaluation of second-generation phosphatidic acid derivatives as lysophosphatidic acid receptor ligands

Cited by 48 publications

References 42 publications

Unique Ligand Selectivity of the GPR92/LPA5 Lysophosphatidate Receptor Indicates Role in Human Platelet Activation

Unique Ligand Selectivity of the GPR92/LPA5 Lysophosphatidate Receptor Indicates Role in Human Platelet Activation

Virtual Screening for LPA2-Specific Agonists Identifies a Nonlipid Compound with Antiapoptotic Actions

Cyclic phosphatidic acid — A unique bioactive phospholipid

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Virtual Screening for LPA₂-Specific Agonists Identifies a Nonlipid Compound with Antiapoptotic Actions