Therapeutic Targets Database
BIDD Pharmainformatics Databases


Target Validation Information
Target NameLeukotriene A-4 hydrolase    
Type of TargetClinical trial target    
Drug Potency against TargetDG051K(d) = 26 nM[1]
1-(4-Phenoxyphenyl)piperazineIC50 = 1.4 nM[1]
(R/S)-2-((4-benzylphenoxy)methyl)piperidineIC50 = 105 nM[2]
N4-[4-(Phenylmethoxy)phenyl]-L-aspartamineIC50 = 1100 nM[3]
2-(7-(benzyloxy)-1H-indol-3-yl)ethanamineIC50 = 12500 nM[4]
(R)-2-((4-phenoxyphenoxy)methyl)piperidineIC50 = 126 nM[2]
N5-[4-(4-methylphenoxy)phenyl]-L-glutamamideIC50 = 13 nM[3]
N5-[4-(3-methylphenoxy)phenyl]-L-glutamamideIC50 = 150 nM[3]
N5-[4-(Phenylmethoxy)phenyl]-D-glutamineIC50 = 1600 nM[3]
N5-[4-(2-Oxo-3-phenylpropoxy)phenyl]-L-glutamineIC50 = 18 nM[3]
N5-(4-Phenoxyphenyl)-L-glutamineIC50 = 19 nM[3]
N5-[4-(Phenylmethoxy)phenyl]-L-glutamineIC50 = 20 nM[3]
(R/S)-2-((4-phenoxyphenoxy)methyl)piperidineIC50 = 207 nM[2]
(R)-N-benzyl-4-(pyrrolidin-2-ylmethoxy)anilineIC50 = 207 nM[5]
4S-4,5-Diamino-N-(4-phenoxyphenyl)pentanamideIC50 = 21 nM[3]
N5-[4-Benzylphenyl]-L-glutamamideIC50 = 21 nM[3]
N5-[4-(N-Phenylamino)phenyl]-L-glutamineIC50 = 210 nM[3]
2-(4-phenoxyphenoxy)ethanamineIC50 = 228 nM[6]
N5-[4-(Phenylmethoxy)phenyl]-L-glutamamideIC50 = 23 nM[3]
2-(4-Piperidin-1-ylmethylphenoxy)benzothiazoleIC50 = 230 nM[7]
4-(4-(pentyloxy)phenoxy)phenolIC50 = 2480 nM[6]
1-[4-(Benzothiazol-2-yloxy)benzyl]piperidin-4-olIC50 = 250 nM[7]
N5-[(4-Phenoxy)-3-pyridyl]-L-glutamamideIC50 = 2600 nM[3]
SA-6541IC50 = 270 nM[8]
2-Amino-N-[4-(phenylmethoxy)phenyl]-acetamideIC50 = 280 nM[3]
2-[4-(2-Piperidin-1-ylethyl)phenoxy]benzothiazoleIC50 = 280 nM[7]
N5-[4-(2-methylphenoxy)phenyl]-L-glutamamideIC50 = 2800 nM[3]
(S)-2-((4-phenoxyphenoxy)methyl)piperidineIC50 = 286 nM[2]
N5-[4-(4-(3-Furyl)phenoxy)phenyl]-L-glutamamideIC50 = 29 nM[3]
8(S)-amino-2(R)-methyl-7-oxononanoic acidIC50 = 300 nM[9]
N5-[4-(3-Phenylpropoxy)phenyl]-L-glutamineIC50 = 31 nM[3]
1-[4-(4-Iodophenoxy)phenyl]piperazineIC50 = 340 nM[1]
(R/S)-2-((4-benzylphenoxy)methyl)piperazineIC50 = 342 nM[2]
2-[4-(2-Azepan-1-ylethoxy)phenoxy]benzooxazoleIC50 = 4 nM[7]
1-(pentyloxy)-4-phenoxybenzeneIC50 = 4130 nM[6]
(R)-2-(4-Benzylphenoxymethyl)pyrrolidineIC50 = 449 nM[1]
N5-[4-(2-phenylethoxy)phenyl]-L-glutamineIC50 = 46 nM[3]
JNJ-10392980IC50 = 51 nM[7]
N1-[4-(Phenylmethoxy)phenyl]-L-aspartamineIC50 = 5400 nM[3]
4-(4-butoxyphenoxy)phenolIC50 = 5560 nM[6]
4-(4-propoxyphenoxy)phenolIC50 = 5690 nM[6]
1-butoxy-4-phenoxybenzeneIC50 = 5720 nM[6]
2-[4-(2-Morpholin-4-ylethoxy)phenoxy]benzooxazoleIC50 = 58 nM[7]
N6-[4-(4-methylphenoxy)phenyl]-L-homoglutamineIC50 = 6 nM[3]
(R)-2-((4-benzylphenoxy)methyl)piperidineIC50 = 60 nM[2]
4-Amino-N-[4-(phenylmethoxy)phenyl]butanamideIC50 = 61 nM[3]
2-[4-(2-Azepan-1-ylethoxy)phenoxy]benzothiazoleIC50 = 66 nM[7]
N1-[4-(Phenylmethoxy)phenyl]-L-glutamineIC50 = 680 nM[3]
N1-[4-(Phenylmethoxy)phenyl]-D-glutamineIC50 = 7200 nM[3]
4-[2-(4-Benzylphenoxy)ethyl]pyridineIC50 = 8.7 nM[1]
2-(4-benzylphenoxy)ethanamineIC50 = 9 nM[6]
N1-[4-(Phenylmethoxy)phenyl]-D-aspartamineIC50 = 9300 nM[3]
N5-[4-(1H-pyrrol-1-yl)phenyl]-L-glutamamideIC50 = 9700 nM[3]
(4-(thiophen-2-yl)phenyl)methanamineIC50 = 98 nM[1]
Action against Disease ModelDG051In 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).[1]
The Effect of Target Knockout, Knockdown or Genetic VariationsLeukotriene 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[10]
Ref 1J 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. To Reference
Ref 2Bioorg 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. To Reference
Ref 3Bioorg 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. To Reference
Ref 4J Med Chem. 2008 Dec 25;51(24):7882-8.Discovery of multitarget inhibitors by combining molecular docking with common pharmacophore matching. To Reference
Ref 5J Med Chem. 2009 Aug 13;52(15):4694-715.Discovery of leukotriene A4 hydrolase inhibitors using metabolomics biased fragment crystallography. To Reference
Ref 6Bioorg 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. To Reference
Ref 7J 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. To Reference
Ref 8Bioorg 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. To Reference
Ref 9J 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. To Reference
Ref 10J Immunol. 2010 Nov 1;185(9):5503-11. Epub 2010 Sep 27.Joint tissues amplify inflammation and alter their invasive behavior via leukotriene B4 in experimental inflammatory arthritis. To Reference


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