cpla2

FAAH cPLA2α-IN-1 is a dual inhibitor of FAAH and cPLA2α, with potent inhibitory activity, exhibiting half-maximal inhibitory concentrations (IC50s) of 32 nM for FAAH and 47 nM for cPLA2α [1].

Giripladib (PLA695)(PLX-695) is a cPLA2-specific inhibitor that inhibits the radiation-induced increase of phosphorylated ERK and phosphorylated Akt in endothelial cells.

AACOCF3 (Arachidonyl trifluoromethyl ketone) is a cell-permeable trifluoromethyl ketone analog of arachidonic acid and a potent, selective slow binding inhibitor of the 85-kDa cytosolic phospholipase A2 (cPLA2). By blocking the production of arachidonate and 12-hydroxyeicosatetraenoic acid in calcium ionophore-challenged platelets, AACOCF3 hinders their synthesis. Additionally, AACOCF3 inhibits glucose-induced insulin secretion from isolated rat islets, making it promising for cardiovascular disease research.

Tanshinone I (Tanshinone A), an active principle isolated from the herbal medicine Salvia miltiorrhiza, displays cytotoxicity against tumor cells.

PFK-158 is an effective and specific inhibitor PFKFB3.

The group IVA phospholipase A2 (PLA2), known as calcium-dependent cytosolic PLA2 (cPLA2), selectively releases arachidonic acid (AA) from membrane phospholipids, playing a central role in initiating the synthesis of prostaglandins (PGs) and leukotrienes (LTs). Pyrrophenone inhibits cPLA2α with an IC50 of 4.2 nM in enzyme assays and potently blocks the release of AA and the production of PGE2 and LTC4 in cells (IC50 = 24, 25, and 14 nM, respectively). Its action is reversible and selective, as pyrrophenone inhibits the secretory type IB and IIA PLA2s with more than a hundred-fold less potency. Pyrrophenone has also been shown to inhibit calcium ionophore (A23187)-stimulated AA release from monocytic cells, interleukin-1-induced PGE2 synthesis in mesangial cells, and the production of PGE2, LTs, and platelet-activating factor by human neutrophils, always with maximal inhibition at concentrations below 1 μM.

AVX-001, a cytosolic phospholipase A2 (cPLA2) inhibitor, is used potentially for the treatment of psoriasis.

The group IVA phospholipase A2 (PLA2), known as calcium-dependent cytosolic PLA2 (cPLA2), selectively releases arachidonic acid from membrane phospholipids, playing a central role in initiating the synthesis of prostaglandins and leukotrienes. AX 048 is a potent group IVA cPLA2 inhibitor that demonstrates 50% inhibition of the enzyme at a mole fraction (XI(50)) of 0.022. Pretreatment with AX 048 (ED50 = 1.2 mg/kg) dose-dependently reduces thermal hyperalgesia evoked by carrageenan injection of rat hind paw. At concentrations as high as 30 μM, AX 048 does not inhibit COX activity or interfere with central cannabinoid receptor signaling.

FKGK 18 is an inhibitor of group VIA (GVIA) calcium-independent phospholipase A2 (iPLA2). It inhibits GVIA iPLA2 by 99.9% at 0.091 mole fraction in a mixed micelle activity assay and is selective for GVIA iPLA2 over GIVA cPLA2 and GV sPLA2 where it shows 80.8 and 36.8% inhibition, respectively. FKGK 18 inhibits iPLA2β activity in cytosolic extracts from INS-1 cells overexpressing iPLA2β (IC50 = ~50 nM) as well as iPLA2γ activity in mouse heart membrane fractions (IC50s = ~1-3 μM). It inhibits glucose-induced increases in prostaglandin E2 production and insulin secretion in human pancreatic islets when used at a concentration of 10 μM and inhibits thapsigargin-induced apoptosis in INS-1 cells overexpressing iPLA2β in a concentration-dependent manner. FKGK 18 (20 mg/kg, 3 times per week) reduces blood glucose levels in an intraperitoneal glucose tolerance test, decreases the incidence of diabetes, and increases serum insulin levels in non-obese diabetic (NOD) mice.

GK563, a selective Ca 2+-independent phospholipase A2 (GVIA iPLA2) inhibitor, exhibits a potent IC50 value of 1 nM and demonstrates 22,000-fold greater activity against GVIA iPLA2 compared to GIVA cPLA2. Its efficacy in reducing β-cell apoptosis triggered by proinflammatory cytokines suggests potential therapeutic benefits in combating autoimmune disorders, including type 1 diabetes.

AK-106, also known as AK106-001616, is a selective inhibitor of cytosolic phospholipase A2 (cPLA2) inhibitor. AK-106 has been shown to have analgesic activites similar to non-steroidal anti-inflammatory drugs (NSAIDs).

Arachidonoyl Thio-PC is a substrate for various phospholipase A2s (PLA2s), including sPLA2, cPLA2, and iPLA2. Cleavage of the sn-2 fatty acid by PLA2 produces a free thiol that reacts with chromogenic reagents like DTNB (Ellman's reagent) and DTP, facilitating PLA2 activity quantitation. Isozyme-specific cPLA2 activity can be measured by excluding or inhibiting sPLA2 and iPLA2 activities in the assay.

PF 5212372 (PLA-950, ZPL-521, ZPL 5212372) is a potent and selective inhibitor of cPLA2.

MAFP (Methyl Arachidonyl Fluorophosphonate) is an effective, active-site directed irreversible inhibitor of anandamide amidase, cPLA2, and iPLA2.

GSK563 is a potent GVIA iPLA2 inhibitor (XI(50) 0.0000021, IC50 1 nM). GSK563 is 22 000 times more active against GVIA iPLA2 than GIVA cPLA2. It was found to reduce β-cell apoptosis induced by proinflammatory cytokines, raising the possibility that it can be beneficial in countering autoimmune diseases, such as type 1 diabetes.

2-Methylbutyrylcarnitine (chloride) acts as a gut microbial metabolite that targets integrin α2β1 on platelets, facilitating the activation of cytosolic phospholipase A2 (cPLA2) and enhancing platelet hyperresponsiveness. This compound further augments platelet hyperreactivity and promotes thrombus formation in mice. It is also characterized as a branched-chain acylcarnitine.

Diheptanoyl Thio-PC is a substrate for all phospholipase A2s (PLA2s) with the exception of cPLA2 and PAF-acetyl hydrolase (PAF-AH). Interaction of this compound with a PLA2 results in cleavage of the sn-2 fatty acid generating a free thiol on the lysophospholipid. This free thiol can be detected using chromogenic substrates such as DTNB (Ellman's reagent) and DTP.

10-Pyrene-PC is a substrate for all PLA2s with the exception of cPLA2 and PAF-AH. Upon phospholipid hydrolysis, 10-pyrenyldecanoic acid is produced from 10-pyrene-PC. The monomeric 10-pyrenyldecanoic acid exhibits fluorescence (excitation 345 nm, emission 395 nm), allowing quantitation of phospholipase activity.