-Disubstituted 4-Sulfamoylbenzoic Acid Derivatives As Inhibitors of Cytosolic Phospholipase A: Synthesis, Aqueous Solubility, and Activity in a Vesicle and a Whole Blood Assay

Overview

Journal Med Chem

Publisher Bentham Science Publishers

Specialty Chemistry

Date 2024 Jul 23

PMID 39041279

Authors

Daniel Borecki

Imke Meyer Zu Vilsendorf

Jorg Fabian

Matthias Lehr

Affiliations

Soon will be listed here.

Abstract

Background: Cytosolic phospholipase A2α (cPLA) is the key enzyme that initiates the arachidonic acid cascade through which pro-inflammatory lipid mediators can be formed. Therefore, cPLA is considered an interesting target for the development of anti-inflammatory drugs. Although several effective inhibitors of the enzyme have been developed, none of them has yet reached clinical application.

Objective: Recently, we have prepared new 4-sulfamoylbenzoic acid derivatives based on a cPLA inhibitor found in a ligand-based virtual screening. The most effective of these compounds were now subjected to further variations in which the substitution pattern on the sulfamoyl nitrogen atom was changed..

Methods: The new compounds were tested in a vesicle assay for cPLA inhibition as well as for their water solubility, metabolic stability, and selectivity towards related enzymes. In addition, they were evaluated in a whole blood assay in which metabolites of the arachidonic acid cascade formed after activation of cPLA were quantified using a combined online dilution/ online solid phase extraction HPLC-MS method.

Results: Inhibitors with submicromolar inhibitory potency were found with favourable water solubility and selectivity. However, their efficacy did not match that of the highly effective, known, structurally related cPLA inhibitor giripladib, which was also tested as a reference. One advantage of some of the new compounds compared to giripladib was their significantly improved water solubility. When analyzing the substances in the whole blood assay, it was found that the obtained inhibition data correlated better with the results when the phorbol ester 12-Otetradecanoylphorbol- 13-acetate was used for activation of the enzyme in the blood cells instead of the calcium ionophore A23187.

Conclusion: New compounds with good activity towards cPLA and reasonable physicochemical properties were identified. Overall, the results obtained could be helpful in the development of clinically applicable inhibitors of this enzyme.

References

Lee C, Lin C, Lee I, Lee H, Yang C . Activation and induction of cytosolic phospholipase A2 by TNF-α mediated through Nox2, MAPKs, NF-κB, and p300 in human tracheal smooth muscle cells. J Cell Physiol. 2011; 226(8):2103-14. DOI: 10.1002/jcp.22537. View

Lee C, Lee I, Lin C, Lee H, Lin W, Yang C . Activation and induction of cytosolic phospholipase A2 by IL-1beta in human tracheal smooth muscle cells: role of MAPKs/p300 and NF-kappaB. J Cell Biochem. 2010; 109(5):1045-56. DOI: 10.1002/jcb.22488. View

Newton R, Kuitert L, Slater D, Adcock I, Barnes P . Cytokine induction of cytosolic phospholipase A2 and cyclooxygenase-2 mRNA is suppressed by glucocorticoids in human epithelial cells. Life Sci. 1997; 60(1):67-78. DOI: 10.1016/s0024-3205(96)00590-5. View

Clark J, Lin L, Kriz R, Ramesha C, Sultzman L, Lin A . A novel arachidonic acid-selective cytosolic PLA2 contains a Ca(2+)-dependent translocation domain with homology to PKC and GAP. Cell. 1991; 65(6):1043-51. DOI: 10.1016/0092-8674(91)90556-e. View

Dessen A . Structure and mechanism of human cytosolic phospholipase A(2). Biochim Biophys Acta. 2000; 1488(1-2):40-7. DOI: 10.1016/s1388-1981(00)00108-6. View

Shimizu T, Wolfe L . Arachidonic acid cascade and signal transduction. J Neurochem. 1990; 55(1):1-15. DOI: 10.1111/j.1471-4159.1990.tb08813.x. View

Ricciotti E, FitzGerald G . Prostaglandins and inflammation. Arterioscler Thromb Vasc Biol. 2011; 31(5):986-1000. PMC: 3081099. DOI: 10.1161/ATVBAHA.110.207449. View

Yokomizo T, Izumi T, Shimizu T . Leukotriene B4: metabolism and signal transduction. Arch Biochem Biophys. 2001; 385(2):231-41. DOI: 10.1006/abbi.2000.2168. View

Uozumi N, Kume K, Nagase T, Nakatani N, Ishii S, Tashiro F . Role of cytosolic phospholipase A2 in allergic response and parturition. Nature. 1997; 390(6660):618-22. DOI: 10.1038/37622. View

10.

Bonventre J, Huang Z, Taheri M, OLeary E, Li E, Moskowitz M . Reduced fertility and postischaemic brain injury in mice deficient in cytosolic phospholipase A2. Nature. 1997; 390(6660):622-5. DOI: 10.1038/37635. View

11.

Hegen M, Sun L, Uozumi N, Kume K, Goad M, Nickerson-Nutter C . Cytosolic phospholipase A2alpha-deficient mice are resistant to collagen-induced arthritis. J Exp Med. 2003; 197(10):1297-302. PMC: 2193788. DOI: 10.1084/jem.20030016. View

12.

Ghosh M, Tucker D, Burchett S, Leslie C . Properties of the Group IV phospholipase A2 family. Prog Lipid Res. 2006; 45(6):487-510. DOI: 10.1016/j.plipres.2006.05.003. View

13.

Niknami M, Patel M, Witting P, Dong Q . Molecules in focus: cytosolic phospholipase A2-alpha. Int J Biochem Cell Biol. 2008; 41(5):994-7. DOI: 10.1016/j.biocel.2008.07.017. View

14.

Linkous A, Yazlovitskaya E . Cytosolic phospholipase A2 as a mediator of disease pathogenesis. Cell Microbiol. 2010; 12(10):1369-77. DOI: 10.1111/j.1462-5822.2010.01505.x. View

15.

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

16.

Kita Y, Shindou H, Shimizu T . Cytosolic phospholipase A and lysophospholipid acyltransferases. Biochim Biophys Acta Mol Cell Biol Lipids. 2019; 1864(6):838-845. DOI: 10.1016/j.bbalip.2018.08.006. View

17.

Soubhye J, Van Antwerpen P, Dufrasne F . Targeting Cytosolic Phospholipase A2α for Novel Anti-Inflammatory Agents. Curr Med Chem. 2018; 25(21):2418-2447. DOI: 10.2174/0929867325666180117103919. View

18.

Batsika C, Gerogiannopoulou A, Mantzourani C, Vasilakaki S, Kokotos G . The design and discovery of phospholipase A inhibitors for the treatment of inflammatory diseases. Expert Opin Drug Discov. 2021; 16(11):1287-1305. DOI: 10.1080/17460441.2021.1942835. View

19.

McKew J, Foley M, Thakker P, Behnke M, Lovering F, Sum F . Inhibition of cytosolic phospholipase A2alpha: hit to lead optimization. J Med Chem. 2006; 49(1):135-58. DOI: 10.1021/jm0507882. View

20.

McKew J, Lee K, Shen M, Thakker P, Foley M, Behnke M . Indole cytosolic phospholipase A2 alpha inhibitors: discovery and in vitro and in vivo characterization of 4-{3-[5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1-(diphenylmethyl)-1H-indol-3-yl]propyl}benzoic acid, efipladib. J Med Chem. 2008; 51(12):3388-413. DOI: 10.1021/jm701467e. View