Cysteinyl-leukotriene type 1 receptor antagonists

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Cysteinyl-leukotriene type 1 receptor antagonists
Drug class
Montelukast the most common used leukotriene type 1 antagonist
Class identifiers
SynonymsCysteinyl-leukotriene type 1 receptor antagonist, CysLT type 1 receptor antagonist, CysLT1 receptor antagonist, Antileukotriene
UseExercise-induced bronchoconstriction, Allergic rhinitis, Asthma
ATC codeR03DC
Biological targetCysteinyl leukotriene receptor 1
Clinical data
Drugs.comDrug Classes
Legal status
In Wikidata

Cysteinyl-leukotriene type 1 receptor antagonists, also known as CysLT1 antagonists, are a class of drugs that hinder the action of leukotriene by binding to the receptor with antagonistic action without having an agonistic effect.[1] These drugs are used to treat asthma, relieve individuals of seasonal allergies rhinitis[2] and prevention of exercise-induced bronchoconstriction.[3] There are currently three different types of drugs within the CysLT1 family, zafirlukast[4] which was first on the market being released in 1996[5],  montelukast[2] which was released in 1998[6] and pranlukast[7] which was released in 2007.[8]

Medical Uses[edit]

The medical uses for Cysteinyl-leukotriene type 1 receptor antagonists are for chronic and prophylactic treatment of asthma.[3][9][10] Other indications have been approved by the FDA for montelukast and they are used for the prevention of exercise-induced bronchoconstriction (EIB), relief of symptoms of allergic rhinitis (AR) that is for relief of seasonal allergic rhinitis and perennial allergic rhinitis (PAR). [3][9]

Adverse effects[edit]

The actions of CysLT1 receptor antagonists (montelukast, zafirlukast and pranlukast) are competitive, as such they hinder the actions of leukotrienes. They prevent different types of asthmatic responses as well as having effects on bronchoconstriction and inflammation. Adverse effects often follow the use of these medications.[11]

Montelukast[edit]

Montelukast has been tested in clinical trials under different conditions to observe different adverse effects. The most common side effects for montelukast are, for example, respiratory infection, fever, headache, cough, abdominal pain, otitis media, rhinorrhea, sinusitis and more.[9]

Zafirlukast[edit]

The adverse effects of zafirlukast are very similar to montelukast. There is a database for safety which incorporates more than 4000 volunteers and 1723 patients which were asthmatic. Some of the side effects are similar to that of montelukast for example headache, infection, abdominal pain, fever, and multiple others.[10]

Mechanism of action[edit]

The biosynthesis for leukotrienes as well as the mechanism of action of cysteinyl leukotriene receptor type 1 antagonists

The cysteinyl leukotrienes (LTC4, LTD4, LTE4) are powerful inflammatory inducing eicosanoids that are produced and released by various cells of the immune system.[12] Leukotrienes are produced from arachidonic acid by 5-lipoxygenase (which is made from phospholipids in the cell membrane) and other various enzymes.[13] The cells of the immune system that release leukotrienes are basophils, eosinophils, mast cells and macrophages following various stimuli for example allergens.[12] They bind to cysteinyl leukotriene receptors (CysLT). One of those receptors is CysLT type-1 (CysLT1) and can be found in many different parts of the human airway as well as on pro-inflammatory cells. The CysLT receptors have been linked to the pathophysiology of allergic rhinitis and asthma.[9]

Zafirlukast and montelukast are powerful CysLT type-1 receptor antagonists. The primary actions of these drugs are that they block the action of leukotrienes, by binding to the receptor with antagonistic action without having an agonistic effect. The primary purpose of the antagonists is to block the actions of leukotriene D4 (LTD4)[9] By competing with LTD4 it will result in reduced effect by the leukotrienes, for example, LTD4 which has bronchoconstriction and vasoconstricting effect, as well as bronchial asthma and inflammation.[1]

Pharmacokinetics[edit]

When comparing the pharmacokinetic properties of montelukast and zafirlukast the two drugs have many similarities. The peak plasma concentrations are around 2,5-4 hours depending on what form is given. Both drugs are plasma protein-bound (-99%) and in vitro studies with rats have indicated low distribution across the blood-brain-barrier. Metabolism of montelukast and zafirlukast are extensive. Montelukast is mainly metabolized CYP2C8 and zafirlukast by CYP2C9. The half-life of montelukast is 2,7-5,5 hours and zafirlukast 8-16 hours.[9][10]

Structure Activity Relationships (SAR)[edit]

This is an example of zafirlukasts pharmacophore

When looking for leukotriene receptor antagonists, researchers began without any assistance of ligand-receptor binding data and approached the issue in three different ways. Those approaches included the structural design of leukotriene analogues, quinoline analogues, and the randomized screening of compounds. Those combined efforts led to a simple SAR: The lipophilic tetraene tail of LTD4 can be imitated by several of more stable aromatic rings, the sulfide of the glycyl-cysteine dipeptide can be supplanted by an alkyl carboxylic acid, and the C1 Carboxylate of LTD4 must be maintained. Further research prioritizing on the three-dimensional demands for antagonist binding to the CysLT receptors elucidated that the pharmacophore requires an acidic negative ionizable usable group, a hydrogen-bond acceptor role, and three hydrophobic regions. From this research, synthetic endeavours lead to the development of montelukast and zafirlukast as cysteinyl-leukotriene type 1 receptor antagonists.[14][15]

Quinolines were shown to be good moiety for CysLT1 receptor antagonist. From weak antagonistic derivatives of quinolines, montelukast was developed. Several changes to the structure can be made without the loss of activity. Among these changes are reducing the quinoline ring, replacing the chlorine with fluorine, inserting an ether linkage in between the two aromatic rings instead of the double bound and adding an amide group for the sulfur. Replacement of the quinoline by benzothiazole, dichlorothienopyridines or alkyl-substituted thiazoles is possible but none of these is superior.[14][16]

This is an example of montelukasts pharmacophore

Zafirlukast is an indole derivative that satisfies the pharmacophore need for an ionizable moiety with a sulfonamide group. Numerous analogues have been organized; nonetheless, everyone of them resulted in diminishing antagonistic activity. Like montelukast, zafirlukast antagonizes bronchoconstrictive by selectively antagonising the CysLT1 receptor and affects all of the leukotrienes (LTC4, LTD4, and LTE4).[14][16]

The qualitative structural requirements and pharmacophore for CysLT1 antagonists were designed from the structural similarity of the agonist LTD4. But that has its limitations as agonist and antagonist do not necessarily bind in the same manner nor to the same site. So the importance of certain moiety may be overestimated and some moieties may be overlooked.[17]

Synthesis[edit]

An example for the synthesis of montelukast sodium[18]

An example for the synthesis of montelukast

An example for the synthesis of zafirlukast[19]

An example for the synthesis of zafirlukast


History[edit]

The receptor for cysteinyl leukotrienes LTC4, LTD4 and LTE4 are a viable target because of the importance of cysteinyl leukotrienes in mediating the responses in asthma.[20][21] It has been discovered that two types of said receptor exist, the CysLT1 receptor as well as the CysLT2 receptor.[21] Leukotriene-receptor antagonists is a special class of drug, formulated as tablets that have both an anti-inflammatory effect as well as a bronchodilating effect.[4]

The development of leukotriene receptor antagonist started with screening a large number of compounds and designing quinoline and structural analogues.[14] An example of a CysLT1 receptor antagonists is montelukast which is a quinoline derivative and zafirlukast which is an indole derivative. Both CysLT1 selective antagonists.[14] Zafirlukast was the first approved CysLT1 receptor antagonist in the USA in September 26th 1996.[5] There are 2 other main medications that have been approved across the world, for example, montelukast which was approved February 2nd, 1996[6] and pranlukast which was approved March 15th, 2007.[8]

There hasn’t just been interest in the CysLT1 receptor, there has also been interest in the CysLT2 receptor which can be found in smooth muscle cells in the airways, as well as inflammatory cells and endothelial cells, which may be a useful target for asthma patients[21]. There have been discoveries of dual CysLT1 and CysLT2 receptor antagonists, for example, Gemilukast which could be a useful therapeutic agent for asthma patients which are non-responsive to montelukast, zafirlukast and pranlukast.[22]

See also[edit]

References[edit]

  1. ^ a b Hooper, Nigel M. (2013). Membrane dipeptidase. Handbook of Proteolytic Ezymes. Academic Press. pp. 1670–1673. ISBN 978-0-12-382219-2.
  2. ^ a b "Montelukast". Medicines Complete. doi:10.18578/BNF.236887386. Retrieved October 9, 2019.
  3. ^ a b c "Montelukast Tablets". Drugs.com. July 1, 2019. Retrieved October 9, 2019.
  4. ^ a b Lipworth, Brian J (January 2, 1999). "Leukotriene-receptor antagonists". New Drug Classes. 354 (9146): 57–62. doi:10.1016/S0140-6736(98)09019-9. PMID 10023966. S2CID 37941601 – via The Lancet.
  5. ^ a b "Drugs@FDA: FDA Approved Drug Products". U.S. Food & Drug Administration. Retrieved October 9, 2019.
  6. ^ a b "Drug Approval Package: Singulair (Montelukast Sodium) NDA# 020829". U.S. Food & Drug Administration. Retrieved October 9, 2019.
  7. ^ "Pranlukast". Drugs.com. Retrieved October 9, 2019.
  8. ^ a b "Pranlukast". DrugCentral: Online drug Compendium. Retrieved October 9, 2019.
  9. ^ a b c d e f "Prescribing information" (PDF). Merck: Inventing for life. February 2019. Retrieved October 9, 2019.
  10. ^ a b c "Accolate - Zafirlukast" (PDF). U.S. Food & Drug Administration. Retrieved October 9, 2019.
  11. ^ Riccioni, G; Bucciarelli, T; Mancini, B; Di Ilio, C; D'Orazio, N (2007). "Antileukotriene Drugs: Clinical Application, Effectiveness and Safety". Current Medicinal Chemistry. 14 (18): 1966–1977. doi:10.2174/092986707781368522. PMID 17691939.
  12. ^ a b Theron, A. J; Steel, H. C; Tintinger, G. R; Gravett, C. M; Anderson, R; Feldman, C (2014). "Cysteinyl Leukotriene Receptor-1 Antagonists as Modulators of Innate Immune Cell Function". Journal of Immunology Research. 2014: 16 pages. doi:10.1155/2014/608930. PMC 4058211. PMID 24971371 – via Hindawi.
  13. ^ O'Donnell, Stella R. (1 June 1993). "Leukotrienes - biosynthesis and mechanisms of action". Australian Prescriber. 22 (3): 55–57. doi:10.18773/austprescr.1999.053.
  14. ^ a b c d e Lemke, Thomas L; Williams, David A; Roche, Victoria F; Zito, S. William (2008). Foye's Principles of Medicinal Chemistry. Lippincott Williams & Wilkins. pp. 1257–1258. ISBN 9780781768795.
  15. ^ Palomer, Albert; Pascual, Jaume; Cabré, Francesc; García, M. Lluïsa; Mauleón, David (January 19, 2000). "Derivation of Pharmacophore and CoMFA Models for Leukotriene D4 Receptor antagonists of the Quinolinyl(bridged)aryl Series". Journal of Medicinal Chemistry. 43 (3): 392–400. doi:10.1021/jm990387k. PMID 10669566.
  16. ^ a b Zhang, Ming-Qiang; Zwaagstra, Mariël E (1997). "Structural Requirements for Leukotriene CysLT1 Receptor Ligands". Current Medicinal Chemistry. 3 (4): 229–246. doi:10.2174/0929867304666220313113236.
  17. ^ Zwaagstra, Mariël E; Schoenmakers, Saskia H. H. F; Nederkoorn, Paul H. J; Gelens, Edith; Timmerman, Henk; Zhang, Ming-Qiang (1998). "Development of a Three-Dimensional CysLt1 (LTD4) Antagonist Model with an Incorporated Amino Acid Residue from the Receptor". Journal of Medicinal Chemistry. 41 (9): 1439–1445. doi:10.1021/jm970180w. PMID 9554877.
  18. ^ Bernstein, Peter R (June 1998). "Chemistry and structure-activity relationships of leukotriene receptor antagonists". American Journal of Respiratory and Critical Care Medicine. 157 (6 Pt 2): 220–226. doi:10.1164/ajrccm.157.6.mar-3. PMID 9647603.
  19. ^ Bollikonda, Satyanarayana; Mohanarangam, Saravanan; Jinna, Rajender Reddy; Kandirelli, Venkata Kiran Kumar; Makthala, Laxman; Sen, Saikat; Chaplin, David A.; Lloyd, Richard C.; Mahoney, Thomas; Dahanukar, Vilas Hareshwar; Oruganti, Srinivas (2015-04-17). "An Enantioselective Formal Synthesis of Montelukast Sodium". The Journal of Organic Chemistry. 80 (8): 3891–3901. doi:10.1021/acs.joc.5b00197. ISSN 0022-3263. PMID 25807000.
  20. ^ O'Byrne, Paul M; Gauvreau, Gail M; Murphy, Desmond M (September 2009). "Efficacy of leukotriene receptor antagonists and synthesis inhibitors in asthma". Journal of Allergy and Clinical Immunology. 124 (3): 397–403. doi:10.1016/j.jaci.2009.05.029. PMID 19608262.
  21. ^ a b c Itadani, Satoshi; Takahashi, Shinya; Ima, Masaki; Sekiguchi, Tetsuya; Fujita, Manabu; Nakayama, Yoshisuke; Takeuchi, Jun (2014). "Discovery of Highly Potent Dual CysLT1 and CysLT2 Antagonist". ACS Medicinal Chemistry Letters. 5 (11): 1230–1234. doi:10.1021/ml500298y. PMC 4233365. PMID 25408836.
  22. ^ Itadani, Satoshi; Yashiro, Kentaro; Aratani, Yoshiyuki; Sekiguchi, Tetsuya; Kinoshita, Atsushi; Moriguchi, Hideki; Ohta, Nobukazu; Takahashi, Shinya; Ishida, Akiharu; Tajima, Yohei; Hisaichi, Katsuya (2015-08-13). "Discovery of Gemilukast (ONO-6950), a Dual CysLT 1 and CysLT 2 Antagonist As a Therapeutic Agent for Asthma". Journal of Medicinal Chemistry. 58 (15): 6093–6113. doi:10.1021/acs.jmedchem.5b00741. ISSN 0022-2623. PMID 26200813.
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