Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTGKOY9)

• DTT 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
• Gene Name: CYSLTR1
• DTT Type: Successful target; [1]
• BioChemical Class: GPCR rhodopsin
• UniProt ID: CLTR1_HUMAN
• TTD ID: T71192
• Sequence:
  MDETGNLTVSSATCHDTIDDFRNQVYSTLYSMISVVGFFGNGFVLYVLIKTYHKKSAFQV
  YMINLAVADLLCVCTLPLRVVYYVHKGIWLFGDFLCRLSTYALYVNLYCSIFFMTAMSFF
  RCIAIVFPVQNINLVTQKKARFVCVGIWIFVILTSSPFLMAKPQKDEKNNTKCFEPPQDN
  QTKNHVLVLHYVSLFVGFIIPFVIIIVCYTMIILTLLKKSMKKNLSSHKKAIGMIMVVTA
  AFLVSFMPYHIQRTIHLHFLHNETKPCDSVLRMQKSVVITLSLAASNCCFDPLLYFFSGG
  NFRKRLSTFRKHSLSSVTYVPRKKASLPEKGEEICKV
• 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.
• KEGG Pathway:
  Calcium signaling pathway (hsa04020)
  Neuroactive ligand-receptor interaction (hsa04080)
• Reactome Pathway:
  G alpha (q) signalling events (R-HSA-416476)
  Leukotriene receptors (R-HSA-391906)

Molecular Interaction Atlas (MIA) of This DTT

4 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Cinalukast	DMFIC0M	Asthma	CA23	Approved	[2]
Montelukast	DMD157S	Allergic asthma	CA23.0	Approved	[1]
Pranlukast	DMYHDCA	Allergic rhinitis	CA08.0	Approved	[3]
Zafirlukast	DMHNQOG	Asthma	CA23	Approved	[4]

7 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
BAY-X-7195	DM2XE80	Asthma	CA23	Phase 2	[5]
Iralukast	DMQ3RWN	Asthma	CA23	Phase 2	[6]
KP-496	DMCO8UZ	Asthma	CA23	Phase 2	[7]
LM-1507.NA	DMW6VA0	Asthma	CA23	Phase 2	[8]
Masilukast	DMDTI0L	Asthma	CA23	Phase 2	[9]
CR-3465	DMT7L30	Allergy	4A80-4A85	Phase 1	[9]
YM-57158	DMS31YW	Allergic rhinitis	CA08.0	Phase 1	[10]

17 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Ablukast	DMNKZ61	Asthma	CA23	Discontinued in Phase 3	[9]
AS-35	DMC2WI7	Asthma	CA23	Discontinued in Phase 2	[11]
DS-4574	DM8GZWC	Asthma	CA23	Discontinued in Phase 2	[12]
FK-011	DMCINOE	Asthma	CA23	Discontinued in Phase 2	[13]
L-660771	DMG5VJF	N. A.	N. A.	Discontinued in Phase 2	[14]
LY-2300559	DMTS1X5	Migraine	8A80	Discontinued in Phase 2	[15]
Sulukast	DMBSLZV	Asthma	CA23	Discontinued in Phase 2	[16]
RG-7152	DMG9U8D	Asthma	CA23	Discontinued in Phase 1	[17]
FPL-55712	DMF1CDK	Asthma	CA23	Terminated	[18]
ICI-198615	DM0195G	Asthma	CA23	Terminated	[19]
L-648051	DMTKCNJ	Asthma	CA23	Terminated	[20]
LM-1376	DMF9XU4	Asthma	CA23	Terminated	[21]
LY-290154	DMPZ7AO	Asthma	CA23	Terminated	[22]
MCI-826	DMXLCB6	Asthma	CA23	Terminated	[23]
MDL-43291	DMBIDQX	Asthma	CA23	Terminated	[24]
OT-4003	DM9YOMX	Asthma	CA23	Terminated	[25]
Tomelukast	DM385D9	Asthma	CA23	Terminated	[26]

10 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
BayCysLT2	DMKFTZA	Discovery agent	N.A.	Investigative	[27]
BAYu9773	DMXQ14V	Discovery agent	N.A.	Investigative	[28]
CGP-57698	DMYZ72J	Discovery agent	N.A.	Investigative	[29]
LTC4	DM702WR	Discovery agent	N.A.	Investigative	[30]
LTD4	DMIUZX3	Discovery agent	N.A.	Investigative	[31]
LTE4	DMCPB0Q	Discovery agent	N.A.	Investigative	[30]
N-methyl LTC4	DM6XYCU	Discovery agent	N.A.	Investigative	[32]
pobilukast	DMURB4Y	Discovery agent	N.A.	Investigative	[31]
WY-46016	DM0AZLE	Discovery agent	N.A.	Investigative	[33]
XGP-510	DMBLR73	Allergy	4A80-4A85	Investigative	[34]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Asthma	CA23	Nasal and bronchial airway	1.96E-02	0.24	0.43

References

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• [5] 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.
• [6] 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.
• [7] 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.
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• [9] Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.
• [10] 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.
• [11] Inhibition of radiolabeled leukotriene-binding by AS-35 in guinea pig lung membrane fraction. Jpn J Pharmacol. 1992 Apr;58(4):357-64.
• [12] 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.
• [13] 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.
• [14] Pharmacology of the leukotriene antagonist verlukast: the (R)-enantiomer of MK-571. Can J Physiol Pharmacol. 1991 Dec;69(12):1847-54.
• [15] Annual Reports in Medicinal Chemistry. Elsevier (ISBN: 9780123964922). 2012, p78
• [16] 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.
• [17] Induction of peroxisomal enzymes by a tetrazole-substituted 2-quinolinylmethoxy leukotriene D4 antagonist. Fundam Appl Toxicol. 1994 Aug;23(2):298-303.
• [18] 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.
• [19] Heterogeneity of binding sites for ICI 198,615 in human lung parenchyma. Biochem Pharmacol. 1992 Oct 6;44(7):1411-5.
• [20] 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.
• [21] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [22] DOI: 10.1021/op060036x
• [23] 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.
• [24] 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.
• [25] Discovery of OT4003, a novel, potent, and orally active cys-LT1 receptor antagonist. Bioorg Med Chem. 1997 Feb;5(2):415-27.
• [26] 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.
• [27] 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.
• [28] 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.
• [29] 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.
• [30] Characterization of the human cysteinyl leukotriene CysLT1 receptor. Nature. 1999 Jun 24;399(6738):789-93.
• [31] Identification, molecular cloning, expression, and characterization of a cysteinyl leukotriene receptor. Mol Pharmacol. 1999 Sep;56(3):657-63.
• [32] 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.
• [33] 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.
• [34] 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. (Target id: 269).