Cysteinyl-leukotriene type 1 receptor antagonists

Last updated
Cysteinyl-leukotriene type 1 receptor antagonists
Drug class
Montelukast skeletal.svg
Montelukast the most common used leukotriene type 1 antagonist
Class identifiers
Synonyms Cysteinyl-leukotriene type 1 receptor antagonist, CysLT type 1 receptor antagonist, CysLT1 receptor antagonist, Antileukotriene
Use Exercise-induced bronchoconstriction, Allergic rhinitis, Asthma
ATC code R03DC
Biological target Cysteinyl leukotriene receptor 1
Clinical data
Drugs.com Drug Classes
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]

Contents

Medical Uses

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

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

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

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

The biosynthesis for leukotrienes as well as the mechanism of action of cysteinyl leukotriene receptor type 1 antagonists Mechanism of action for CysLT1 receptors antagonists.png
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

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)

This is an example of zafirlukasts pharmacophore Zafirlukast Pharmacophore .png
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 Montelukast Pharmacophore.png
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

An example for the synthesis of montelukast sodium [18]

An example for the synthesis of montelukast Montelukast Synthesis.png
An example for the synthesis of montelukast

An example for the synthesis of zafirlukast [19]

An example for the synthesis of zafirlukast Zafirlukast Synthesis.png
An example for the synthesis of zafirlukast


History

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

Related Research Articles

Leukotriene Class of inflammation mediator molecules

Leukotrienes are a family of eicosanoid inflammatory mediators produced in leukocytes by the oxidation of arachidonic acid (AA) and the essential fatty acid eicosapentaenoic acid (EPA) by the enzyme arachidonate 5-lipoxygenase.

Zafirlukast

Zafirlukast is an orally administered leukotriene receptor antagonist (LTRA) used for the chronic treatment of asthma. While zafirlukast is generally well tolerated, headache and stomach upset often occur. Some rare side effects can occur, which can be life-threatening, such as liver failure. Churg-Strauss syndrome has been associated with zafirlukast, but the relationship isn't thought to be causative in nature. Overdoses of zafirlukast tend to be self-limiting.

Montelukast Medication used in asthma or COPD

Montelukast, sold under the brand name Singulair among others, is a medication used in the maintenance treatment of asthma. It is generally less preferred for this use than inhaled corticosteroids. It is not useful for acute asthma attacks. Other uses include allergic rhinitis and hives of long duration. For allergic rhinitis it is a second-line treatment.

Aspirin exacerbated respiratory disease Medical condition

Aspirin exacerbated respiratory disease (AERD), also termed aspirin-induced asthma, is a medical condition initially defined as consisting of three key features: asthma, respiratory symptoms exacerbated by aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), and nasal polyps. The symptoms of respiratory reactions in this syndrome are hypersensitivity reactions to NSAIDs rather than the typically described true allergic reactions that trigger other common allergen-induced asthma, rhinitis, or hives. The NSAID-induced reactions do not appear to involve the common mediators of true allergic reactions, immunoglobulin E or T cells. Rather, AERD is a type of NSAID-induced hypersensitivity syndrome. EAACI/WHO classifies the syndrome as one of five types of NSAID hypersensitivity or NSAID hypersensitivity reactions.

Bronchoconstriction Constriction of the terminal airways in the lungs

Bronchoconstriction is the constriction of the airways in the lungs due to the tightening of surrounding smooth muscle, with consequent coughing, wheezing, and shortness of breath.

Ketotifen Second generation noncompetitive H1 antihistamine

Ketotifen, sold under the brand name Zaditor among others, is a second-generation noncompetitive H1-antihistamine and mast cell stabilizer. It is most commonly sold as a salt with fumaric acid, ketotifen fumarate, and is available in two forms. In its ophthalmic form, it is used to treat allergic conjunctivitis. In its oral form, it is used to prevent asthma attacks or anaphylaxis, as well as various mast cell, allergic-type disorders.

Pranlukast

Pranlukast is a cysteinyl leukotriene receptor-1 antagonist. This drug works similarly to Merck & Co.'s montelukast (Singulair). It is widely used in Japan.

Thromboxane receptor Mammalian protein found in Homo sapiens

The thromboxane receptor (TP) also known as the prostanoid TP receptor is a protein that in humans is encoded by the TBXA2R gene, The thromboxane receptor is one among the five classes of prostanoid receptors and was the first eicosanoid receptor cloned. The TP receptor derives its name from its preferred endogenous ligand thromboxane A2.

An antileukotriene, also known as leukotriene modifier and leukotriene receptor antagonist, is a medication which functions as a leukotriene-related enzyme inhibitor or leukotriene receptor antagonist and consequently opposes the function of these inflammatory mediators; leukotrienes are produced by the immune system and serve to promote bronchoconstriction, inflammation, microvascular permeability, and mucus secretion in asthma and COPD. Leukotriene receptor antagonists are sometimes colloquially referred to as leukasts.

Leukotriene E4 Chemical compound

Leukotriene E4 (LTE4) is a cysteinyl leukotriene involved in inflammation. It is known to be produced by several types of white blood cells, including eosinophils, mast cells, tissue macrophages, and basophils, and recently was also found to be produced by platelets adhering to neutrophils. It is formed from the sequential conversion of LTC4 to LTD4 and then to LTE4, which is the final and most stable cysteinyl leukotriene. Compared to the short half lives of LTC4 and LTD4, LTE4 is relatively stable and accumulates in breath condensation, in plasma, and in urine, making it the dominant cysteinyl leukotriene detected in biologic fluids. Therefore, measurements of LTE4, especially in the urine, are commonly monitored in clinical research studies.

Most of the eicosanoid receptors are integral membrane protein G protein-coupled receptors (GPCRs) that bind and respond to eicosanoid signaling molecules. Eicosanoids are rapidly metabolized to inactive products and therefore are short-lived. Accordingly, the eicosanoid-receptor interaction is typically limited to a local interaction: cells, upon stimulation, metabolize arachidonic acid to an eicosanoid which then binds cognate receptors on either its parent cell or on nearby cells to trigger functional responses within a restricted tissue area, e.g. an inflammatory response to an invading pathogen. In some cases, however, the synthesized eicosanoid travels through the blood to trigger systemic or coordinated tissue responses, e.g. prostaglandin (PG) E2 released locally travels to the hypothalamus to trigger a febrile reaction. An example of a non-GPCR receptor that binds many eicosanoids is the PPAR-γ nuclear receptor.

Leukotriene D4 Chemical compound

Leukotriene D4 (LTD4) is one of the leukotrienes. Its main function in the body is to induce the contraction of smooth muscle, resulting in bronchoconstriction and vasoconstriction. It also increases vascular permeability. LTD4 is released by basophils. Other leukotrienes that function in a similar manner are leukotrienes C4 and E4. Pharmacological agents that inhibit the function of these leukotrienes are leukotriene receptor antagonists (e.g., zafirlukast, montelukast) and are useful for asthmatic individuals.

GPR17 Protein-coding gene in the species Homo sapiens

Uracil nucleotide/cysteinyl leukotriene receptor is a G protein-coupled receptor that in humans is encoded by the GPR17 gene located on chromosome 2 at position q21. The actual activating ligands for and some functions of this receptor are disputed.

Cysteinyl leukotriene receptor 1 Protein-coding gene in the species Homo sapiens

Cysteinyl leukotriene receptor 1, also termed CYSLTR1, is a receptor for cysteinyl leukotrienes (LT). CYSLTR1, by binding these cysteinyl LTs contributes to mediating various allergic and hypersensitivity reactions in humans as well as models of the reactions in other animals.

OXGR1

2-Oxoglutarate receptor 1 (OXGR1), also known as cysteinyl leukotriene receptor E (CysLTE) and GPR99, is a protein that in humans is encoded by the OXGR1 gene. The Gene has recently been nominated as a receptor not only for 2-oxogluterate but also for the three cysteinyl leukotrienes (CysLTs), particularly leukotriene E4 (LTE4) and to far lesser extents LTC4 and LTE4. Recent studies implicate GPR99 as a cellular receptor which is activated by LTE4 thereby causing these cells to contribute to mediating various allergic and hypersensitivity responses.

Cysteinyl leukotriene receptor 2 Protein-coding gene in the species Homo sapiens

Cysteinyl leukotriene receptor 2, also termed CYSLTR2, is a receptor for cysteinyl leukotrienes (LT). CYSLTR2, by binding these cysteinyl LTs contributes to mediating various allergic and hypersensitivity reactions in humans. However, the first discovered receptor for these CsLTs, cysteinyl leukotriene receptor 1 (CysLTR1), appears to play the major role in mediating these reactions.

A cannabinoid receptor antagonist, also known simply as a cannabinoid antagonist or as an anticannabinoid, is a type of cannabinoidergic drug that binds to cannabinoid receptors (CBR) and prevents their activation by endocannabinoids. They include antagonists, inverse agonists, and antibodies of CBRs. The discovery of the endocannabinoid system led to the development of CB1 receptor antagonists. The first CBR inverse agonist, rimonabant, was described in 1994. Rimonabant blocks the CB1 receptor selectively and has been shown to decrease food intake and regulate body-weight gain. The prevalence of obesity worldwide is increasing dramatically and has a great impact on public health. The lack of efficient and well-tolerated drugs to cure obesity has led to an increased interest in research and development of CBR antagonists. Cannabidiol (CBD), a naturally occurring cannabinoid, is a non-competitive CB1/CB2 receptor antagonist. And Δ9-tetrahydrocannabivarin (THCV), a naturally occurring cannabinoid, modulate the effects of THC via direct blockade of cannabinoid CB1 receptors, thus behaving like first-generation CB1 receptor inverse agonists, such as rimonabant. CBD is a very low-affinity CB1 ligand, that can nevertheless affect CB1 receptor activity in vivo in an indirect manner, while THCV is a high-affinity CB1 receptor ligand and potent antagonist in vitro and yet only occasionally produces effects in vivo resulting from CB1 receptor antagonism. THCV has also high affinity for CB2 receptors and signals as a partial agonist, differing from both CBD and rimonabant.

Relief from chronic pain remains a recognized unmet medical need. Consequently, the search for new analgesic agents is being intensively studied by the pharmaceutical industry. The TRPV1 receptor is an ion channel that has been implicated in mediation of many types of pain and therefore studied most extensively. The first competitive antagonist, capsazepine, was first described in 1990, since then development of novel TRPV1 antagonists has come a long way. This effort has led to the identification of several TRPV1 antagonists that have entered clinical trials as analgesic agents. Should these new chemical entities relieve symptoms of chronic pain then this class of compounds may offer one of the first novel mechanisms for the treatment of pain, in many years.

The leukotriene (LT) receptors are G protein-coupled receptors that bind and are activated by the leukotrienes. They include the following proteins:

Asthma trigger

Asthma triggers are factors or stimuli that provoke the exacerbation of asthma symptoms or increase the degree of airflow disruption, which can lead to an asthma attack. An asthma attack is characterized by an obstruction of the airway, hypersecretion of mucus and bronchoconstriction due to the contraction of smooth muscles around the respiratory tract. Its symptoms include a wide range of manifestations such as breathlessness, coughing, a tight chest and wheezing.

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