Catalog Number
ACM1130067343
Description
CAY10594 is a potent phospholipase D2 inhibitor. CAY10594 ameliorates acetaminophen-induced acute liver injury by regulating the phosphorylated-GSK-3β/JNK axis. CAY10594 administration markedly blocked the acute liver injury in a dose-dependent manner, showing almost complete inhibition with 8 mg/kg of CAY10594. CAY10594 administration strongly blocked GSK-3β (Serine 9)/JNK phosphorylation in the APAP-induced acute liver injury model. Consistently, sustained JNK activation in the cytosol and mitochondria from hepatocytes were also decreased in CAY10594-treated mice.
Synonyms
CAY10594; CAY-10594; CAY 10594
IUPAC Name
N-[2-(4-oxo-1-phenyl-1,3,8-triazaspiro[4,5]dec-8-yl)ethyl]-2-naphthalenecarboxamide
Molecular Formula
C26H28N4O2
Canonical SMILES
O=C(C1=CC=C2C=CC=CC2=C1)NCCN(CC3)CCC3(N(C4=CC=CC=C4)CN5)C5=O
InChI
InChI=1S/C26H28N4O2/c31-24(22-11-10-20-6-4-5-7-21(20)18-22)27-14-17-29-15-12-26(13-16-29)25(32)28-19-30(26)23-8-2-1-3-9-23/h1-11,18H,12-17,19H2,(H,27,31)(H,28,32)
InChI Key
FAIFAFUXFFWVNQ-UHFFFAOYSA-N
Solubility
Soluble in DMSO
Shelf Life
>3 years if stored properly
Storage
Dry, dark and at 0-4 °C for short term (days to weeks) or -20 °C for long term (months to years).
Biological Target
PLD2 inhibitor
Drug Formulation
This drug may be formulated in DMSO
Elemental Analysis
C, 72.87; H, 6.59; N, 13.07; O, 7.47
HS Tariff Code
2934.99.9001
In Vitro Activity
The current study investigated the mode of action of this compound on P2X7 activation. Measurements of ATP-induced ethidium(+) uptake revealed that CAY10593 impaired P2X7-induced pore formation in human RPMI 8226 B cells, P2X7-transfected HEK-293 cells and peripheral blood mononuclear cells. Concentration response curves demonstrated that CAY10593 impaired P2X7-induced pore formation in RPMI 8226 cells more potently than the PLD2 antagonist CAY10594 and the non-specific PLD antagonist halopemide. Electrophysiology measurements demonstrated that CAY10593 also inhibited P2X7-induced inward currents. Notably, RT-PCR demonstrated that PLD1 was absent in RPMI 8226 cells, while choline-Cl medium or 1-butanol, which block PLD stimulation and signalling respectively did not impair P2X7 activation in these cells. This data indicates that CAY10593 impairs human P2X7 independently of PLD1 stimulation and highlights the importance of ensuring that compounds used in signalling studies downstream of P2X7 activation do not affect the receptor itself.
Reference: Pupovac A, Stokes L, Sluyter R. CAY10593 inhibits the human P2X7 receptor independently of phospholipase D1 stimulation. Purinergic Signal. 2013 Dec;9(4):609-19. doi: 10.1007/s11302-013-9371-6. Epub 2013 Jun 21. PMID: 23793974; PMCID: PMC3889394.
In Vivo Activity
CAY10594 administration strongly blocked GSK-3β (Serine 9)/JNK phosphorylation in the APAP-induced acute liver injury model. Consistently, sustained JNK activation in the cytosol and mitochondria from hepatocytes were also decreased in CAY10594-treated mice. Many types of immune cells are also implicated in APAP-induced liver injury. However, neutrophil and monocyte populations were not different between vehicle- and CAY10594-administered mice which are challenged with APAP. Therapeutic administration of CAY10594 also significantly attenuated liver damage caused by the APAP challenge, eliciting an enhanced survival rate. Taken together, these results indicate that PLD2 is involved in the intrinsic response pathway of hepatocytes driving the pathogenesis of APAP-induced acute liver injury, and PLD2 may therefore represent an important therapeutic target for patients with drug-induced liver injury.
Reference: Lee SK, Bae GH, Kim YS, Kim HS, Lee M, Ghim J, Zabel BA, Ryu SH, Bae YS. A phospholipase D2 inhibitor, CAY10594, ameliorates acetaminophen-induced acute liver injury by regulating the phosphorylated-GSK-3β/JNK axis. Sci Rep. 2019 May 10;9(1):7242. doi: 10.1038/s41598-019-43673-x. PMID: 31076618; PMCID: PMC6510900.
Shipping
Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Stock Solution Storage
0-4 °C for short term (days to weeks), or -20 °C for long term (months).
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