Target Information

Target General Information

Target ID

T71192 (Former ID: TTDS00183)

Target Name

Leukotriene CysLT1 receptor (CYSLTR1)

Synonyms

Leukotriene D4-receptor; LTD4 receptor; HMTMF81; HG55; G-protein coupled receptor HG55; Cysteinyl leukotriene receptor 1; Cysteinyl leukotriene D4 receptor; CysLTR1; CYSLT1

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Gene Name

CYSLTR1

Target Type

Successful target

[1]

Disease

[+] 1 Target-related Diseases

Asthma [ICD-11: CA23]

Function

Stimulation by LTD4 results in the contraction and proliferation of smooth muscle, edema, eosinophil migration and damage to the mucus layer in the lung. This response is mediated via a G-protein that activates a phosphatidylinositol-calcium second messenger system. The rank order of affinities for the leukotrienes is LTD4 >> LTE4 = LTC4 >> LTB4. Receptor for cysteinyl leukotrienes mediating bronchoconstriction of individuals with and without asthma.

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BioChemical Class

GPCR rhodopsin

UniProt ID

CLTR1_HUMAN

Sequence

MDETGNLTVSSATCHDTIDDFRNQVYSTLYSMISVVGFFGNGFVLYVLIKTYHKKSAFQV
YMINLAVADLLCVCTLPLRVVYYVHKGIWLFGDFLCRLSTYALYVNLYCSIFFMTAMSFF
RCIAIVFPVQNINLVTQKKARFVCVGIWIFVILTSSPFLMAKPQKDEKNNTKCFEPPQDN
QTKNHVLVLHYVSLFVGFIIPFVIIIVCYTMIILTLLKKSMKKNLSSHKKAIGMIMVVTA
AFLVSFMPYHIQRTIHLHFLHNETKPCDSVLRMQKSVVITLSLAASNCCFDPLLYFFSGG
NFRKRLSTFRKHSLSSVTYVPRKKASLPEKGEEICKV

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3D Structure

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PDB

HIT2.0 ID

T81BQ4

Drugs and Modes of Action

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Approved Drug(s)

[+] 4 Approved Drugs

Cinalukast

Drug Info

Approved

Asthma

[2]

Montelukast

Drug Info

Approved

Asthma

[3], [4]

Pranlukast

Drug Info

Approved

Asthma

[4], [5]

Zafirlukast

Drug Info

Approved

Asthma

[6], [7]

Clinical Trial Drug(s)

[+] 8 Clinical Trial Drugs

Claritin/Singulair

Drug Info

Phase 3

Allergic rhinitis

[8], [9], [10]

BAY-X-7195

Drug Info

Phase 2

Asthma

[11]

Iralukast

Drug Info

Phase 2

Asthma

[12], [13]

KP-496

Drug Info

Phase 2

Asthma

[14]

LM-1507.NA

Drug Info

Phase 2

Asthma

[15]

Masilukast

Drug Info

Phase 2

Asthma

[16]

CR-3465

Drug Info

Phase 1

Allergy

[17]

YM-57158

Drug Info

Phase 1

Allergic rhinitis

[18]

Discontinued Drug(s)

[+] 16 Discontinued Drugs

Ablukast

Drug Info

Discontinued in Phase 3

Asthma

[19]

AS-35

Drug Info

Discontinued in Phase 2

Asthma

[20]

DS-4574

Drug Info

Discontinued in Phase 2

Asthma

[21]

FK-011

Drug Info

Discontinued in Phase 2

Asthma

[22]

LY-2300559

Drug Info

Discontinued in Phase 2

Migraine

[23]

Sulukast

Drug Info

Discontinued in Phase 2

Asthma

[24], [25]

RG-7152

Drug Info

Discontinued in Phase 1

Asthma

[26]

FPL-55712

Drug Info

Terminated

Asthma

[27]

ICI-198615

Drug Info

Terminated

Asthma

[28], [29]

L-648051

Drug Info

Terminated

Asthma

[30]

LM-1376

Drug Info

Terminated

Asthma

[31]

LY-290154

Drug Info

Terminated

Asthma

[32]

MCI-826

Drug Info

Terminated

Asthma

[33]

MDL-43291

Drug Info

Terminated

Asthma

[34]

OT-4003

Drug Info

Terminated

Asthma

[35]

Tomelukast

Drug Info

Terminated

Asthma

[36]

Mode of Action

[+] 3 Modes of Action

Antagonist

[+] 12 Antagonist drugs

Cinalukast

Drug Info

[2]

Montelukast

Drug Info

[1], [37]

Pranlukast

Drug Info

[38]

Zafirlukast

Drug Info

[7], [37], [39]

LM-1507.NA

Drug Info

[42], [10]

RG-7152

Drug Info

[26], [10]

ICI-198615

Drug Info

[54]

MCI-826

Drug Info

[58], [10]

BayCysLT2

Drug Info

[62]

BAYu9773

Drug Info

[63]

pobilukast

Drug Info

[66]

XGP-510

Drug Info

[67]

Modulator

[+] 23 Modulator drugs

Claritin/Singulair

Drug Info

[8], [9]

BAY-X-7195

Drug Info

[40]

Iralukast

Drug Info

[41]

KP-496

Drug Info

[14]

Masilukast

Drug Info

[43]

CR-3465

Drug Info

[43]

YM-57158

Drug Info

[18]

Ablukast

Drug Info

[43]

AS-35

Drug Info

[44], [45]

DS-4574

Drug Info

[46], [47]

FK-011

Drug Info

[48]

L-660771

Drug Info

[49], [50]

LY-2300559

Drug Info

[51]

Sulukast

Drug Info

[52]

FPL-55712

Drug Info

[53]

L-648051

Drug Info

[55]

LM-1376

Drug Info

[56]

LY-290154

Drug Info

[57]

MDL-43291

Drug Info

[59]

OT-4003

Drug Info

[35]

Tomelukast

Drug Info

[60], [61]

CGP-57698

Drug Info

[64]

WY-46016

Drug Info

[69]

Agonist

[+] 4 Agonist drugs

LTC4

Drug Info

[65]

LTD4

Drug Info

[66], [67]

LTE4

Drug Info

[65]

N-methyl LTC4

Drug Info

[68]

Cell-based Target Expression Variations

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Cell-based Target Expression Variations

Cell-based Target Expression Variations Info

Different Human System Profiles of Target	Top
Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target. A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020). Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function. Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006). Human Similarity Proteins Human Pathway Affiliation

Different Human System Profiles of Target

Top

Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.

A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020).

Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.

Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006).

Human Similarity Proteins

Human Pathway Affiliation

Protein Name	Pfam ID	Percentage of Identity (%)	E value
Mas-related G-protein coupled receptor MRG (MAS1L)		24.183 (74/306)	1.03E-04

KEGG Pathway	Pathway ID	Affiliated Target
Calcium signaling pathway	hsa04020	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
Neuroactive ligand-receptor interaction	hsa04080	Affiliated Target
Class: Environmental Information Processing => Signaling molecules and interaction	Pathway Hierarchy

Chemical Structure based Activity Landscape of Target

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Drug Property Profile of Target

Top

(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five

Co-Targets

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Co-Targets

Co-Targets Info

Target Poor or Non Binders

Top

Target Poor or Non Binders

Target Poor or Non Binders Info

Target Regulators

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Target-interacting Proteins

Target-interacting Proteins Info

Target Profiles in Patients

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Target Expression
Profile (TEP)

Target Expression Profile Info

Target Affiliated Biological Pathways

Top

KEGG Pathway

[+] 2 KEGG Pathways

Calcium signaling pathway

Neuroactive ligand-receptor interaction

NetPath Pathway

[+] 3 NetPath Pathways

TGF_beta_Receptor Signaling Pathway

IL4 Signaling Pathway

IL3 Signaling Pathway

PID Pathway

[+] 1 PID Pathways

Endothelins

Reactome

[+] 2 Reactome Pathways

Leukotriene receptors

G alpha (q) signalling events

WikiPathways

[+] 4 WikiPathways

GPCRs, Class A Rhodopsin-like

Gastrin-CREB signalling pathway via PKC and MAPK

GPCR ligand binding

GPCR downstream signaling

Target-Related Models and Studies

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Target Validation

Target Validation Info

References

Top

REF 1

Protective potential of montelukast against hepatic ischemia/reperfusion injury in rats. J Surg Res. 2010 Mar;159(1):588-94.

REF 2

Prolonged protection against exercise-induced bronchoconstriction by the leukotriene D4-receptor antagonist cinalukast. J Allergy Clin Immunol. 1997 Feb;99(2):210-5.

REF 3

URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 3340).

REF 4

Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007 Mar;70(3):461-77.

REF 5

REF 6

REF 7

Role of antileukotriene agents in asthma therapy. J Am Osteopath Assoc. 2000 Jan;100(1):32, 37-43.

REF 8

Montelukast, a leukotriene receptor antagonist, for the treatment of persistent asthma in children aged 2 to 5 years. Pediatrics. 2001 Sep;108(3):E48.

REF 9

A review of montelukast in the treatment of asthma and allergic rhinitis. Expert Opin Pharmacother. 2004 Mar;5(3):679-86.

REF 10

Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015

REF 11

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800003794)

REF 12

REF 13

Iralukast Novartis AG. IDrugs. 1998 May;1(1):147-50.

REF 14

Effects of KP-496, a novel dual antagonist for leukotriene D4 and thromboxane A2 receptors, on contractions induced by various agonists in the guinea pig trachea. Allergol Int. 2006 Dec;55(4):403-10.

REF 15

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800010469)

REF 16

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800015230)

REF 17

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800019601)

REF 18

In vitro pharmacologic profile of YM158, a new dual antagonist for LTD4 and TXA2 receptors. J Pharmacol Exp Ther. 1998 Nov;287(2):633-9.

REF 19

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800002358)

REF 20

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800001439)

REF 21

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800000587)

REF 22

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800010718)

REF 23

ClinicalTrials.gov (NCT01184508) A Study in Migraine Prevention. U.S. National Institutes of Health.

REF 24

REF 25

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800000090)

REF 26

Induction of peroxisomal enzymes by a tetrazole-substituted 2-quinolinylmethoxy leukotriene D4 antagonist. Fundam Appl Toxicol. 1994 Aug;23(2):298-303.

REF 27

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800000089)

REF 28

REF 29

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800002386)

REF 30

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800000103)

REF 31

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800006199)

REF 32

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800007201)

REF 33

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800001711)

REF 34

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800000087)

REF 35

Discovery of OT4003, a novel, potent, and orally active cys-LT1 receptor antagonist. Bioorg Med Chem. 1997 Feb;5(2):415-27.

REF 36

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800000075)

REF 37

Knockouts model the 100 best-selling drugs--will they model the next 100 Nat Rev Drug Discov. 2003 Jan;2(1):38-51.

REF 38

Beneficial effects of leukotriene receptor antagonists in the prevention of cedar pollinosis in a community setting. J Investig Allergol Clin Immunol. 2009;19(3):195-203.

REF 39

Inhibitory effects of zafirlukast on respiratory bursts of human neutrophils. Drugs Exp Clin Res. 2002;28(4):133-45.

REF 40

The effect of a novel leukotriene C4/D4 antagonist, BAY-x-7195, on experimental allergic reactions. Prostaglandins. 1995 Nov-Dec;50(5-6):269-85.

REF 41

Pharmacological characterization of the cysteinyl-leukotriene antagonists CGP 45715A (iralukast) and CGP 57698 in human airways in vitro. Br J Pharmacol. 1998 Feb;123(3):590-8.

REF 42

Pharmacological differences among CysLT(1) receptor antagonists with respect to LTC(4) and LTD(4) in human lung parenchyma. Biochem Pharmacol. 2002 Apr 15;63(8):1537-46.

REF 43

Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.

REF 44

Inhibition of radiolabeled leukotriene-binding by AS-35 in guinea pig lung membrane fraction. Jpn J Pharmacol. 1992 Apr;58(4):357-64.

REF 45

Peptide leukotriene antagonistic activity of AS-35, a new antiallergic drug. Jpn J Pharmacol. 1992 Apr;58(4):347-55.

REF 46

Inhibitory effect of DS-4574, a mast cell stabilizer with peptidoleukotriene receptor antagonism, on gastric acid secretion in rats. Eur J Pharmacol. 1994 Apr 1;255(1-3):229-34.

REF 47

Antagonistic action of DS-4574 against leukotrienes in guinea-pig smooth muscle. Arch Int Pharmacodyn Ther. 1991 Nov-Dec;314:147-59.

REF 48

Evaluation of human peroxisome proliferator-activated receptor (PPAR) subtype selectivity of a variety of anti-inflammatory drugs based on a novel assay for PPAR delta(beta). J Pharmacol Sci. 2003 Nov;93(3):347-55.

REF 49

Pharmacology of the leukotriene antagonist verlukast: the (R)-enantiomer of MK-571. Can J Physiol Pharmacol. 1991 Dec;69(12):1847-54.

REF 50

Verlukast (MK-0679) conjugation with glutathione by rat liver and kidney cytosols and excretion in the bile. Drug Metab Dispos. 1995 Oct;23(10):1085-93.

REF 51

Annual Reports in Medicinal Chemistry. Elsevier (ISBN: 9780123964922). 2012, p78

REF 52

The pharmacological evaluation of LY 170680, a novel leukotriene D4 and E4 antagonist in the guinea-pig. Br J Pharmacol. 1989 Sep;98(1):259-67.

REF 53

Effect of the leukotriene receptor antagonists FPL 55712, LY 163443, and MK-571 on the elimination of cysteinyl leukotrienes in the rat. Br J Pharmacol. 1991 Apr;102(4):865-70.

REF 54

Heterogeneity of binding sites for ICI 198,615 in human lung parenchyma. Biochem Pharmacol. 1992 Oct 6;44(7):1411-5.

REF 55

Effects of a leukotriene D4 receptor antagonist, L-648,051, and a dual inhibitor lypoxygenase and cyclooxygenase, BW-755C, on digoxin-induced arrhy... Arch Int Pharmacodyn Ther. 1993 Jan-Feb;321:72-80.

REF 56

Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.

REF 57

DOI: 10.1021/op060036x

REF 58

Leukotriene receptors in the skin of rats differ from those of mouse skin or rat stomach strip. Eur J Pharmacol. 1992 Oct 20;221(2-3):333-42.

REF 59

Conformationally restricted leukotriene receptor antagonists: [(octahydro-2-oxo-7-tetradecylidene-2H-1-benzopyran-8-yl)thio]ace tic acids. Pharmacology. 1990;40(5):271-6.

REF 60

Effects of chronic treatment with the leukotriene D4 antagonist compound LY171883 on Fischer 344 rats and rhesus monkeys. Fundam Appl Toxicol. 1990 Jan;14(1):123-30.

REF 61

Effect of the peroxisome proliferator LY171883 on triglyceride accumulation in rats fed a fat-free diet. Biochem Pharmacol. 1991 Sep 12;42(7):1487-91.

REF 62

Synthesis of cysteinyl leukotrienes in human endothelial cells: subcellular localization and autocrine signaling through the CysLT2 receptor. FASEB J. 2011 Oct;25(10):3519-28.

REF 63

Molecular cloning and characterization of a second human cysteinyl leukotriene receptor: discovery of a subtype selective agonist. Mol Pharmacol. 2000 Dec;58(6):1601-8.

REF 64

A kinetic binding study to evaluate the pharmacological profile of a specific leukotriene C(4) binding site not coupled to contraction in human lun... Mol Pharmacol. 2000 Jun;57(6):1182-9.

REF 65

Characterization of the human cysteinyl leukotriene CysLT1 receptor. Nature. 1999 Jun 24;399(6738):789-93.

REF 66

Identification, molecular cloning, expression, and characterization of a cysteinyl leukotriene receptor. Mol Pharmacol. 1999 Sep;56(3):657-63.

REF 67

REF 68

Differential signaling of cysteinyl leukotrienes and a novel cysteinyl leukotriene receptor 2 (CysLT agonist, N-methyl-leukotriene C in calcium reporter and beta arrestin assays. Mol Pharmacol. 2011 Feb;79(2):270-8.

REF 69

N-[(arylmethoxy)phenyl] carboxylic acids, hydroxamic acids, tetrazoles, and sulfonyl carboxamides.Potent orally active leukotriene D4 antagonists of novel structure.J Med Chem.1990 Jan;33(1):240-5.

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