Synthesis and Structure-activity Relationships for Some Novel Diflapolin Derivatives with Benzimidazole Subunit

Overview

Journal J Enzyme Inhib Med Chem

Specialty Biochemistry

Date 2022 Sep 20

PMID 36124840

Authors

Lisa Vieider

Eva Zoeller

Erik Romp

Martin Schoenthaler

Victor Hernandez-Olmos

Veronika Temml

Thomas Hasenoehrl

Daniela Schuster

Oliver Werz

Ulrike Garscha

Barbara Matuszczak

Affiliations

Soon will be listed here.

Abstract

A series of derivatives of the potent dual soluble epoxide hydrolase (sEH)/5-lipoxygenase-activating protein (FLAP) inhibitor diflapolin was designed, synthesised, and characterised. These novel compounds, which contain a benzimidazole subunit were evaluated for their inhibitory activity against sEH and FLAP. Molecular modelling tools were applied to analyse structure-activity relationships (SAR) on both targets and to predict solubility and gastrointestinal (GI) absorption. The most promising dual inhibitors of these series are , and .

References

Zhang C, Duan J, Yang H, Sun C, Zhong W, Tao J . COX-2/sEH dual inhibitor PTUPB alleviates bleomycin-induced pulmonary fibrosis in mice via inhibiting senescence. FEBS J. 2019; 287(8):1666-1680. PMC: 7174142. DOI: 10.1111/febs.15105. View

Hanna V, Hafez E . Synopsis of arachidonic acid metabolism: A review. J Adv Res. 2018; 11:23-32. PMC: 6052663. DOI: 10.1016/j.jare.2018.03.005. View

Meirer K, Glatzel D, Kretschmer S, Wittmann S, Hartmann M, Blocher R . Design, Synthesis and Cellular Characterization of a Dual Inhibitor of 5-Lipoxygenase and Soluble Epoxide Hydrolase. Molecules. 2016; 22(1). PMC: 6155600. DOI: 10.3390/molecules22010045. View

Fischer L, Hornig M, Pergola C, Meindl N, Franke L, Tanrikulu Y . The molecular mechanism of the inhibition by licofelone of the biosynthesis of 5-lipoxygenase products. Br J Pharmacol. 2007; 152(4):471-80. PMC: 2050828. DOI: 10.1038/sj.bjp.0707416. View

Abramovitz M, Wong E, Cox M, Richardson C, Li C, Vickers P . 5-lipoxygenase-activating protein stimulates the utilization of arachidonic acid by 5-lipoxygenase. Eur J Biochem. 1993; 215(1):105-11. DOI: 10.1111/j.1432-1033.1993.tb18012.x. View

Garscha U, Romp E, Pace S, Rossi A, Temml V, Schuster D . Pharmacological profile and efficiency in vivo of diflapolin, the first dual inhibitor of 5-lipoxygenase-activating protein and soluble epoxide hydrolase. Sci Rep. 2017; 7(1):9398. PMC: 5571211. DOI: 10.1038/s41598-017-09795-w. View

Waltenberger B, Garscha U, Temml V, Liers J, Werz O, Schuster D . Discovery of Potent Soluble Epoxide Hydrolase (sEH) Inhibitors by Pharmacophore-Based Virtual Screening. J Chem Inf Model. 2016; 56(4):747-62. DOI: 10.1021/acs.jcim.5b00592. View

Daina A, Michielin O, Zoete V . iLOGP: a simple, robust, and efficient description of n-octanol/water partition coefficient for drug design using the GB/SA approach. J Chem Inf Model. 2014; 54(12):3284-301. DOI: 10.1021/ci500467k. View

Gerstmeier J, Weinigel C, Barz D, Werz O, Garscha U . An experimental cell-based model for studying the cell biology and molecular pharmacology of 5-lipoxygenase-activating protein in leukotriene biosynthesis. Biochim Biophys Acta. 2014; 1840(9):2961-9. DOI: 10.1016/j.bbagen.2014.05.016. View

10.

Steinhilber D, Hofmann B . Recent advances in the search for novel 5-lipoxygenase inhibitors. Basic Clin Pharmacol Toxicol. 2013; 114(1):70-7. DOI: 10.1111/bcpt.12114. View

11.

Ho J, Lee M, Rauch C, Aznavour K, Park J, Luz J . Structure-based, multi-targeted drug discovery approach to eicosanoid inhibition: Dual inhibitors of mPGES-1 and 5-lipoxygenase activating protein (FLAP). Biochim Biophys Acta Gen Subj. 2020; 1865(2):129800. DOI: 10.1016/j.bbagen.2020.129800. View

12.

Sacks D, Baxter B, Campbell B, Carpenter J, Cognard C, Dippel D . Multisociety Consensus Quality Improvement Revised Consensus Statement for Endovascular Therapy of Acute Ischemic Stroke. Int J Stroke. 2018; 13(6):612-632. DOI: 10.1177/1747493018778713. View

13.

Chiasson A, Robichaud S, Moutombi F, Hebert M, Mbarik M, Surette M . New Zileuton-Hydroxycinnamic Acid Hybrids: Synthesis and Structure-Activity Relationship towards 5-Lipoxygenase Inhibition. Molecules. 2020; 25(20). PMC: 7587396. DOI: 10.3390/molecules25204686. View

14.

Jones G, Willett P, Glen R, Leach A, Taylor R . Development and validation of a genetic algorithm for flexible docking. J Mol Biol. 1997; 267(3):727-48. DOI: 10.1006/jmbi.1996.0897. View

15.

Spector A . Arachidonic acid cytochrome P450 epoxygenase pathway. J Lipid Res. 2008; 50 Suppl:S52-6. PMC: 2674692. DOI: 10.1194/jlr.R800038-JLR200. View

16.

Hiesinger K, Wagner K, Hammock B, Proschak E, Hwang S . Development of multitarget agents possessing soluble epoxide hydrolase inhibitory activity. Prostaglandins Other Lipid Mediat. 2018; 140:31-39. PMC: 6345559. DOI: 10.1016/j.prostaglandins.2018.12.003. View

17.

Haeggstrom J . Leukotriene biosynthetic enzymes as therapeutic targets. J Clin Invest. 2018; 128(7):2680-2690. PMC: 6026001. DOI: 10.1172/JCI97945. View

18.

Daina A, Michielin O, Zoete V . SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep. 2017; 7:42717. PMC: 5335600. DOI: 10.1038/srep42717. View

19.

Liu J, Yang J, Inceoglu B, Qiu H, Ulu A, Hwang S . Inhibition of soluble epoxide hydrolase enhances the anti-inflammatory effects of aspirin and 5-lipoxygenase activation protein inhibitor in a murine model. Biochem Pharmacol. 2009; 79(6):880-7. PMC: 3285377. DOI: 10.1016/j.bcp.2009.10.025. View

20.

Boyum A . Isolation of mononuclear cells and granulocytes from human blood. Isolation of monuclear cells by one centrifugation, and of granulocytes by combining centrifugation and sedimentation at 1 g. Scand J Clin Lab Invest Suppl. 1968; 97:77-89. View