Target Information

Target General Infomation
Target ID
T03691
Former ID
TTDC00130
Target Name
Leukotriene A-4 hydrolase
Gene Name
LTA4H
Synonyms
LTA-4hydrolase; LTA-H; Leukotriene A(4) hydrolase; Leukotriene A(4)Leukotriene A-4 hydrolase hydrolase; Leukotriene A4 hydrolase; LTA4H
Target Type
Successful
Disease Acute myeloid leukemia [ICD9: 205; ICD10: C92.0]
Inflammatory disease [ICD9: 140-229, 147, 173, 573.3, 710-719; ICD10: C11, C44, K75.9, M00-M25]
Myocardial infarction [ICD9: 410; ICD10: I21, I22]
Function
Epoxide hydrolase that catalyzes the final step in the biosynthesis of the proinflammatory mediator leukotriene B4. Has also aminopeptidase activity.
BioChemical Class
Etherhydrolase
Target Validation
T03691
UniProt ID
P09960
EC Number
EC 3.3.2.6
Sequence
MPEIVDTCSLASPASVCRTKHLHLRCSVDFTRRTLTGTAALTVQSQEDNLRSLVLDTKDL
TIEKVVINGQEVKYALGERQSYKGSPMEISLPIALSKNQEIVIEISFETSPKSSALQWLT
PEQTSGKEHPYLFSQCQAIHCRAILPCQDTPSVKLTYTAEVSVPKELVALMSAIRDGETP
DPEDPSRKIYKFIQKVPIPCYLIALVVGALESRQIGPRTLVWSEKEQVEKSAYEFSETES
MLKIAEDLGGPYVWGQYDLLVLPPSFPYGGMENPCLTFVTPTLLAGDKSLSNVIAHEISH
SWTGNLVTNKTWDHFWLNEGHTVYLERHICGRLFGEKFRHFNALGGWGELQNSVKTFGET
HPFTKLVVDLTDIDPDVAYSSVPYEKGFALLFYLEQLLGGPEIFLGFLKAYVEKFSYKSI
TTDDWKDFLYSYFKDKVDVLNQVDWNAWLYSPGLPPIKPNYDMTLTNACIALSQRWITAK
EDDLNSFNATDLKDLSSHQLNEFLAQTLQRAPLPLGHIKRMQEVYNFNAINNSEIRFRWL
RLCIQSKWEDAIPLALKMATEQGRMKFTRPLFKDLAAFDKSHDQAVRTYQEHKASMHPVT
AMLVGKDLKVD
Drugs and Mode of Action
Drug(s) Bestatin Drug Info Approved Acute myeloid leukemia [468215], [551871]
DG051 Drug Info Discontinued in Phase 2 Myocardial infarction [541672], [548272]
Inhibitor (4-(thiophen-2-yl)phenyl)methanamine Drug Info [530549]
(4-fluorophenyl)(pyridin-4-yl)methanone Drug Info [551374]
(R)-2-((4-benzylphenoxy)methyl)piperidine Drug Info [530833]
(R)-2-((4-phenoxyphenoxy)methyl)piperidine Drug Info [530833]
(R)-2-(4-Benzylphenoxymethyl)pyrrolidine Drug Info [530549]
(R)-N-benzyl-4-(pyrrolidin-2-ylmethoxy)aniline Drug Info [530267]
(R/S)-2-((4-benzylphenoxy)methyl)piperazine Drug Info [530833]
(R/S)-2-((4-benzylphenoxy)methyl)piperidine Drug Info [530833]
(R/S)-2-((4-phenoxyphenoxy)methyl)piperidine Drug Info [530833]
(S)-2-((4-phenoxyphenoxy)methyl)piperidine Drug Info [530833]
1-(2,2'-bithiophen-5-yl)methanamine Drug Info [551374]
1-(4-Phenoxyphenyl)piperazine Drug Info [530549]
1-(4-thiophen-2-ylphenyl)methanamine Drug Info [551374]
1-(pentyloxy)-4-phenoxybenzene Drug Info [529770]
1-butoxy-4-phenoxybenzene Drug Info [529770]
1-[4-(4-Iodophenoxy)phenyl]piperazine Drug Info [530549]
1-[4-(Benzothiazol-2-yloxy)benzyl]piperidin-4-ol Drug Info [529569]
2-(4-benzylphenoxy)ethanamine Drug Info [529770]
2-(4-phenoxyphenoxy)ethanamine Drug Info [529770]
2-(4-Piperidin-1-ylmethylphenoxy)benzothiazole Drug Info [529569]
2-(7-(benzyloxy)-1H-indol-3-yl)ethanamine Drug Info [529868]
2-Amino-N-[4-(phenylmethoxy)phenyl]-acetamide Drug Info [529408]
2-[4-(2-Azepan-1-ylethoxy)phenoxy]benzooxazole Drug Info [529569]
2-[4-(2-Azepan-1-ylethoxy)phenoxy]benzothiazole Drug Info [529569]
2-[4-(2-Morpholin-4-ylethoxy)phenoxy]benzooxazole Drug Info [529569]
2-[4-(2-Piperidin-1-ylethyl)phenoxy]benzothiazole Drug Info [529569]
3-(Benzyloxy)Pyridin-2-Amine Drug Info [551393]
4-(2-amino-1,3-thiazol-4-yl)phenol Drug Info [551374]
4-(4-(pentyloxy)phenoxy)phenol Drug Info [529770]
4-(4-butoxyphenoxy)phenol Drug Info [529770]
4-(4-propoxyphenoxy)phenol Drug Info [529770]
4-amino-N-[4-(benzyloxy)phenyl]butanamide Drug Info [551374]
4-Amino-N-[4-(phenylmethoxy)phenyl]butanamide Drug Info [529408]
4-[2-(4-Benzylphenoxy)ethyl]pyridine Drug Info [530549]
4S-4,5-Diamino-N-(4-phenoxyphenyl)pentanamide Drug Info [529408]
5-[2-(1H-pyrrol-1-yl)ethoxy]-1H-indole Drug Info [551374]
5-[2-(4-hydroxyphenyl)ethyl]benzene-1,3-diol Drug Info [551374]
8(S)-amino-2(R)-methyl-7-oxononanoic acid Drug Info [534266]
Acetate Ion Drug Info [551393]
Bestatin Drug Info [551391]
DG051 Drug Info [536080], [536517]
JNJ-10392980 Drug Info [529569]
N-(pyridin-3-ylmethyl)aniline Drug Info [551374]
N-benzyl-4-[(2R)-pyrrolidin-2-ylmethoxy]aniline Drug Info [551374]
N-methyl-1-(2-thiophen-2-ylphenyl)methanamine Drug Info [551374]
N-[4-(benzyloxy)phenyl]glycinamide Drug Info [551374]
N1-[4-(Phenylmethoxy)phenyl]-D-aspartamine Drug Info [529408]
N1-[4-(Phenylmethoxy)phenyl]-D-glutamine Drug Info [529408]
N1-[4-(Phenylmethoxy)phenyl]-L-aspartamine Drug Info [529408]
N1-[4-(Phenylmethoxy)phenyl]-L-glutamine Drug Info [529408]
N4-[4-(Phenylmethoxy)phenyl]-L-aspartamine Drug Info [529408]
N5-(4-Phenoxyphenyl)-L-glutamine Drug Info [529408]
N5-[(4-Phenoxy)-3-pyridyl]-L-glutamamide Drug Info [529408]
N5-[4-(1H-pyrrol-1-yl)phenyl]-L-glutamamide Drug Info [529408]
N5-[4-(2-methylphenoxy)phenyl]-L-glutamamide Drug Info [529408]
N5-[4-(2-Oxo-3-phenylpropoxy)phenyl]-L-glutamine Drug Info [529408]
N5-[4-(2-phenylethoxy)phenyl]-L-glutamine Drug Info [529408]
N5-[4-(3-methylphenoxy)phenyl]-L-glutamamide Drug Info [529408]
N5-[4-(3-Phenylpropoxy)phenyl]-L-glutamine Drug Info [529408]
N5-[4-(4-(3-Furyl)phenoxy)phenyl]-L-glutamamide Drug Info [529408]
N5-[4-(4-methylphenoxy)phenyl]-L-glutamamide Drug Info [529408]
N5-[4-(N-Phenylamino)phenyl]-L-glutamine Drug Info [529408]
N5-[4-(Phenylmethoxy)phenyl]-D-glutamine Drug Info [529408]
N5-[4-(Phenylmethoxy)phenyl]-L-glutamamide Drug Info [529408]
N5-[4-(Phenylmethoxy)phenyl]-L-glutamine Drug Info [529408]
N5-[4-Benzylphenyl]-L-glutamamide Drug Info [529408]
N6-[4-(4-methylphenoxy)phenyl]-L-homoglutamine Drug Info [529408]
SA-6541 Drug Info [529829]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
Pathways
BioCyc Pathway Leukotriene biosynthesis
KEGG Pathway Arachidonic acid metabolism
Metabolic pathways
PathWhiz Pathway Arachidonic Acid Metabolism
WikiPathways Arachidonic acid metabolism
Eicosanoid Synthesis
References
Ref 468215(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: 5151).
Ref 541672(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: 6548).
Ref 548272Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800024010)
Ref 551871Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
Ref 529408Bioorg Med Chem. 2008 May 1;16(9):4963-83. Epub 2008 Mar 20.Synthesis of glutamic acid analogs as potent inhibitors of leukotriene A4 hydrolase.
Ref 529569J Med Chem. 2008 Jul 24;51(14):4150-69. Epub 2008 Jun 28.Identification of a potent, selective, and orally active leukotriene a4 hydrolase inhibitor with anti-inflammatory activity.
Ref 529770Bioorg Med Chem Lett. 2008 Dec 15;18(24):6549-52. Epub 2008 Oct 14.Activation and inhibition of leukotriene A4 hydrolase aminopeptidase activity by diphenyl ether and derivatives.
Ref 529829Bioorg Med Chem Lett. 2009 Jan 15;19(2):442-6. Epub 2008 Nov 18.Synthesis and biological evaluation of N-mercaptoacylcysteine derivatives as leukotriene A4 hydrolase inhibitors.
Ref 529868J Med Chem. 2008 Dec 25;51(24):7882-8.Discovery of multitarget inhibitors by combining molecular docking with common pharmacophore matching.
Ref 530267J Med Chem. 2009 Aug 13;52(15):4694-715.Discovery of leukotriene A4 hydrolase inhibitors using metabolomics biased fragment crystallography.
Ref 530549J Med Chem. 2010 Jan 28;53(2):573-85.Discovery of 4-[(2S)-2-{[4-(4-chlorophenoxy)phenoxy]methyl}-1-pyrrolidinyl]butanoic acid (DG-051) as a novel leukotriene A4 hydrolase inhibitor of leukotriene B4 biosynthesis.
Ref 530833Bioorg Med Chem Lett. 2010 May 1;20(9):2851-4. Epub 2010 Mar 12.Discovery of novel leukotriene A4 hydrolase inhibitors based on piperidine and piperazine scaffolds.
Ref 534266J Nat Prod. 1996 Oct;59(10):962-4.Isolation and structure of leukotriene-A4 hydrolase inhibitor: 8(S)-amino-2(R)-methyl-7-oxononanoic acid produced by Streptomyces diastaticus.
Ref 536080Effects of a 5-lipoxygenase-activating protein inhibitor on biomarkers associated with risk of myocardial infarction: a randomized trial. JAMA. 2005 May 11;293(18):2245-56.
Ref 536517BAY x 1005 attenuates atherosclerosis in apoE/LDLR - double knockout mice. J Physiol Pharmacol. 2007 Sep;58(3):583-8.
Ref 551374The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
Ref 551391DrugBank 3.0: a comprehensive resource for 'omics' research on drugs. Nucleic Acids Res. 2011 Jan;39(Database issue):D1035-4. Nucleic Acids Res. 2011 January
Ref 551393How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6.

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