Varespladib (LY315920)

IC50: 9 ± 1 nM or 7.3 x 10-6 mole fraction for sPLA2 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.

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].

Clinical trials: Varespladib methyl, an oral prodrug of LY-315920, effectively reduced LDL-C and inflammatory biomarkers in ACS patients treated with conventional atorvastatin therapy. There were no treatment differences in clinical cardiovascular events [2].

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.

Varespladib (LY315920) Appears to Be a Potent, Broad-Spectrum, Inhibitor of Snake Venom Phospholipase A2 and a Possible Pre-Referral Treatment for Envenomation.[Pubmed:27571102]

Toxins (Basel). 2016 Aug 25;8(9). pii: toxins8090248.

Snakebite remains a neglected medical problem of the developing world with up to 125,000 deaths each year despite more than a century of calls to improve snakebite prevention and care. An estimated 75% of fatalities from snakebite occur outside the hospital setting. Because phospholipase A2 (PLA2) activity is an important component of venom toxicity, we sought candidate PLA2 inhibitors by directly testing drugs. Surprisingly, varespladib and its orally bioavailable prodrug, methyl-varespladib showed high-level secretory PLA2 (sPLA2) inhibition at nanomolar and picomolar concentrations against 28 medically important snake venoms from six continents. In vivo proof-of-concept studies with varespladib had striking survival benefit against lethal doses of Micrurus fulvius and Vipera berus venom, and suppressed venom-induced sPLA2 activity in rats challenged with 100% lethal doses of M. fulvius venom. Rapid development and deployment of a broad-spectrum PLA2 inhibitor alone or in combination with other small molecule inhibitors of snake toxins (e.g., metalloproteases) could fill the critical therapeutic gap spanning pre-referral and hospital setting. Lower barriers for clinical testing of safety tested, repurposed small molecule therapeutics are a potentially economical and effective path forward to fill the pre-referral gap in the setting of snakebite.

Highly specific and broadly potent inhibitors of mammalian secreted phospholipases A2.[Pubmed:18605714]

J Med Chem. 2008 Aug 14;51(15):4708-14.

We report a series of inhibitors of secreted phospholipases A2 (sPLA2s) based on substituted indoles, 6,7-benzoindoles, and indolizines derived from LY315920, a well-known indole-based sPLA2 inhibitor. Using the human group X sPLA2 crystal structure, we prepared a highly potent and selective indole-based inhibitor of this enzyme. Also, we report human and mouse group IIA and IIE specific inhibitors and a substituted 6,7-benzoindole that inhibits nearly all human and mouse sPLA2s in the low nanomolar range.

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.[Pubmed:10027849]

J Pharmacol Exp Ther. 1999 Mar;288(3):1117-24.

LY315920 is a potent, selective inhibitor of recombinant human, group IIA, nonpancreatic secretory PLA2 (sPLA2). In a chromogenic isolated enzyme assay, LY315920 inhibited sPLA2 activity with an IC50 of 9 +/- 1 nM or 7.3 x 10(-6) mole fraction, which approached the stiochiometric limit of this assay. The true potency of LY315920 was defined using a deoxycholate/phosphatidylcholine assay with a mole fraction of 1.5 x 10(-6). LY315920 was 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 release of thromboxane A2 (TXA2) from isolated guinea pig lung bronchoalveolar lavage cells was inhibited by LY315920 with an IC50 of 0.79 microM. The release of TXA2 from these cells by N-formyl-methionyl-leucyl-phenylalanine or arachidonic acid was not inhibited. The i.v. administration of LY315920, 5 min before harvesting the bronchoalveolar lavage cells, resulted in the inhibition of sPLA2-induced production of TXA2 with an ED50 of 16.1 mg/kg. Challenge of guinea pig lung pleural strips with sPLA2 produced contractile responses that were suppressed in a concentration-dependent manner by LY315920 with an apparent KB of 83 +/- 14 nM. Contractile responses induced by arachidonic acid were not altered. Intravenous or oral administration of LY315920 to transgenic mice expressing the human sPLA2 protein inhibited serum sPLA2 activity in a dose-related manner over a 4-h time course. LY315920 is a potent and selective sPLA2 inhibitor and represents a new class of anti-inflammatory agent designated SPI. This agent is currently undergoing clinical evaluation and should help to define the role of sPLA2 in various inflammatory disease states.

Varespladib (LY315920) is a potent and selective group IIA, secretory phospholipase A2 (sPLA2) inhibitor with an IC50 of 9 nM. Varespladib exhibits the significant inhibitory effect on sPLA2 activity in serum from various species including rat, rabbit, guinea pig and human with IC50s of 8.1 nM, 5.0 nM, 3.2 nM and 6.2 nM, respectively.

Varespladib (LY315920),172732-68-2,Varespladib,Natural Products,Phospholipase, buy Varespladib (LY315920) , Varespladib (LY315920) supplier , purchase Varespladib (LY315920) , Varespladib (LY315920) cost , Varespladib (LY315920) manufacturer , order Varespladib (LY315920) , high purity Varespladib (LY315920)