Highly Potent 2-Oxoester Inhibitors of Cytosolic Phospholipase A (GIVA CPLA)

Overview

Journal ACS Omega

Publisher American Chemical Society

Specialty Chemistry

Date 2018 Sep 11

PMID 30197994

Citations 3

Authors

Anastasia Psarra

Maroula G Kokotou

Gerasimia Galiatsatou

Varnavas D Mouchlis

Edward A Dennis

George Kokotos

Affiliations

Soon will be listed here.

Abstract

Cytosolic phospholipase A (GIVA cPLA) has attracted great interest as a medicinal target because it initiates the eicosanoid cascade and is involved in a number of inflammatory diseases. As a consequence, the development of potent synthetic inhibitors is of great importance. We have developed highly potent 2-oxoester inhibitors of GIVA cPLA presenting (50) values between 0.000019 and 0.000066. We demonstrate that the 2-oxoester functionality is essential for in vitro inhibitory activity, making these inhibitors useful research reagents. However, their high reactivity results in rapid degradation of the inhibitors in human plasma, limiting their pharmaceutical utility without further modification.

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References

Vasquez A, Mouchlis V, Dennis E . Review of four major distinct types of human phospholipase A. Adv Biol Regul. 2017; 67:212-218. PMC: 5807221. DOI: 10.1016/j.jbior.2017.10.009. View

Ong W, Farooqui T, Kokotos G, Farooqui A . Synthetic and natural inhibitors of phospholipases A2: their importance for understanding and treatment of neurological disorders. ACS Chem Neurosci. 2015; 6(6):814-31. DOI: 10.1021/acschemneuro.5b00073. View

Six D, Barbayianni E, Loukas V, Constantinou-Kokotou V, Hadjipavlou-Litina D, Stephens D . Structure-activity relationship of 2-oxoamide inhibition of group IVA cytosolic phospholipase A2 and group V secreted phospholipase A2. J Med Chem. 2007; 50(17):4222-35. DOI: 10.1021/jm0613673. View

Kokotou M, Galiatsatou G, Magrioti V, Koutoulogenis G, Barbayianni E, Limnios D . 2-Oxoesters: A Novel Class of Potent and Selective Inhibitors of Cytosolic Group IVA Phospholipase A. Sci Rep. 2017; 7(1):7025. PMC: 5539244. DOI: 10.1038/s41598-017-07330-5. View

Kanai S, Ishihara K, Kawashita E, Tomoo T, Nagahira K, Hayashi Y . ASB14780, an Orally Active Inhibitor of Group IVA Phospholipase A2, Is a Pharmacotherapeutic Candidate for Nonalcoholic Fatty Liver Disease. J Pharmacol Exp Ther. 2015; 356(3):604-14. DOI: 10.1124/jpet.115.229906. View

Kim E, Tunset H, Cebulla J, Vettukattil R, Helgesen H, Feuerherm A . Anti-vascular effects of the cytosolic phospholipase A2 inhibitor AVX235 in a patient-derived basal-like breast cancer model. BMC Cancer. 2016; 16:191. PMC: 4782288. DOI: 10.1186/s12885-016-2225-1. View

Dennis E, Norris P . Eicosanoid storm in infection and inflammation. Nat Rev Immunol. 2015; 15(8):511-23. PMC: 4606863. DOI: 10.1038/nri3859. View

Bhowmick R, Clark S, Bonventre J, Leong J, McCormick B . Cytosolic Phospholipase Aα Promotes Pulmonary Inflammation and Systemic Disease during Streptococcus pneumoniae Infection. Infect Immun. 2017; 85(11). PMC: 5649009. DOI: 10.1128/IAI.00280-17. View

Leslie C . Cytosolic phospholipase A₂: physiological function and role in disease. J Lipid Res. 2015; 56(8):1386-402. PMC: 4513982. DOI: 10.1194/jlr.R057588. View

10.

Kokotos G, Hsu Y, Burke J, Baskakis C, Kokotos C, Magrioti V . Potent and selective fluoroketone inhibitors of group VIA calcium-independent phospholipase A2. J Med Chem. 2010; 53(9):3602-10. PMC: 2865582. DOI: 10.1021/jm901872v. View

11.

Tomoo T, Nakatsuka T, Katayama T, Hayashi Y, Fujieda Y, Terakawa M . Design, synthesis, and biological evaluation of 3-(1-Aryl-1H-indol-5-yl)propanoic acids as new indole-based cytosolic phospholipase A2α inhibitors. J Med Chem. 2014; 57(17):7244-62. DOI: 10.1021/jm500494y. View

12.

Li Z, Qu M, Sun Y, Wan H, Chai F, Liu L . Blockage of cytosolic phospholipase A2 alpha sensitizes aggressive breast cancer to doxorubicin through suppressing ERK and mTOR kinases. Biochem Biophys Res Commun. 2018; 496(1):153-158. DOI: 10.1016/j.bbrc.2018.01.016. View

13.

Stephens D, Barbayianni E, Constantinou-Kokotou V, Peristeraki A, Six D, Cooper J . Differential inhibition of group IVA and group VIA phospholipases A2 by 2-oxoamides. J Med Chem. 2006; 49(9):2821-8. PMC: 2544624. DOI: 10.1021/jm050993h. View

14.

Kokotou M, Limnios D, Nikolaou A, Psarra A, Kokotos G . Inhibitors of phospholipase A and their therapeutic potential: an update on patents (2012-2016). Expert Opin Ther Pat. 2016; 27(2):217-225. DOI: 10.1080/13543776.2017.1246540. View

15.

Kokotos G, Feuerherm A, Barbayianni E, Shah I, Saether M, Magrioti V . Inhibition of group IVA cytosolic phospholipase A2 by thiazolyl ketones in vitro, ex vivo, and in vivo. J Med Chem. 2014; 57(18):7523-35. DOI: 10.1021/jm500192s. View

16.

Lipinski C, Lombardo F, Dominy B, Feeney P . Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev. 2001; 46(1-3):3-26. DOI: 10.1016/s0169-409x(00)00129-0. View

17.

Omland S, Habicht A, Damsbo P, Wilms J, Johansen B, Gniadecki R . A randomized, double-blind, placebo-controlled, dose-escalation first-in-man study (phase 0) to assess the safety and efficacy of topical cytosolic phospholipase A2 inhibitor, AVX001, in patients with mild to moderate plaque psoriasis. J Eur Acad Dermatol Venereol. 2017; 31(7):1161-1167. DOI: 10.1111/jdv.14128. View

18.

Dennis E, Cao J, Hsu Y, Magrioti V, Kokotos G . Phospholipase A2 enzymes: physical structure, biological function, disease implication, chemical inhibition, and therapeutic intervention. Chem Rev. 2011; 111(10):6130-85. PMC: 3196595. DOI: 10.1021/cr200085w. View

19.

Di L, Kerns E, Hong Y, Chen H . Development and application of high throughput plasma stability assay for drug discovery. Int J Pharm. 2005; 297(1-2):110-9. DOI: 10.1016/j.ijpharm.2005.03.022. View

20.

Kokotos G, Six D, Loukas V, Smith T, Constantinou-Kokotou V, Hadjipavlou-Litina D . Inhibition of group IVA cytosolic phospholipase A2 by novel 2-oxoamides in vitro, in cells, and in vivo. J Med Chem. 2004; 47(14):3615-28. DOI: 10.1021/jm030485c. View