Target Validation Information
Target ID T03691
Target Name Leukotriene A-4 hydrolase
Target Type
Successful
Drug Potency against Target (R)-2-((4-benzylphenoxy)methyl)piperidine Drug Info IC50 = 60 nM [530833]
2-[4-(2-Azepan-1-ylethoxy)phenoxy]benzooxazole Drug Info IC50 = 4 nM [529569]
1-(pentyloxy)-4-phenoxybenzene Drug Info IC50 = 4130 nM [529770]
2-(4-benzylphenoxy)ethanamine Drug Info IC50 = 9 nM [529770]
4-(4-butoxyphenoxy)phenol Drug Info IC50 = 5560 nM [529770]
(R/S)-2-((4-benzylphenoxy)methyl)piperidine Drug Info IC50 = 105 nM [530833]
2-(7-(benzyloxy)-1H-indol-3-yl)ethanamine Drug Info IC50 = 12500 nM [529868]
2-Amino-N-[4-(phenylmethoxy)phenyl]-acetamide Drug Info IC50 = 280 nM [529408]
N5-[4-(3-Phenylpropoxy)phenyl]-L-glutamine Drug Info IC50 = 31 nM [529408]
1-[4-(4-Iodophenoxy)phenyl]piperazine Drug Info IC50 = 340 nM [530549]
N5-[4-(2-methylphenoxy)phenyl]-L-glutamamide Drug Info IC50 = 2800 nM [529408]
(S)-2-((4-phenoxyphenoxy)methyl)piperidine Drug Info IC50 = 286 nM [530833]
(4-(thiophen-2-yl)phenyl)methanamine Drug Info IC50 = 98 nM [530549]
2-[4-(2-Morpholin-4-ylethoxy)phenoxy]benzooxazole Drug Info IC50 = 58 nM [529569]
(R)-2-(4-Benzylphenoxymethyl)pyrrolidine Drug Info IC50 = 449 nM [530549]
(R)-N-benzyl-4-(pyrrolidin-2-ylmethoxy)aniline Drug Info IC50 = 207 nM [530267]
8(S)-amino-2(R)-methyl-7-oxononanoic acid Drug Info IC50 = 300 nM [534266]
2-(4-Piperidin-1-ylmethylphenoxy)benzothiazole Drug Info IC50 = 230 nM [529569]
2-[4-(2-Azepan-1-ylethoxy)phenoxy]benzothiazole Drug Info IC50 = 66 nM [529569]
SA-6541 Drug Info IC50 = 270 nM [529829]
JNJ-10392980 Drug Info IC50 = 51 nM [529569]
1-[4-(Benzothiazol-2-yloxy)benzyl]piperidin-4-ol Drug Info IC50 = 250 nM [529569]
1-(4-Phenoxyphenyl)piperazine Drug Info IC50 = 1.4 nM [530549]
N1-[4-(Phenylmethoxy)phenyl]-D-glutamine Drug Info IC50 = 7200 nM [529408]
4-[2-(4-Benzylphenoxy)ethyl]pyridine Drug Info IC50 = 8.7 nM [530549]
N5-[4-(4-(3-Furyl)phenoxy)phenyl]-L-glutamamide Drug Info IC50 = 29 nM [529408]
N5-[4-(3-methylphenoxy)phenyl]-L-glutamamide Drug Info IC50 = 150 nM [529408]
N5-[4-(4-methylphenoxy)phenyl]-L-glutamamide Drug Info IC50 = 13 nM [529408]
N5-[4-Benzylphenyl]-L-glutamamide Drug Info IC50 = 21 nM [529408]
(R/S)-2-((4-phenoxyphenoxy)methyl)piperidine Drug Info IC50 = 207 nM [530833]
N6-[4-(4-methylphenoxy)phenyl]-L-homoglutamine Drug Info IC50 = 6 nM [529408]
(R)-2-((4-phenoxyphenoxy)methyl)piperidine Drug Info IC50 = 126 nM [530833]
N5-[4-(1H-pyrrol-1-yl)phenyl]-L-glutamamide Drug Info IC50 = 9700 nM [529408]
N5-[4-(2-phenylethoxy)phenyl]-L-glutamine Drug Info IC50 = 46 nM [529408]
4-Amino-N-[4-(phenylmethoxy)phenyl]butanamide Drug Info IC50 = 61 nM [529408]
N5-[4-(N-Phenylamino)phenyl]-L-glutamine Drug Info IC50 = 210 nM [529408]
N5-[4-(Phenylmethoxy)phenyl]-L-glutamamide Drug Info IC50 = 23 nM [529408]
(R/S)-2-((4-benzylphenoxy)methyl)piperazine Drug Info IC50 = 342 nM [530833]
N5-[4-(2-Oxo-3-phenylpropoxy)phenyl]-L-glutamine Drug Info IC50 = 18 nM [529408]
N5-[(4-Phenoxy)-3-pyridyl]-L-glutamamide Drug Info IC50 = 2600 nM [529408]
N5-[4-(Phenylmethoxy)phenyl]-L-glutamine Drug Info IC50 = 20 nM [529408]
N4-[4-(Phenylmethoxy)phenyl]-L-aspartamine Drug Info IC50 = 1100 nM [529408]
N5-[4-(Phenylmethoxy)phenyl]-D-glutamine Drug Info IC50 = 1600 nM [529408]
N5-(4-Phenoxyphenyl)-L-glutamine Drug Info IC50 = 19 nM [529408]
N1-[4-(Phenylmethoxy)phenyl]-L-glutamine Drug Info IC50 = 680 nM [529408]
4S-4,5-Diamino-N-(4-phenoxyphenyl)pentanamide Drug Info IC50 = 21 nM [529408]
2-[4-(2-Piperidin-1-ylethyl)phenoxy]benzothiazole Drug Info IC50 = 280 nM [529569]
4-(4-propoxyphenoxy)phenol Drug Info IC50 = 5690 nM [529770]
2-(4-phenoxyphenoxy)ethanamine Drug Info IC50 = 228 nM [529770]
1-butoxy-4-phenoxybenzene Drug Info IC50 = 5720 nM [529770]
4-(4-(pentyloxy)phenoxy)phenol Drug Info IC50 = 2480 nM [529770]
N1-[4-(Phenylmethoxy)phenyl]-L-aspartamine Drug Info IC50 = 5400 nM [529408]
N1-[4-(Phenylmethoxy)phenyl]-D-aspartamine Drug Info IC50 = 9300 nM [529408]
DG051 Drug Info K(d) = 26 nM [530549]
Action against Disease Model DG051 In preclinical studies DG051 has been shown in h uMan blood ex vivo and in animal models to be a potent inhibitor of LTB4 production. It was potent in the HWB assay with IC50 value of 37 nM. It was a potent inhibitor of LTA4H aminopeptidase activity against l-alanine p-nitroanilide (IC50 = 72 nM). [530549] Drug Info
The Effect of Target Knockout, Knockdown or Genetic Variations Leukotriene B(4) (LTB(4)) is a potent proinflammatory lipid mediator that initiates and amplifies synovial inflammation in the K/BxN model of arthritis. We sought to elucidate mechanisms by which mesenchymal-derived fibroblast-like synoviocytes (FLSs) perpetuate synovial inflammation. We focused on the abilities of FLSs to contribute to LTB(4) synthesis and to respond to LTB(4) within the joint. Using a series of bone marrow chimeras generated from 5-lipoxygenase(-/-) and leukotriene A(4) (LTA(4)) hydrolase(-/-) mice, we demonstrate that FLSs generate sufficient levels of LTB(4) production through transcellular metabolism in K/BxN ser uM-induced arthritis to drive inflammatory arthritis. FLSs-which comprise the predominant lineage populating the synovial lining-are competent to metabolize exogenous LTA(4) into LTB(4) ex vivo. Stimulation of FLSs with TNF increased their capacity to generate LTB(4) 3-fold without inducing the expression of LTA(4) hydrolase protein. Moreover, LTB(4) (acting via LTB(4) receptor 1) was found to modulate the migratory and invasive activity of FLSs in vitro and also promote joint erosion by pannus tissue in vivo. Our results identify novel roles for FLSs and LTB(4) in joints, placing LTB(4) regulation of FLS biology at the center of a previously unrecognized amplification loop for synovial inflammation and tissue pathology [530833]
References
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 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 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 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 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 529868J Med Chem. 2008 Dec 25;51(24):7882-8.Discovery of multitarget inhibitors by combining molecular docking with common pharmacophore matching.
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 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 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 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 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 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 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 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 530267J Med Chem. 2009 Aug 13;52(15):4694-715.Discovery of leukotriene A4 hydrolase inhibitors using metabolomics biased fragment crystallography.
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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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.

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