Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTN53ZF)

• DTT Name: Leukotriene B4 receptor 1 (LTB4R)
• Synonyms: P2Y7; P2Y purinoceptor 7; P2RY7; Leukotriene B(4) receptor BLT1; LTB4-R1; LTB4-R 1; LTB4-R; GPR16; G-protein coupled receptor 16; Chemoattractant receptor-like 1; CMKRL1; BLTR; BLT1; BLT
• Gene Name: LTB4R
• DTT Type: Clinical trial target; [1]
• BioChemical Class: GPCR rhodopsin
• UniProt ID: LT4R1_HUMAN
• TTD ID: T59626
• Sequence:
  MNTTSSAAPPSLGVEFISLLAIILLSVALAVGLPGNSFVVWSILKRMQKRSVTALMVLNL
  ALADLAVLLTAPFFLHFLAQGTWSFGLAGCRLCHYVCGVSMYASVLLITAMSLDRSLAVA
  RPFVSQKLRTKAMARRVLAGIWVLSFLLATPVLAYRTVVPWKTNMSLCFPRYPSEGHRAF
  HLIFEAVTGFLLPFLAVVASYSDIGRRLQARRFRRSRRTGRLVVLIILTFAAFWLPYHVV
  NLAEAGRALAGQAAGLGLVGKRLSLARNVLIALAFLSSSVNPVLYACAGGGLLRSAGVGF
  VAKLLEGTGSEASSTRRGGSLGQTARSGPAALEPGPSESLTASSPLKLNELN
• Function: The activity of this receptor is mediated by G proteins which activate a phosphatidylinositol-calcium second messenger system. May be the cardiac P2Y receptor involved in the regulation of cardiac muscle contraction through modulation of L-type calcium currents. Is a receptor for leukotriene B4, a potent chemoattractant involved in inflammation and immune response. Receptor for extracellular ATP > UTP and ADP.
• KEGG Pathway: 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

3 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Amelubant	DMUMCB9	Pulmonary disease	1B10-1F85	Phase 2	[2]
LTB4	DME26RS	Human immunodeficiency virus infection	1C62	Phase 2	[1]
Biomed 101	DMQ9KZW	Kidney cancer	2C90.0	Phase 1	[3]

21 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
CI-949	DMN4QSW	Asthma	CA23	Discontinued in Phase 2	[4]
CP-195543	DM1OSUR	Rheumatoid arthritis	FA20	Discontinued in Phase 2	[5]
LTB 019	DM6G0PN	Asthma	CA23	Discontinued in Phase 2	[6]
LY-223982	DMWB7DO	Asthma	CA23	Discontinued in Phase 2	[7]
LY293111	DM03FHA	Pancreatic cancer	2C10	Discontinued in Phase 2	[8]
SB-201993	DMIF4VJ	Psoriasis vulgaris	EA90	Discontinued in Phase 2	[9]
CP-105696	DM1C4IN	Inflammatory bowel disease	DD72	Discontinued in Phase 1	[10]
TAK-683	DMRD8HK	Prostate cancer	2C82.0	Discontinued in Phase 1	[11]
DW-1350	DM3L0T1	Osteoporosis	FB83.0	Terminated	[12]
LY-210073	DMUEB4P	Asthma	CA23	Terminated	[13]
LY-255283	DMFIR0S	Asthma	CA23	Terminated	[14]
LY-292728	DMU24HR	N. A.	N. A.	Terminated	[15]
RG-14893	DMKFQC7	Asthma	CA23	Terminated	[16]
Ro-25-4094	DMVB0C3	Inflammation	1A00-CA43.1	Terminated	[17]
RP-66153	DMX4E75	Asthma	CA23	Terminated	[18]
RP-66364	DM6HJX7	Inflammation	1A00-CA43.1	Terminated	[19]
RP-69698	DMUY4FD	Inflammation	1A00-CA43.1	Terminated	[20]
SB-201146	DMGNZUX	N. A.	N. A.	Terminated	[9]
SB-209247	DMVBNTP	Psoriasis vulgaris	EA90	Terminated	[21]
SC-51146	DMI0QZ3	N. A.	N. A.	Terminated	[22]
SC-53228	DMSKHGQ	Asthma	CA23	Terminated	[22]

13 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(3S,4R)-3-Benzyl-7-isopropyl-chroman-4-ol	DMET6IS	Discovery agent	N.A.	Investigative	[10]
(LTB4-(Csa)4)2-Glu-H Conjugate	DMRGIF3	Discovery agent	N.A.	Investigative	[23]
DTPA Conjugate	DMNS265	Discovery agent	N.A.	Investigative	[23]
HYNIC Analogue	DMETS37	Discovery agent	N.A.	Investigative	[23]
Leucettamidine	DM94JXH	Discovery agent	N.A.	Investigative	[24]
LEUCETTAMINE A	DMIZVA6	Discovery agent	N.A.	Investigative	[24]
LY-282210	DMBSFDE	Discovery agent	N.A.	Investigative	[15]
SC-50073	DMU2WIS	Discovery agent	N.A.	Investigative	[22]
SC-50135	DMI2KE7	Discovery agent	N.A.	Investigative	[22]
SC-50676	DM8RJ0V	Discovery agent	N.A.	Investigative	[22]
SC-52073	DM0E2SM	Discovery agent	N.A.	Investigative	[22]
SC-52569	DMLOJ42	Discovery agent	N.A.	Investigative	[22]
SC-53229	DMYH12X	Discovery agent	N.A.	Investigative	[22]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Renal cancer	2C82	Kidney	3.40E-01	0.21	0.53
Rheumatoid arthritis	FA20	Synovial tissue	1.25E-01	-0.14	-0.53
Psoriasis	EA90	Skin	9.18E-26	1.41	2
Asthma	CA23	Nasal and bronchial airway	8.73E-05	0.21	0.21
Osteoporosis	FA20	Bone marrow	3.18E-01	0.18	0.83

References

• [1] LTB4 promotes insulin resistance in obese mice by acting on macrophages, hepatocytes and myocytes. Nat Med. 2015 Mar;21(3):239-47.
• [2] Leukotriene receptor antagonists in children with cystic fibrosis lung disease : anti-inflammatory and clinical effects. Paediatr Drugs. 2005;7(6):353-63.
• [3] Biomed 101, a leukotriene B4 inhibitor, may decrease IL-2 toxicity. 2003 ASCO Annual Meeting. 2003.
• [4] Inhibition of histamine, leukotriene C4/D4, and thromboxane B2 release from human leukocytes and human chopped lung mast cells by the allergic mediator release inhibitor, CI-949. J Allergy Clin Immunol. 1990 Dec;86(6 Pt 1):902-8.
• [5] The synthesis of CP-195543, an LTB4 antagonist for the treatment of inflammatory diseases. Curr Opin Drug Discov Devel. 1999 Nov;2(6):550-6.
• [6] Effect of the oral leukotriene B4 receptor antagonist LTB019 on inflammatory sputum markers in patients with chronic obstructive pulmonary disease. Pulm Pharmacol Ther. 2008;21(2):409-17.
• [7] Specific inhibition of leukotriene B4-induced neutrophil activation by LY223982. J Pharmacol Exp Ther. 1992 Dec;263(3):1009-14.
• [8] The Role of PPARgamma Receptors and Leukotriene B(4) Receptors in Mediating the Effects of LY293111 in Pancreatic Cancer. PPAR Res. 2008;2008:827096.
• [9] (E)-3-[6-[[(2,6-dichlorophenyl)thio]methyl]-3-(2-phenylethoxy)-2- pyridinyl]-2-propenoic acid: a high-affinity leukotriene B4 receptor antagonist w... J Med Chem. 1996 Sep 13;39(19):3837-41.
• [10] 3-Substituted-4-hydroxy-7-chromanylacetic acid derivatives as antagonists of the leukotriene B4 (LTB4) receptor, Bioorg. Med. Chem. Lett. 7(17):2307-2312 (1997).
• [11] A second leukotriene B(4) receptor, BLT2. A new therapeutic target in inflammation and immunological disorders. J Exp Med. 2000 Aug 7;192(3):421-32.
• [12] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800026850)
• [13] Design, synthesis, and pharmacological evaluation of potent xanthone dicarboxylic acid leukotriene B4 receptor antagonists. J Med Chem. 1993 Jun 11;36(12):1726-34.
• [14] o-phenylphenols: potent and orally active leukotriene B4 receptor antagonists. J Med Chem. 1993 Nov 26;36(24):3978-81.
• [15] Biphenylyl-substituted xanthones: highly potent leukotriene B4 receptor antagonists. J Med Chem. 1993 Nov 26;36(24):3982-4.
• [16] Structure-activity relationships study of two series of leukotriene B4 antagonists: novel indolyl and naphthyl compounds substituted with a 2-[methyl(2-phenethyl)amino]-2-oxoethyl side chain. J Med Chem. 1996 Sep 13;39(19):3756-68.
• [17] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800005401)
• [18] Omega-[(omega-arylalkyl)thienyl]alkanoic acids: from specific LTA4 hydrolase inhibitors to LTB4 receptor antagonists. J Med Chem. 1992 Aug 21;35(17):3170-9.
• [19] WO patent application no. 1997,0297,75, Compositions comprising a cyclooxygenase-2 inhibitor and a leukotriene b4 receptor antagonist.
• [20] omega-[(4,6-Diphenyl-2-pyridyl)oxy]alkanoic acid derivatives: a new family of potent and orally active LTB4 antagonists. J Med Chem. 1992 Nov 13;35(23):4315-24.
• [21] Formation and protein binding of the acyl glucuronide of a leukotriene B4 antagonist (SB-209247): relation to species differences in hepatotoxicity. Drug Metab Dispos. 2005 Feb;33(2):271-81.
• [22] Synthesis and pharmacological activity of SC-53228, a leukotriene B4 receptor antagonist with high intrinsic potency and selectivity, Bioorg. Med. Chem. Lett. 4(6):811-816 (1994).
• [23] Synthesis of leukotriene B4 antagonists labeled with In-111 or Tc-99m to image infectious and inflammatory foci. J Med Chem. 2005 Oct 6;48(20):6442-53.
• [24] New leukotriene B4 receptor antagonist: leucettamine A and related imidazole alkaloids from the marine sponge Leucetta microraphis. J Nat Prod. 1993 Jan;56(1):116-21.