400
Views
5
CrossRef citations to date
0
Altmetric
Review

Drug discovery strategies for novel leukotriene A4 hydrolase inhibitors

ORCID Icon, ORCID Icon, ORCID Icon, ORCID Icon & ORCID Icon
Pages 1483-1495 | Received 30 Apr 2021, Accepted 24 Jun 2021, Published online: 16 Jul 2021

References

  • Di Gennaro A, Haeggstrom JZ. The leukotrienes: immune-modulating lipid mediators of disease. Adv Immunol. 2012;116:51–92.
  • Peters-Golden M, Henderson WR Jr. Leukotrienes. N Engl J Med. 2007Nov01;357(18):1841–1854.
  • Leslie CC. Cytosolic phospholipase A(2): physiological function and role in disease. J Lipid Res. 2015 Aug;56(8):1386–1402.
  • Radmark O, Werz O, Steinhilber D, et al. 5-Lipoxygenase, a key enzyme for leukotriene biosynthesis in health and disease. Biochim Biophys Acta. 2015 Apr;1851(4):331–339. .
  • Haeggstrom JZ. Leukotriene A4 hydrolase and the committed step in leukotriene B4 biosynthesis. Clin Rev Allergy Immunol [ Spring-Summer]. 1999;17(1–2):111–131.
  • Lam BK, Austen KF. Leukotriene C4 synthase: a pivotal enzyme in cellular biosynthesis of the cysteinyl leukotrienes. Prostaglandins Other Lipid Mediat. 2002 Aug;68-69:511–520.
  • Ackermann JA, Hofheinz K, Zaiss MM, et al. The double-edged role of 12/15-lipoxygenase during inflammation and immunity. Biochim Biophys Acta Mol Cell Biol Lipids. 2017 Apr;1862(4):371–381.
  • Bhatt L, Roinestad K, Van T, et al. Recent advances in clinical development of leukotriene B4 pathway drugs. Semin Immunol. 2017 Oct;33:65–73.
  • Haeggstrom JZ. Leukotriene biosynthetic enzymes as therapeutic targets. J Clin Invest. 2018Jul2;128(7):2680–2690.
  • Grossman J, Faiferman I, Dubb JW, et al. Results of the first U.S. double-blind, placebo-controlled, multicenter clinical study in asthma with pranlukast, a novel leukotriene receptor antagonist. J Asthma. 1997;34(4):321–328.
  • Israel E, Rubin P, Kemp JP, et al. The effect of inhibition of 5-lipoxygenase by zileuton in mild-to-moderate asthma. Ann Intern Med. 1993 Dec 1;119(11):1059–1066.
  • Reiss TF, Chervinsky P, Dockhorn RJ, et al. Montelukast, a once-daily leukotriene receptor antagonist, in the treatment of chronic asthma: a multicenter, randomized, double-blind trial. Montelukast clinical research study group. Arch Intern Med. 1998 Jun 8;158(11):1213–1220.
  • Suissa S, Dennis R, Ernst P, et al. Effectiveness of the leukotriene receptor antagonist zafirlukast for mild-to-moderate asthma. A randomized, double-blind, placebo-controlled trial. Ann Intern Med. 1997 Feb 1;126(3):177–183.
  • Caliskan B, Banoglu E. Overview of recent drug discovery approaches for new generation leukotriene A4 hydrolase inhibitors. Expert Opin Drug Discov. 2013 Jan;8(1):49–63.
  • Werz O, Gerstmeier J, Garscha U. Novel leukotriene biosynthesis inhibitors (2012-2016) as anti-inflammatory agents. Expert Opin Ther Pat. 2017 May;27(5):607–620.
  • Thunnissen MM, Nordlund P, Haeggstrom JZ. Crystal structure of human leukotriene A(4) hydrolase, a bifunctional enzyme in inflammation. Nat Struct Biol. 2001 Feb;8(2):131–135.
  • Haeggstrom JZ. Leukotriene A4 hydrolase/aminopeptidase, the gatekeeper of chemotactic leukotriene B4 biosynthesis. J Biol Chem. 2004 Dec 03;279(49):50639–50642.
  • Stsiapanava A, Samuelsson B, Haeggstrom JZ. Capturing LTA4 hydrolase in action: insights to the chemistry and dynamics of chemotactic LTB4 synthesis. Proc Natl Acad Sci U S A. 2017 Sep 5;114(36):9689–9694.
  • Haeggstrom JZ, Tholander F, Wetterholm A. Structure and catalytic mechanisms of leukotriene A4 hydrolase. Prostaglandins Other Lipid Mediat. 2007 May;83(3):198–202.
  • Tholander F, Muroya A, Roques BP, et al. Structure-based dissection of the active site chemistry of leukotriene A4 hydrolase: implications for M1 aminopeptidases and inhibitor design. Chem Biol. 2008 Sep 22;15(9):920–929.
  • Griffin KJ, Gierse J, Krivi G, et al. Opioid peptides are substrates for the bifunctional enzyme LTA4 hydrolase/aminopeptidase. Prostaglandins. 1992 Sep;44(3):251–257.
  • Snelgrove RJ, Jackson PL, Hardison MT, et al. A critical role for LTA4H in limiting chronic pulmonary neutrophilic inflammation. Science. 2010 Oct 1;330(6000):90–94.
  • Numao S, Hasler F, Laguerre C, et al. Feasibility and physiological relevance of designing highly potent aminopeptidase-sparing leukotriene A4 hydrolase inhibitors. Sci Rep. 2017 Oct 19;7(1):13591.
  • Iversen L, Fogh K, Ziboh VA, et al. Leukotriene B4 formation during human neutrophil keratinocyte interactions: evidence for transformation of leukotriene A4 by putative keratinocyte leukotriene A4 hydrolase. J Invest Dermatol. 1993 Mar;100(3):293–298.
  • Sala A, Bolla M, Zarini S, et al. Release of leukotriene A4 versus leukotriene B4 from human polymorphonuclear leukocytes. J Biol Chem. 1996 Jul 26;271(30):17944–17948.
  • Afonso PV, Janka-Junttila M, Lee YJ, et al. LTB4 is a signal-relay molecule during neutrophil chemotaxis. Dev Cell. 2012 May 15;22(5):1079–1091.
  • Lammermann T, Afonso PV, Angermann BR, et al. Neutrophil swarms require LTB4 and integrins at sites of cell death in vivo. Nature. 2013 Jun 20;498(7454):371–375.
  • Chen LY, Eberlein M, Alsaaty S, et al. Cooperative and redundant signaling of leukotriene B4 and leukotriene D4 in human monocytes. Allergy. 2011 Oct;66(10):1304–1311. .
  • Costa MF, de Souza-Martins R, de Souza MC, et al. Leukotriene B4 mediates gammadelta T lymphocyte migration in response to diverse stimuli. J Leukoc Biol. 2010 Feb;87(2):323–332. .
  • Flamand L, Tremblay MJ, Leukotriene BP. B4 triggers the in vitro and in vivo release of potent antimicrobial agents. J Immunol. 2007 Jun 15;178(12):8036–8045.
  • Goodarzi K, Goodarzi M, Tager AM, et al. Leukotriene B4 and BLT1 control cytotoxic effector T cell recruitment to inflamed tissues. Nat Immunol. 2003 Oct;4(10):965–973.
  • Okamoto F, Saeki K, Sumimoto H, et al. Leukotriene B4 augments and restores Fc gammaRs-dependent phagocytosis in macrophages. J Biol Chem. 2010 Dec 24;285(52):41113–41121.
  • Fourie AM. Modulation of inflammatory disease by inhibitors of leukotriene A4 hydrolase. Curr Opin Invest Drugs. 2009 Nov;10(11):1173–1182.
  • Helgadottir A, Manolescu A, Helgason A, et al. A variant of the gene encoding leukotriene A4 hydrolase confers ethnicity-specific risk of myocardial infarction. Nat Genet. 2006 Jan;38(1):68–74.
  • Qiu H, Gabrielsen A, Agardh HE, et al. Expression of 5-lipoxygenase and leukotriene A4 hydrolase in human atherosclerotic lesions correlates with symptoms of plaque instability. Proc Natl Acad Sci U S A. 2006 May 23;103(21):8161–8166.
  • Li P, Oh DY, Bandyopadhyay G, et al. LTB4 promotes insulin resistance in obese mice by acting on macrophages, hepatocytes and myocytes. Nat Med. 2015 Mar;21(3):239–247.
  • Mothe-Satney I, Filloux C, Amghar H, et al. Adipocytes secrete leukotrienes: contribution to obesity-associated inflammation and insulin resistance in mice. Diabetes. 2012 Sep;61(9):2311–2319.
  • Jupp J, Hillier K, Elliott DH, et al. Colonic expression of leukotriene-pathway enzymes in inflammatory bowel diseases. Inflamm Bowel Dis. 2007 May;13(5):537–546. .
  • Elborn JS, Horsley A, MacGregor G, et al. Phase I Studies of Acebilustat: biomarker response and safety in patients with Cystic Fibrosis. Clin Transl Sci. 2017 Jan;10(1):28–34. .
  • Corhay JL, Henket M, Nguyen D, et al. Leukotriene B4 contributes to exhaled breath condensate and sputum neutrophil chemotaxis in COPD. Chest. 2009 Oct;136(4):1047–1054.
  • Chen M, Lam BK, Kanaoka Y, et al. Neutrophil-derived leukotriene B4 is required for inflammatory arthritis. J Exp Med. 2006 Apr 17;203(4):837–842.
  • Penno CA, Jager P, Laguerre C, et al. Lipidomics Profiling of Hidradenitis Suppurativa skin lesions reveals lipoxygenase pathway dysregulation and accumulation of proinflammatory Leukotriene B4. J Invest Dermatol. 2020 Dec;140(12):2421–2432 e10. .
  • Zouboulis CC, Seltmann H, Alestas T. Zileuton prevents the activation of the leukotriene pathway and reduces sebaceous lipogenesis. Exp Dermatol. 2010 Feb;19(2):148–150.
  • He R, Chen Y, Cai Q. The role of the LTB4-BLT1 axis in health and disease. Pharmacol Res. 2020 Aug;158:104857.
  • Markert C, Thoma G, Srinivas H, et al. Discovery of LYS006, a Potent and Highly Selective Inhibitor of Leukotriene A4 Hydrolase. J Med Chem. 2021 Feb 25;64(4):1889–1903.
  • Rask-Madsen J, Bukhave K, Laursen LS, et al. 5-Lipoxygenase inhibitors for the treatment of inflammatory bowel disease. Agents Actions. 1992;36(S1):C37–46. Spec No. .
  • Serhan CN, Yacoubian S, Yang R. Anti-inflammatory and proresolving lipid mediators. Annu Rev Pathol. 2008;3(1):279–312.
  • Rao NL, Dunford PJ, Xue X, et al. Anti-inflammatory activity of a potent, selective leukotriene A4 hydrolase inhibitor in comparison with the 5-lipoxygenase inhibitor zileuton. J Pharmacol Exp Ther. 2007 Jun;321(3):1154–1160.
  • Penno CA, Wack N, Laguerre C, et al. Comment on “An extracellular matrix fragment drives epithelial remodeling and airway hyperresponsiveness.” Sci Transl Med. 2019 Jun 19;11(497). doi: https://doi.org/10.1126/scitranslmed.aav4538.
  • Grice CAFA, Lee-Dutra A. Leukotriene A4 hydrolase: biology, inhibitors and clinical applications. In: laufer JILaS, editor. Anti-Inflammatory Drug Discovery. Vol. 26. RSC Drug Discovery Series. 2012; 26:58–103. RSC; 2012. p. 58-103.
  • Penning TD, Chandrakumar NS, Chen BB, et al. Structure-activity relationship studies on 1-[2-(4-Phenylphenoxy)ethyl]pyrrolidine (SC-22716), a potent inhibitor of leukotriene A(4) (LTA(4)) hydrolase. J Med Chem. 2000 Feb 24;43(4):721–735.
  • Penning TD, Russell MA, Chen BB, et al. Synthesis of potent leukotriene A(4) hydrolase inhibitors. Identification of 3-[methyl[3-[4-(phenylmethyl)phenoxy]propyl]amino]propanoic acid. J Med Chem. 2002 Aug 1;45(16):3482–3490.
  • Grice CA, Tays KL, Savall BM, et al. Identification of a potent, selective, and orally active leukotriene a4 hydrolase inhibitor with anti-inflammatory activity. J Med Chem. 2008 Jul 24;51(14):4150–4169.
  • Tanis VM, Bacani GM, Blevitt JM, et al. Azabenzthiazole inhibitors of leukotriene A(4) hydrolase. Bioorg Med Chem Lett. 2012 Dec 15;22(24):7504–7511.
  • Davies DR, Mamat B, Magnusson OT, et al. Discovery of leukotriene A4 hydrolase inhibitors using metabolomics biased fragment crystallography. J Med Chem. 2009 Aug 13;52(15):4694–4715.
  • Sandanayaka V, Mamat B, Mishra RK, et al. Discovery of 4-[(2S)-2-{[4-(4-chlorophenoxy)phenoxy]methyl}-1-pyrrolidinyl]butanoic acid (DG-051) as a novel leukotriene A4 hydrolase inhibitor of leukotriene B4 biosynthesis. J Med Chem. 2010 Jan 28;53(2):573–585.
  • Sandanayaka V, Mamat B, Bhagat N, et al. Discovery of novel leukotriene A4 hydrolase inhibitors based on piperidine and piperazine scaffolds. Bioorg Med Chem Lett. 2010 May 1;20(9):2851–2854.
  • Davies DRMB, Magnusson OT, Magnusson OT. Corrections to discovery of leukotriene A4 hydrolase inhibitors using metabolomics biased fragment crystallography. J Med Chem. 2010 March 11;53(5):2330–2331.
  • Kirkland TA, Adler M, Bauman JG, et al. Synthesis of glutamic acid analogs as potent inhibitors of leukotriene A4 hydrolase. Bioorg Med Chem. 2008 May 1;16(9):4963–4983.
  • Elborn JS, Ahuja S, Springman E, et al. EMPIRE-CF: a phase II randomized placebo-controlled trial of once-daily, oral acebilustat in adult patients with cystic fibrosis - Study design and patient demographics. Contemp Clin Trials. 2018 Sep;72:86–94.
  • Ye B, Bauman J, Chen M, et al. Synthesis of N-alkyl glycine amides as potent inhibitors of leukotriene A(4) hydrolase. Bioorg Med Chem Lett. 2008 Jul 15;18(14):3891–3894.
  • Seock-Kyu KBJ, Evans J, Evans J, et al. Discovery of novel and potent aryl diamines as leukotriene A4 hydrolase inhibitors. Bioorg Med Chem Lett. 2008;18(14):3895–3898. .
  • Akthar S, Patel DF, Beale RC, et al. Matrikines are key regulators in modulating the amplitude of lung inflammation in acute pulmonary infection. Nat Commun. 2015 Sep;24(6):8423. .
  • Patel DF, Peiro T, Shoemark A, et al. An extracellular matrix fragment drives epithelial remodeling and airway hyperresponsiveness. Sci Transl Med. 2018 Aug 22;10(455):eaaq0693.
  • Patel DF, Snelgrove RJ. The multifaceted roles of the matrikine Pro-Gly-Pro in pulmonary health and disease. Eur Respir Rev. 2018 Jun 30;27(148):180017.
  • Gaggar A, Weathington N. Bioactive extracellular matrix fragments in lung health and disease. J Clin Invest. 2016 Sep 1;126(9):3176–3184.
  • Hardison MT, Brown MD, Snelgrove RJ, et al. Cigarette smoke enhances chemotaxis via acetylation of proline-glycine-proline. Front Biosci (Elite Ed). 2012 Jun;1(4):2402–2409.
  • O’Reilly PJ, Ding Q, Akthar S, et al. Angiotensin-converting enzyme defines matrikine-regulated inflammation and fibrosis. JCI Insight. 2017 Nov 16;2(22). doi: https://doi.org/10.1172/jci.insight.91923.
  • Haddox JL, Pfister RR, Muccio DD, et al. Bioactivity of peptide analogs of the neutrophil chemoattractant, N-acetyl-proline-glycine-proline. Invest Ophthalmol Vis Sci. 1999 Sep;40(10):2427–2429.
  • Weathington NM, van Houwelingen AH, Noerager BD, et al. A novel peptide CXCR ligand derived from extracellular matrix degradation during airway inflammation. Nat Med. 2006 Mar;12(3):317–323. .
  • Afonso PV, McCann CP, Kapnick SM, et al. Discoidin domain receptor 2 regulates neutrophil chemotaxis in 3D collagen matrices. Blood. 2013 Feb 28;121(9):1644–1650.
  • Hahn CS, Scott DW, Xu X, et al. The matrikine N-alpha-PGP couples extracellular matrix fragmentation to endothelial permeability. Sci Adv. 2015;1(3):e1500175. .
  • de Kruijf P, Lim HD, Overbeek SA, et al. The collagen-breakdown product N-acetyl-Proline-Glycine-Proline (N-alpha-PGP) does not interact directly with human CXCR1 and CXCR2. Eur J Pharmacol. 2010 Sep 15;643(1):29–33.
  • Low CM, Akthar S, Patel DF, et al. The development of novel LTA4H modulators to selectively target LTB4 generation. Sci Rep. 2017 Mar 17;7(1):44449.
  • Jiang X, Zhou L, Wu Y, et al. Modulating the substrate specificity of LTA4H aminopeptidase by using chemical compounds and small-molecule-guided mutagenesis. Chembiochem. 2010 May 17;11(8):1120–1128.
  • De Oliveira EO, Wang K, Kong HS, et al. Effect of the leukotriene A4 hydrolase aminopeptidase augmentor 4-methoxydiphenylmethane in a pre-clinical model of pulmonary emphysema. Bioorg Med Chem Lett. 2011 Nov 15;21(22):6746–6750.
  • Stsiapanava A, Olsson U, Wan M, et al. Binding of Pro-Gly-Pro at the active site of leukotriene A4 hydrolase/aminopeptidase and development of an epoxide hydrolase selective inhibitor. Proc Natl Acad Sci U S A. 2014 Mar 18;111(11):4227–4232.
  • Lee KH, Petruncio G, Shim A, et al. Effect of modifier structure on the activation of Leukotriene A4 Hydrolase aminopeptidase activity. J Med Chem. 2019 Dec 12;62(23):10605–10616.
  • Konig S, Pace S, Pein H, et al. Gliotoxin from Aspergillus fumigatus Abrogates Leukotriene B4 formation through Inhibition of Leukotriene A4 Hydrolase. Cell Chem Biol. 2019 Apr 18;26(4):524–534 e5.
  • Li X, Xie M, Lu C, et al. Design and synthesis of Leukotriene A4 hydrolase inhibitors to alleviate idiopathic pulmonary fibrosis and acute lung injury. Eur J Med Chem. 2020 Oct 1;203:112614. .
  • ClinicalTrials.gov. [ cited 2021 April 27th]. Available from: https://www.clinicaltrials.gov/ct2/results?cond=&term=BI691751&cntry=&state=&city=&dist
  • Ingelheim B [2020-December-2]. [cited 2021 April 29]. Available from: https://trials.boehringer-ingelheim.com/public/trial_results_documents/1334/_english_13341c2248492COpdf.pdf
  • Genetics D. [ cited 2021 April 29]. Available from: https://www.decode.com/positive-results-from-phase-iia-study-pave-way-for-phase-iib-trial-of-dg051-for-the-prevention-of-heart-attack
  • Barchuk W, Lambert J, Fuhr R, et al. Effects of JNJ-40929837, a leukotriene A4 hydrolase inhibitor, in a bronchial allergen challenge model of asthma. Pulm Pharmacol Ther. 2014 Oct;29(1):15–23.
  • Smith CM, Christie PE, Hawksworth RJ, et al. Urinary leukotriene E4 levels after allergen and exercise challenge in bronchial asthma. Am Rev Respir Dis. 1991 Dec;144(6):1411–1413.
  • Ward PD, La D. Testicular distribution and toxicity of a novel LTA4H inhibitor in rats. Toxicol Appl Pharmacol. 2014 Jul 1;278(1):26–30.
  • Elborn JS, Bhatt L, Grosswald R, et al. Phase I studies of acebilustat: pharmacokinetics, pharmacodynamics, food effect, and CYP3A induction. Clin Transl Sci. 2017 Jan;10(1):20–27.
  • Celtaxsys. [ cited 2018]. [cited 2021 Apr 29]. Available from: (http://www.celtaxsys.com/2018/08/02/celtaxsys-announces-results-of-phase-2-trial-showing-clinically-meaningful-improvement-in-pulmonaryexacerbations-in-cystic-fibrosis-patients
  • Funk CD, Ardakani A. A novel strategy to mitigate the hyperinflammatory response to COVID-19 by targeting leukotrienes. Front Pharmacol. 2020;11:1214.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.