172732-68-2

Usage

Uses

Used in Pharmaceutical Industry:
VARESPLADIB is used as a PLA2 inhibitor for its ability to modulate the activity of the Phospholipase A2 enzyme family, which are involved in various cellular processes such as inflammation and cell membrane repair. By inhibiting these enzymes, VARESPLADIB may help in the treatment of conditions where PLA2 activity is dysregulated.
Used in Neurodegenerative Disease Research:
VARESPLADIB is used as a secretory phospholipase A (sPLA2) inhibitor for testing its effect on human astrocytes subjected to psychosine-induced toxicity. This application aims to investigate the potential protective effects of VARESPLADIB in neurodegenerative diseases where PLA2 activity may contribute to cellular damage.
Used in Venom Research:
VARESPLADIB is used in combination with snake venom metalloproteinases (SVMP)-inhibitor, marimastat, to test its protective functionality on envenoming by vipers. This application explores the potential of VARESPLADIB in neutralizing the harmful effects of venom from certain snake species, which may have implications for the development of antivenom treatments.

Biological Activity

phospholipases (plas) produce rate-limiting precursors in the various types of biologically active lipid biosynthesis. increased levels of human nonpancreatic secretory phospholipase a2 (hnps-pla2) have been detected in several pathological conditions. ly315920 was selected for evaluation clinically as an hnps-pla2 inhibitor.

Biochem/physiol Actions

Varespladib is effective against viper and elapid venoms and is used in snakebite therapy. It is reported to interact with the hydrophobic channel of the PLA2-like toxin in in vitro structural studies. It blocks inflammatory cascades related to the sPLA2.

in vitro

the true potency of ly315920 was defined to be a mole fraction of 1.5 x 10-6 using a deoxycholate/phosphatidylcholine assay. ly315920 was found to be 40-fold less active against human, group ib, pancreatic spla2 and was inactive against cytosolic pla2 and the constitutive and inducible forms of cyclooxygenase. human spla2-induced thromboxane a2 release from isolated guinea pig lung bronchoalveolar lavage cells was inhibited by ly315920 with the ic50 of 0.79 μm [1].

in vivo

the i.v. administration of ly315920, 5 min before the bronchoalveolar lavage cells harvest, led to the inhibition of spla2-induced production of txa2 with an ed50 of 16.1 mg/kg. [2].

IC 50

9 ± 1 nm or 7.3 x 10-6 mole fraction for spla2 activity

references

[1] snyder dw, bach nj, dillard rd, draheim se, carlson dg, fox n, roehm nw, armstrong ct, chang ch, hartley lw, johnson lm, roman cr, smith ac, song m, fleisch jh. pharmacology of ly315920/s-5920, [[3-(aminooxoacetyl)-2-ethyl-1- (phenylmethyl)-1h-indol-4-yl]oxy] acetate, a potent and selective secretory phospholipase a2 inhibitor: a new class of anti-inflammatory drugs, spi. j pharmacol exp ther. 1999;288(3):1117-24.[2] rosenson rs, hislop c, elliott m, stasiv y, goulder m, waters d. effects of varespladib methyl on biomarkers and major cardiovascular events in acute coronary syndrome patients. j am coll cardiol. 2010;56(14):1079-88.

InChI:InChI=1/C21H20N2O5.Na/c1-2-14-19(20(26)21(22)27)18-15(9-6-10-16(18)28-12-17(24)25)23(14)11-13-7-4-3-5-8-13;/h3-10H,2,11-12H2,1H3,(H2,22,27)(H,24,25);/q;+1/p-1

Upstream product

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Relevant academic research and scientific papers

Regioselective synthesis of 4- and 7-alkoxyindoles from 2,3-dihalophenols: Application to the preparation of indole inhibitors of phospholipase A 2

(Chemical Equation Presented) An efficient and regioselective synthesis of 4- and 7-alkoxyindoles has been developed from commercially available starting materials such as 3-halophenols and 3-chloroanisole. Directed ortho-metalation followed by two pallad

The first potent inhibitor of mammalian group X secreted phospholipase A2: Elucidation of sites for enhanced binding

Using the X-ray structure of human group X secreted phospholipase A 2 (hGX), we carried out structure-based design of indole-based inhibitors and prepared the compounds using a new synthetic route. The most potent compound inhibited hGX and the mouse orthologue with an IC50 of 75 nM. This compound is the most potent hGX inhibitor reported to date and was also found to inhibit a subset of the other mouse and human SPLA 2S.

Method for treating sepsis

A novel method of treating and/or preventing sepsis.

Indole sPLA2 inhibitors

A class of novel acylsulfonamide substituted indole compounds is disclosed together with the use of such compounds for inhibiting sPLA2mediated release of fatty acids for treatment of inflammatory diseases.

Method for the treatment of renal dysfunction with spla2 inhibitors

A method is disclosed for the treatment of of the symptoms associated with renal dysfunction by administering to an animal in need thereof a therapeutically effective amount of a sPLA2 inhibitor, such as a 1H-indole-3-glyoxylamide.

METHOD FOR TRATMENT OF NON-RHEUMATOID ARTHRITIS

A method is disclosed for the treatment of non-rheumatoid arthritis by administering to a mammal in need thereof a therapeutically effective amount of an sPLA 2 inhibitor.

Method for the treatment of cystic fibrosis

A method is disclosed for the treatment of cystic fibrosis by administering to a human in need thereof a therapeutically effective amount of an sPLA2inhibitor, such as a 1H-indole-3-glyoxylamide.

Combination therapy for the treatment of inflammatory and respiratory diseases

A pharmaceutical composition for the treatment of Inflammatory Disease or Respiratory Disease in mammals, which comprises, as active ingredients, a neutrophil elastase inhibitor and an sPLA2 inhibitor.

SPLA2 inhibitor compounds for treatment of disease

The present invention is directed to compounds for treating inflammatory bowel disease. More specifically, the present invention is directed to 1H-indole-3-glyoxyamide compounds a sPLA2inhibitors for treating inflammatory bowel disease.

Treatment for alzheimer's disease

This invention is a method of treating a mammal, including a human, susceptible to having Alzheimer's disease, to prevent or delay the onset of Alzheimer's disease; said method comprising administering to said mammal a prophylactically effective amount of