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Recent Patents on Inflammation & Allergy Drug Discovery


ISSN (Print): 1872-213X
ISSN (Online): 2212-2710

Review Article

The Role of Leukotrienes Inhibitors in the Management of Chronic Inflammatory Diseases

Author(s): Deepak Meshram, Khushbo Bhardwaj, Charulata Rathod, Gail B. Mahady and Kapil K. Soni*

Volume 14 , Issue 1 , 2020

Page: [15 - 31] Pages: 17

DOI: 10.2174/1872213X14666200130095040

Price: $65


Background: Leukotrienes are powerful mediators of inflammation and interact with specific receptors in target cell membrane to initiate an inflammatory response. Thus, Leukotrienes (LTs) are considered to be potent mediators of inflammatory diseases including allergic rhinitis, inflammatory bowel disease and asthma. Leukotriene B4 and the series of cysteinyl leukotrienes (C4, D4, and E4) are metabolites of arachidonic acid metabolism that cause inflammation. The cysteinyl LTs are known to increase vascular permeability, bronco-constriction and mucus secretion.

Objectives: To review the published data for leukotriene inhibitors of plant origin and the recent patents for leukotriene inhibitors, as well as their role in the management of inflammatory diseases.

Methods: Published data for leukotrienes antagonists of plant origin were searched from 1938 to 2019, without language restrictions using relevant keywords in both free text and Medical Subject Headings (MeSH terms) format. Literature and patent searches in the field of leukotriene inhibitors were carried out by using numerous scientific databases including Science Direct, PubMed, MEDLINE, Google Patents, US Patents, US Patent Applications, Abstract of Japan, German Patents, European Patents, WIPO and NAPRALERT. Finally, data from these information resources were analyzed and reported in the present study.

Results: Currently, numerous anti-histaminic medicines are available including chloropheneremine, brompheniramine, cetirizine, and clementine. Furthermore, specific leukotriene antagonists from allopathic medicines are also available including zileuton, montelukast, pranlukast and zafirlukast and are considered effective and safe medicines as compared to the first generation medicines. The present study reports leukotrienes antagonistic agents of natural products and certain recent patents that could be an alternative medicine in the management of inflammation in respiratory diseases.

Conclusion: The present study highlights recent updates on the pharmacology and patents on leukotriene antagonists in the management of inflammation respiratory diseases.

Keywords: Allergy, antagonists, asthma, cyclooxygenase, inflammation, leukotrienes, rhinitis, secondary metabolites.

Haeggström JZ. Leukotriene biosynthetic enzymes as therapeutic targets. J Clin Invest 2018; 128(7): 2680-90.
[] [PMID: 30108195 ]
Yokomizo T, Nakamura M, Shimizu T. Leukotriene receptors as potential therapeutic targets. J Clin Invest 2018; 128(7): 2691-701.
Feldberg W, Kellaway CH. The liberation of histamine by Staphylococcal toxin and mercuric chloride. Aust J Exp Biol Med Sci 1938; 16: 249.
Kellaway CH, Trethewie RE. The liberation of a slow reacting smooth muscle stimulating substance in anaphylaxis. J Exp Physiol 1940; 30: 121-45.
Drazen JM, Austen KF. Leukotrienes and airway responses. Am Rev Respir Dis 1987; 136(4): 985-98.
[] [PMID: 2821857 ]
Penrose JE, Spector J, Lam BK, Friend DS, Xu K, Jack RM, et al. LTC4 synthase at nuclear membrane. Am J Respir Crit Care Med 1995; 152: 283-9.
[] [PMID: 7599836 ]
Mashima R, Okuyama T. The role of lipoxygenases in pathophysiology; new insights and future perspectives. Redox Biol 2015; 6: 297-310.
[] [PMID: 26298204 ]
Gür ZT, Çalışkan B, Banoglu E. Drug discovery approaches targeting 5-Lipoxygenase-Activating Protein (FLAP) for inhibition of cellular leukotriene biosynthesis. Eur J Med Chem 2018; 153(153): 34-48.
[] [PMID: 28784429 ]
Kasimir S, Schönfeld W, Hilger RA, König W. Analysis of leukotriene B4 metabolism in human promyelocytic HL-60 cells. Biochem J 1991; 279(Pt 1): 283-8.
[] [PMID: 1656940 ]
Henderson WR Jr. The role of leukotrienes in inflammation. Ann Intern Med 1994; 121(9): 684-97.
[] [PMID: 7944079]
Zaitsu M, Hamasaki Y, Yamamoto S, Kita M, Hayasaki R, Muro E, et al. Effect of dexamethasone on leukotriene synthesis in DMSO-stimulated HL-60 cell. Prostaglandins Leukot Essent Fatty Acids 1998; 59(6): 385-93.
Singh S. Mechanism of action of antiinflammatory effect of fixed oil of Ocimum basilicum Linn. Indian J Exp Biol 1999; 37(3): 248-52.
[PMID: 10641154 ]
Tsai MJ, Wu PH, Sheu CC, Hsu YL, Chang WA, Hung JY, et al. Cysteinyl leukotriene receptor antagonists decrease cancer risk in asthma patients. Sci Rep Internet 2016; 6: 23979.
[] [PMID: 27052782 ]
Suknuntha K, Yubolphan R, Krueaprasertkul K, Srihirun S, Sibmooh N, Vivithanaporn P. Leukotriene receptor antagonists inhibit mitogenic activity in triple negative breast cancer cells. Asian Pac J Cancer Prev 2018; 19(3): 833-7.
[PMID: 29582642]
Chen X, Wang S, Wu N, Yang CS. Leukotriene A4 hydrolase as a target for cancer prevention and therapy. Curr Cancer Drug Targets 2004; 4(3): 267-83.
[] [PMID: 15134534 ]
Qamar KA, Dar A, Siddiqui BS, Kabir N, Aslam H, Ahmed S, et al. Anticancer activity of Ocimum basilicum and the effect of ursolic acid on the cytoskeleton of MCF-7 human breast cancer cells. Lett Drug Des Discov 2010; 7: 726-36.
Kathirvel P, Ravi S. Chemical composition of the essential oil from basil (Ocimum basilicum Linn.) and its in vitro cytotoxicity against HeLa and HEp-2 human cancer cell lines and NIH 3T3 mouse embryonic fibroblasts. Nat Prod Res 2012; 26(12): 1112-8.
[] [PMID: 21939371 ]
Jua EM, Leea SE, Hwangb HJ, Kima JH. Antioxidant and anticancer activity of extract from Betula platyphylla var. japonica. Life Sci 2004; 74(8): 1013-26.
Manoharan S, Panjamurthy K, Menon VP, Balakrishnan S, Alias LM. Protective effect of Withaferin-A on tumour formation in 7,12-dimethylbenz[a]anthracene induced oral carcinogenesis in hamsters. Indian J Exp Biol 2009; 47(1): 16-23.
[PMID: 19317347]
Raghavenra H, Diwakr BT, Lokesh BR, Naidu KA. Eugenol-the active principle from cloves inhibits 5-lipoxygenase activity and leukotriene-C4 in human PMNL cells. Prostaglandins Leukot Essent Fatty Acids 2006; 74(1): 23-7.
[] [PMID: 16216483]
Yadav B, Bajaj A, Saxena M, Saxena AK. In vitro anticancer activity of the root, stem and leaves of Withania somnifera against various human cancer cell lines. Indian J Pharm Sci 2010; 72(5): 659-63.
[] [PMID: 21695006]
Chen CY, Kao CL, Liu CM. The cancer prevention, anti-inflammatory and anti-oxidation of bioactive phytochemicals targeting the TLR4 signaling pathway. Int J Mol Sci 2018; 19(9): 2729.
[] [PMID: 30213077 ]
Liu M, Yokomizo T. The role of leukotrienes in allergic diseases. Allergol Int 2015; 64(1): 17-26.
[] [PMID: 25572555]
Soni KK, Raut N, Lawal TO, Patel U, Mahady GB. A purified fraction of Ocimum tenuiflorum (L.) inhibits LTC4, LTA4 and COX-2 activities, down-regulates mRNA expression in HL-60 cells and reduces lung inflammation in an OVA induced asthma model in BALB/c mice. Immunol Endocr Metab Agents Med Chem 2017; (17): 115-26.
Miyahara N, Miyahara S, Takeda K, Gelfand EW. Role of the LTB4/BLT1 pathway in allergen-induced airway hyperresponsiveness and inflammation. Allergol Int 2006; 55(2): 91-7.
[] [PMID: 17075244 ]
Shah BN, Patel NP, Pandya P. Role of leukotriene in inflammation and anti-leukotriene therapy. J Pharm Res 2008; 1(2): 113-25.
Wunder F, Tinel H, Kast R, Geerts A, Becker EM, Kolkhof P, et al. Pharmacological characterization of the first potent and selective antagonist at the Cysteinyl Leukotriene 2 (CysLT(2)) receptor. Br J Pharmacol 2010; 160(2): 399-409.
[] [PMID: 20423349]
Soni KK, Patel U, Artwolt J, Nunamaker E, Mahady GB. Reduction of OVA-induced lung inflammation in mice treated with Ayurvedic herbs using 2-D and 3-D imaging. Pharm Biol 2012; 50: 564.
Soni KK, Shrivastava PN, Jones T, Mahady JL, Patel U, Mukherjee P, et al. Extracts of Bacopa monnieri (L) Pennell down-regulate the expression of leukotriene C4 synthase mRNA in HL-60 cells and suppress OVA induced inflammation in BALB/c Mice. Curr Bioact Compd 2014. 10: 021-30.
Singh RK, Tandon R, Dastidar SG, Ray A. A review on leukotrienes and their receptors with reference to asthma. J Asthma 2013; 50(9): 922-31.
[] [PMID: 23859232]
Pergola C, Gerstmeier J, Mönch B, Çalişkan B, Luderer S, Weinigel C, et al. The novel benzimidazole derivative BRP-7 inhibits leukotriene biosynthesis in vitro and in vivo by targeting 5-Lipoxygenase-Activating Protein (FLAP). Br J Pharmacol 2014; 171(12): 3051-64.
[] [PMID: 24641614]
Han RT, Kim S, Choi K, Jwa H, Lee J, Kim HY, et al. Asthma-like airway inflammation and responses in a rat model of atopic dermatitis induced by neonatal capsaicin treatment. J Asthma Allergy 2017; 10: 181-9.
[] [PMID: 28572736 ]
Bankova LG, Dwyer DF, Yoshimoto E, Ualiyeva S, McGninty JW, Raff H, et al. The cysteinyl leukotriene 3 receptor regulates expansion of IL-25-producing airway brush cells leading to type 2 inflammation. Sci Immunol 2018; 3(28): 9453.
[] [PMID: 30291131 ]
Gur ZT, Caliskan B, Garcha U, Olgac A, Schubert US, Gerstmeier J, et al. Identification of multi-target inhibitors of leukotriene and prostaglandin E2 biosynthesis by structural tuning of the FLAP inhibitor BRP-7. Eur J Med Chem 2018; 150(150): 876-99.
[] [PMID: 29597170 ]
Jain B, Jain VK, Ahirwar D, Ahirwar B. Acute oral toxicity and in vitro leukotriene inhibitory property of hydro-alcoholic extract of Nicotiana tabacum in guinea pig Lung strips. Int J Green Pharm 2018; 12(2): 107-14.
Murphy RC, Folco G. Lysophospholipid acyltransferases and leukotriene biosynthesis: Intersection of the Lands cycle and the arachidonate PI cycle. J Lipid Res 2019; 60(2): 219-26.
[] [PMID: 30606731]
Guimaraes JP, Filgueiras LR, Martins JO, Jancar S. Leukotriene involvement in the insulin receptor pathway and macrophage profiles in muscles from type 1 diabetic mice. Mediat Inflamm 2019; p. 4596127.
Currie GP, Srivastava P, Dempsey OJ, Lee DKC. Therapeutic modulation of allergic airways disease with leukotriene receptor antagonists. QJM 2005; 98(3): 171-82.
[] [PMID: 15728398 ]
Currie GP, Haggart K, Lee DK, Fowler SJ, Wilson AM, Brannan JD, et al. Effects of mediator antagonism on mannitol and adenosine monophosphate challenges. Clin Exp Allergy 2003; 33(6): 783-8.
[] [PMID: 12801313 ]
Lipworth BJ. Systemic adverse effects of inhaled corticosteroid therapy: A systematic review and meta-analysis. Arch Intern Med 1999; 159(9): 941-55.
[] [PMID: 10326936 ]
Lipworth BJ, Wilson AM. Dose response to inhaled corticosteroids: Benefits and risks. Semin Respir Crit Care Med 1998; 19: 625-46.
Lee DK, Robb FM, Sims EJ, Currie GP, McFarlane LC, Lipworth BJ. Systemic bioactivity of intranasal triamcinolone and mometosone in perennial allergic rhinitis 2003. 55: 310-13.
Joseph GA, Yuan G, Cheuk KL. Benzofuran 2-carboxylic acid esters useful as inhibitors of leukotriene biosynthesis. US4663347 (1987).
Edwin SW, Alexander K. Synthetic flavonoidsas inhibitors of leukotrienes and 5-lpoxygenase. US4889941 (1989).
Daines RA, Kingsbury WD, Pendrak I. Benzoic acid derivatives for treating leukotrienerelated diseases. WO9118880 (1991).
Zamboni R, Guay D, Labelle M. Quinoline derivatives as leukotriene ntagonists. WO1993021159 (1993).
Brooks DW, Woods KW, Rodrigues KE. Indole carboxylate derivatives which inhibits leukotriene biosynthesis. WO9412179 (1994).
Cohen N. Substituted pyridine leukotriene B4 antagonists.AU690258 (1995).
Norbert D, Wolfram H, Labaudiniere R. Substituted quinolyl exhibiting selective compound leukotriene B4 antagonist activity.S5492915 (1996).
Gareau Y, Labelle M, Dufresne C, et al. Heteroaryl diol acid as leukotriene antagonists. WO9640638 , (1996).
Fleisch JH, Jackson WT, Sawyer JS. Leukotriene antagonists useful for treating ischemia reperfusion injury. WO9842346 (1998).
Makovec F, Peris W, Rovati LC. Tyrosine derivatives with antileukotriene activity. WO2001058892 (2001).
Rubin PD. Methods and compositions using terfenadine metabolites in combination with leukotriene inhibitors. US6509353 (2003).
Liversidge G, Jenkins S, Wertz C, Bosch H. Nanoparticulate leukotriene receptor antagonist/corticosteroid formulations. WO2006099591 (2006).
Maus J, Fyrnys B, Hoffmann T, et al. The combination of anti-cholinergic and leukotriene receptor antagonists for the treatment of respiratory diseases. WO2006097250 (2006).
Arnaiz D, Davey D, Guilford W, et al. Di-amine derivatives as inhibitors of leukotriene A4 hydrolase. WO2007079078 (2007).
Armstrong HM, Change LL, Chu L, Sisco RM. OK, H.O., Xu, J., Ujjainwalla, F. Diphenylmethane derivatives as inhibitors of leukotriene biosynthesis. US20090258885 In: (2009).
Armstrong M, Reisdorph NAM, Rabinovitch N. Measurement and analysis of leukotrienes. WO2010045633 (2010).
Gosselin F, Vydra V. Compounds and methods for leukotriene biosynthesis inhibition. US7915298 (2011).
Dominique R, Goodnow RA, Kowalczyk A, Qiao JLQ, Sidduri A, Tilley JW. Leukotriene B4 inhibitors. US8093253 (2012).
Berry A, Chen Z, Lombaert SD, et al. Biarylamide inhibitors of leukotriene production. WO201208281 (2012).
Kim JH, Cho AC, Kim GY, et al. Use of inhibitors of leukotriene B4 receptor BLT2 for treating human cancer. US8288357 (2012).
Rathod R, Bhatt T, Joshi K, Dole B, Murty-Kadiyala VNS, Thennati R. Cysteinyl leukotriene antagonists. WO2013051024 (2013).
Taub R, Bortz T, Franc J, et al. Phenylalkyl n-hydroxyurea for treating leukotriene related pathologies. US20130190514 (2013).
Kim JH, Choi JA, Kim EY, et al. Method of treating cancer with antibodies against long-form leukotriene B4 receptor BLT2. US8518889 (2014).
Bylock LA. Benzodioxanes in combination with other actives for inhibiting leukotriene production. WO2013131901 (2014).
Bartolozzi A, Bosanac T, Chen Z, et al. Oxadiazole inhibitors of leukotriene production. US8658661 (2014).
Lombart SD, Liu W, Lo HY, Nemoto PA. Benzimidazole inhibitors of leukotriene production. US8772304 (2014).
Wojciak JM, Dickerson CT, Visentin DB, Sabbadini RA. Compositions and methods for binding Cysteinyl Leukotrienes (CysLTs) for treatment of disease. US20150152172 (2015).
Rubinstein M, Dvash-Riesefeild E. Inhibitors of leukotriene mediated activity for alleviating chemotherapy side effects and stress induced cell death. WO2015125137 (2015).
Heim-Riether A, Padyana AK, Liang S, Taylor SJ, Zhang Q. Arylpyrazole ethers as inhibitors of leukotriene A4 hydrolase. US9139567 (2015).
Stack DR. Leukotriene B4 antagonist compound. US9187411 (2015).
Nicolls MR, Tian W, Rajadas J. Treatment of pulmonary hypertension with Leukotrienes inhibitors. US2013025178 (2013).
Maus J, Fyrnys B, Hofmann T, Weingart M, Szelenyl I. The combination of anticholinergic and leukotriene receptor antagonists for the treatment of respiratory diseases. EP1863476 (2016).
Abeywardane A, Brunette SR, Burke MJ, et al. Inhibitors of leukotriene production. US9403830 (2016).
Gosselin J, Gaudreault E. Use of leukotriene B4 in combination with a toll-like receptor legend, a rig-i-like receptor legend, or a nodlike receptor legend to enhance the innate immune response.US20170151204 (2017).
Kim JH. Use of inhibitors of leukotriene B4 receptor BLT2 for treating asthma. US9772324 (2017).
Rubinstein M, Dvash-Riesefeild E. Inhibitors of leukotrienemediated activity for treating side Orengo, effects of statin therapy.US20180064682 (2018).
Orengo JM, Allinne J, Murphy AJ, Yancopoulo GD. Methods of treating inflammatory conditions. WO2018102597 (2018).
Roinestad K, Guilford W, Kirkland T, Bhatt L, Springman E. Monamine and monoamine derivatives as inhibitors of leukotriene A4 hydrolase. WO2018107158 (2018).
George JT, Emiola A. Leukotriene receptor antagonists and their derivatives for use as antibacterial agents. US20180185332 (2018).
Rockson SG, Nicolls MR, Tian WA, Jiang X, Kim J. LTB4 inhibition to prevent and treat human lymphedema. US20180193296 (2018).
Benison J. Reduction of pro-inflammatory HDL using a leukotriene inhibitor. WO2018152405 (2019)
Bresnick SD. Prophylactic leukotriene inhibitor and implant displacement therapy for prevention and treatment of capsular contracture in silicone breast augmentation. US10179129 (2019).
May BC. Use of levocetirizine and montelukast in the treatment of autoimmune disorders. US10201537 (2019).
Choi Y, Kim JH, Lee K, et al. Novel compound having BLT inhibitory activity and composition,for preventing or treating inflammatory diseases, comprising same as active ingredient. US20190071395
Paiement N, Zerbe HG, Conway JW, Obeid R, Aigner L, Michael J. Method of treatment and device for the improved bioavailability of leukotriene receptor antagonists. US20190133925 (2019).
Roinestad K, Guilford W, Kirkland T, Bhatt L, Springman EB. Pendant amines and derivatives as inhibitors of leukotriene A4 hydrolase. US20190161437 (2019).
Amin N, Graham N, Pirozzi G, Teper A. Methods for treating or preventing asthma by administering an IL-4R antagonist.US20190169299 (2019).
Lai Y. Cyclopropyl unsaturated quinoline compound used as leukotriene receptor antagonist and applications thereof. US10315997 (2019)
Springman EB, Pugh MM, Bhatt L, Grosswald R. Methods of inhibiting leukotriene A4 hydrolase. US10350197 (2019).
Sai L, Yanqiu Z, Dongmei C, Yinjun L. Effect of rosuvastatin and benazepril on matrix metalloproteinase-2, matrix metalloproteinase-9 and leukotriene B4 of patients with acute myocardial infarction. Trop J Pharm Res 2019; 18(3): 625-30.
Sasaki F, Yokomizo T. The leukotriene receptors as the therapeutic targets of inflammatory diseasesInt Immunol 2019. 23; 31(9): 607-15.
Seresirikachorn K, Chitsuthipakorn W, Kanjanawasee D, Khattiyawittayakun L, Snidvongs K. Leukotriene receptor antagonist addition to H1-antihistamine is effective for treating allergic rhinitis: A systematic review and meta-analysis. Am J Rhinol Allergy 2019; 33(5): 591-600.
[] [PMID: 31007040 ]
Jo-Watanabe A, Okuno T, Yokomizo T. The role of leukotrienes as potential therapeutic targets in allergic disorders. Int J Mol Sci 2019; 20(14): 3580.
[] [PMID: 31336653 ]
Archambault AS, Poirier S, Lefebvre JS, Robichaud PP, Larose MC, Turcotte C, et al. 20-Hydroxy- and 20-carboxy-leukotriene (LT) B4 downregulate LTB4 -mediated responses of human neutrophils and eosinophils. J Leukoc Biol 2019; 105(6): 1131-42.
[] [PMID: 30676680 ]
Kawai Y, Narita Y, Yamawaki-Ogata A, Usui A, Komori K. Montelukast, a cysteinyl leukotriene receptor 1 antagonist, induces M2 macrophage polarization and inhibits murine aortic aneurysm formation. BioMed Res Int 2019; 20199104680
[] [PMID: 31263710 ]
Doucet MS, Jougleux JL, Poirier SJ, Cormier M, Léger JL, Surette ME, et al. Identification of peracetylated quercetin as a selective 12-lipoxygenase pathway inhibitor in human platelets. Mol Pharmacol 2019; 95(1): 139-50.
[] [PMID: 30404890 ]
Rahman SO, Singh RK, Hussain S, Akhtar M, Najmi AK. A novel therapeutic potential of cysteinyl leukotrienes and their receptors modulation in the neurological complications associated with Alzheimer’s disease. Eur J Pharmacol Internet 2019; 842: 208-20.
[] [PMID: 30389631 ]
Venugopal N, Acharya P, Zarei M, Talahalli RR. Cysteinyl leukotriene receptor antagonism: A promising pharmacological strategy for lowering the severity of arthritis. Inflammopharmacology 2019; 27(5): 923-31.
[] [PMID: 31309487 ]

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