Target Information

Target General Information

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Target ID

T35734 (Former ID: TTDR01203)

Target Name

Soluble epoxide hydrolase (EPHX2)

Synonyms

Bifunctional epoxide hydrolase 2

Gene Name

EPHX2

Target Type

Clinical trial target

[1]

Disease

[+] 2 Target-related Diseases

Hypertension [ICD-11: BA00-BA04]

Chronic obstructive pulmonary disease [ICD-11: CA22]

Function

Bifunctional enzyme. The C-terminal domain has epoxide hydrolase activity and acts on epoxides (alkene oxides, oxiranes) and arene oxides. Plays a role in xenobiotic metabolism by degrading potentially toxic epoxides (By similarity). Also determines steady-state levels of physiological mediators. The N-terminal domain has lipid phosphatase activity, with the highest activity towards threo-9,10-phosphonooxy-hydroxy-octadecanoic acid, followed by erythro-9,10-phosphonooxy-hydroxy-octadecanoic acid, 12-phosphonooxy-octadec-9Z-enoic acid and 12-phosphonooxy-octadec-9E-enoic acid.

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BioChemical Class

Ether bond hydrolase

UniProt ID

HYES_HUMAN

Sequence

MTLRAAVFDLDGVLALPAVFGVLGRTEEALALPRGLLNDAFQKGGPEGATTRLMKGEITL
SQWIPLMEENCRKCSETAKVCLPKNFSIKEIFDKAISARKINRPMLQAALMLRKKGFTTA
ILTNTWLDDRAERDGLAQLMCELKMHFDFLIESCQVGMVKPEPQIYKFLLDTLKASPSEV
VFLDDIGANLKPARDLGMVTILVQDTDTALKELEKVTGIQLLNTPAPLPTSCNPSDMSHG
YVTVKPRVRLHFVELGSGPAVCLCHGFPESWYSWRYQIPALAQAGYRVLAMDMKGYGESS
APPEIEEYCMEVLCKEMVTFLDKLGLSQAVFIGHDWGGMLVWYMALFYPERVRAVASLNT
PFIPANPNMSPLESIKANPVFDYQLYFQEPGVAEAELEQNLSRTFKSLFRASDESVLSMH
KVCEAGGLFVNSPEEPSLSRMVTEEEIQFYVQQFKKSGFRGPLNWYRNMERNWKWACKSL
GRKILIPALMVTAEKDFVLVPQMSQHMEDWIPHLKRGHIEDCGHWTQMDKPTEVNQILIK
WLDSDARNPPVVSKM

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3D Structure

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PDB

ADReCS ID

BADD_A01328 ; BADD_A04278

HIT2.0 ID

T63YQM

Drugs and Modes of Action

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Clinical Trial Drug(s)

[+] 2 Clinical Trial Drugs

AR9281

Drug Info

Phase 2

Hypertension

[2]

GSK2256294

Drug Info

Phase 1

Chronic obstructive pulmonary disease

[3]

Mode of Action

[+] 2 Modes of Action

Inhibitor

[+] 105 Inhibitor drugs

AR9281

Drug Info

[1]

1,3-DIPHENYLUREA

Drug Info

[5]

1-(1-Adamantyl)-3-(1-propionylpiperidin-4-yl)urea

Drug Info

[6]

1-(1-Propionylpiperidin-4-yl)-3-m-tolylurea

Drug Info

[6]

1-(1-Propionylpiperidin-4-yl)-3-o-tolylurea

Drug Info

[6]

1-(1-Propionylpiperidin-4-yl)-3-p-tolylurea

Drug Info

[6]

1-(3-(3-morpholinopropoxy)phenyl)-3-phenylurea

Drug Info

[7]

1-(3-Chloro-phenyl)-3-(4-hydroxy-decyl)-urea

Drug Info

[8]

1-(3-Chloro-phenyl)-3-cyclohexyl-urea

Drug Info

[8]

1-(4-(3-morpholinopropoxy)phenyl)-3-phenylurea

Drug Info

[7]

1-adamantan-1-yl-3-((R)-1-phenyl-ethyl)-urea

Drug Info

[9]

1-adamantan-1-yl-3-(1-benzyl-piperidin-4-yl)-urea

Drug Info

[10]

1-adamantan-1-yl-3-(1-butyl-piperidin-4-yl)-urea

Drug Info

[10]

1-adamantan-1-yl-3-(1-ethyl-piperidin-4-yl)-urea

Drug Info

[10]

1-adamantan-1-yl-3-(1-propyl-piperidin-4-yl)-urea

Drug Info

[10]

1-adamantan-1-yl-3-(2-heptyloxyethyl)urea

Drug Info

[11]

1-Adamantan-1-yl-3-(2-hydroxy-phenyl)-urea

Drug Info

[12]

1-adamantan-1-yl-3-(2-hydroxyethyl)urea

Drug Info

[11]

1-Adamantan-1-yl-3-(2-methoxy-phenyl)-urea

Drug Info

[12]

1-adamantan-1-yl-3-(3-hexyloxypropyl)urea

Drug Info

[11]

1-Adamantan-1-yl-3-(3-hydroxy-phenyl)-urea

Drug Info

[12]

1-adamantan-1-yl-3-(3-hydroxypropyl)urea

Drug Info

[11]

1-Adamantan-1-yl-3-(3-methoxy-phenyl)-urea

Drug Info

[12]

1-Adamantan-1-yl-3-(4-hydroxy-decyl)-urea

Drug Info

[8]

1-Adamantan-1-yl-3-(4-hydroxy-phenyl)-urea

Drug Info

[12]

1-adamantan-1-yl-3-(4-hydroxybutyl)urea

Drug Info

[11]

1-Adamantan-1-yl-3-(4-methoxy-phenyl)-urea

Drug Info

[12]

1-adamantan-1-yl-3-(4-pentyloxybutyl)urea

Drug Info

[11]

1-adamantan-1-yl-3-(4-pentyloxycylclohexyl)urea

Drug Info

[11]

1-adamantan-1-yl-3-(5-butoxypentyl)urea

Drug Info

[11]

1-adamantan-1-yl-3-(5-hydroxypentyl)urea

Drug Info

[11]

1-adamantan-1-yl-3-(6-hydroxyhexyl)urea

Drug Info

[11]

1-adamantan-1-yl-3-(6-propyloxyhexyl)urea

Drug Info

[11]

1-Adamantan-1-yl-3-decyl-urea

Drug Info

[8]

1-Adamantan-1-yl-3-phenyl-urea

Drug Info

[12]

1-adamantan-1-yl-3-piperidin-4-yl-urea

Drug Info

[10]

1-adamantan-1-yl-3-piperidin-4-ylmethyl-urea

Drug Info

[10]

1-adamantan-1-yl-3-[4-(4-fluorophenoxy)butyl]urea

Drug Info

[1]

1-Cycloheptyl-3-(1-propionylpiperidin-4-yl)urea

Drug Info

[6]

1-Cyclohexyl-3-(1-propionylpiperidin-4-yl)urea

Drug Info

[6]

1-Cyclohexyl-3-(4-methoxy-phenyl)-urea

Drug Info

[8]

1-Cyclohexyl-3-phenethyl-urea

Drug Info

[8]

1-Cyclohexyl-3-phenyl-urea

Drug Info

[8]

1-Octyl-3-(1-propionylpiperidin-4-yl)urea

Drug Info

[6]

1-Phenyl-3-(1-propionylpiperidin-4-yl)urea

Drug Info

[6]

12-(3-Adamantan-1-yl-ureido)-dodeca noic acid

Drug Info

[13]

12-(3-n-Hexylureido)dodec-8(Z)-enoic acid

Drug Info

[14]

12-(3-n-Pentylureidooxy)dodec-8(Z)-enoic acid

Drug Info

[14]

13-(3-n-Pentylthioureido)tridec-8(Z)-enoic Acid

Drug Info

[14]

13-(3-n-Pentylureido)tridec-5(Z)-enoic acid

Drug Info

[14]

13-(3-n-Pentylureido)tridec-8(E)-enoic acid

Drug Info

[14]

13-(3-n-Pentylureido)tridec-8-ynoic acid

Drug Info

[14]

13-(3-Pentyluredo)tridec-8(Z)-enoic acid

Drug Info

[14]

13-(5-n-Pentylfuran-2-yl)tridec-8(Z)-enoic acid

Drug Info

[14]

13-(N-Isopropylheptanamido)tridec-8(Z)-enoic acid

Drug Info

[14]

13-(N-Methyl-n-heptnamido)tridec-8(Z)-enoic acid

Drug Info

[14]

13-(n-Pentylcarbamoyloxy)tridec-8(Z)-enoic acid

Drug Info

[14]

13-n-Heptanamidotridec-5-ynoic acid

Drug Info

[14]

13-n-Heptanamidotridec-8(Z)-enoic acid

Drug Info

[14]

14-(n-Hexylamino)-14-oxotetradec-8(Z)-enoic acid

Drug Info

[14]

16-(3-Ethylureido)hexadec-11(Z)-enoic acid

Drug Info

[14]

2-Adamantan-1-yl-N-decyl-acetamide

Drug Info

[8]

2-Cyclohexyl-N-(4-methoxy-phenyl)-acetamide

Drug Info

[8]

2-Cyclohexyl-N-phenethyl-acetamide

Drug Info

[8]

2-Cyclohexyl-N-phenyl-acetamide

Drug Info

[8]

3-(3-Adamantan-1-yl-ureido)-benzoic acid

Drug Info

[12]

4,4-Diphenyl-N-(pyridin-3-yl)-butyramide

Drug Info

[15]

4-(3-Adamantan-1-yl-ureido)-benzoic acid

Drug Info

[12]

4-(3-cyclohexylureido)butanoic acid

Drug Info

[5], [16]

6-amino-N-(2,4-dichlorobenzyl)nicotinamide

Drug Info

[17]

6-amino-N-(3,3-diphenylpropyl)nicotinamide

Drug Info

[17]

6-{[(CYCLOHEXYLAMINO)CARBONYL]AMINO}HEXANOIC ACID

Drug Info

[5]

9-(3-n-Pentylureido)non-4(Z)-enoic acid

Drug Info

[14]

9-(3-n-Pentylureido)non-4-ynoic acid

Drug Info

[14]

Cis-1-adamantan-1-yl-3-(4-hydroxycyclohexyl)urea

Drug Info

[1]

Cis-1-adamantan-1-yl-3-(4-methoxycyclohexyl)urea

Drug Info

[1]

Dodecanoic acid adamantan-1-ylamide

Drug Info

[8]

EXRD-4605

Drug Info

[3]

Methyl 14-(3-n-butylureido)tetradec-8(Z)-enoate

Drug Info

[14]

Methyl 4-(3-cyclohexylureido)butanoate

Drug Info

[16]

Methyl 6-(3-cyclohexylureido)hexanoate

Drug Info

[16]

N,N'-dicyclohexyl-urea

Drug Info

[1]

N-(3,3-Diphenyl-propyl)-2-pyridine-3-ylacetamide

Drug Info

[15]

N-(3,3-Diphenyl-propyl)-isonicotinamide

Drug Info

[15]

N-(3,3-diphenyl-propyl)-nicotinamide

Drug Info

[15]

N-(3-Chloro-phenyl)-2-cyclohexyl-acetamide

Drug Info

[8]

N-(3-Phenyl-propyl)-nicotinamide

Drug Info

[15]

N-(4,4-Diphenyl-butyl)-nicotinamide

Drug Info

[15]

N-(biphenyl-3-yl)benzo[d]isoxazol-3-amine

Drug Info

[18]

N-(biphenyl-4-yl)benzo[d]isoxazol-3-amine

Drug Info

[18]

N-(naphthalen-1-yl)benzo[d]isoxazol-3-amine

Drug Info

[18]

N-(naphthalen-2-yl)benzo[d]isoxazol-3-amine

Drug Info

[18]

N-adamantyl-N'-cyclohexylurea

Drug Info

[1]

N-benzyl-6-(3,3,3-trifluoropropoxy)nicotinamide

Drug Info

[17]

N-Cyclohexyl-2-(4-methoxy-phenyl)-acetamide

Drug Info

[8]

N-Cyclohexyl-2-phenyl-acetamide

Drug Info

[8]

N-Cyclohexyl-4-phenyl-butyramide

Drug Info

[8]

N-Cyclohexyl-N'-(4-Iodophenyl)Urea

Drug Info

[19]

N-Cyclohexyl-N'-(Propyl)Phenyl Urea

Drug Info

[5]

100

N-Cyclohexyl-N'-Decylurea

Drug Info

[5]

101

N-[(CYCLOHEXYLAMINO)CARBONYL]GLYCINE

Drug Info

[5]

102

N-[3,3-Bis-(4-fluorophenyl)-propyl]-benzamide

Drug Info

[15]

103

N-[3,3-Bis-(4-fluorophenyl)-propyl]-nicotinamide

Drug Info

[15]

104

Trans,trans-1,3-bis-(4-hydroxycyclohexyl)urea

Drug Info

[1]

105

[4-(3-Adamantan-1-yl-ureido)-phenyl]-acetic acid

Drug Info

[12]

Modulator

[+] 1 Modulator drugs

GSK2256294

Drug Info

[3], [4]

Chemical Structure based Activity Landscape of Target

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Drug Property Profile of Target

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(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five

Co-Targets

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Co-Targets

Co-Targets Info

Target Poor or Non Binders

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Target Poor or Non Binders

Target Poor or Non Binders Info

Target Regulators

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Target-interacting Proteins

Target-interacting Proteins Info

Target Profiles in Patients

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Target Expression
Profile (TEP)

Target Expression Profile Info

Target Affiliated Biological Pathways

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KEGG Pathway

[+] 3 KEGG Pathways

Arachidonic acid metabolism

Metabolic pathways

Peroxisome

Pathwhiz Pathway

[+] 1 Pathwhiz Pathways

Arachidonic Acid Metabolism

WikiPathways

[+] 3 WikiPathways

Metapathway biotransformation

Arachidonate Epoxygenase / Epoxide Hydrolase

Arachidonic acid metabolism

Target-Related Models and Studies

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Target Validation

Target Validation Info

References

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REF 1

Orally bioavailable potent soluble epoxide hydrolase inhibitors. J Med Chem. 2007 Aug 9;50(16):3825-40.

REF 2

ClinicalTrials.gov (NCT00847899) Evaluation of Soluble Epoxide Hydrolase (s-EH) Inhibitor in Patients With Mild to Moderate Hypertension and Impaired Glucose Tolerance. U.S. National Institutes of Health.

REF 3

Soluble epoxide hydrolase inhibition does not prevent cardiac remodeling and dysfunction after aortic constriction in rats and mice. J Cardiovasc Pharmacol. 2013 Apr;61(4):291-301.

REF 4

In vitro and in vivo characterization of a novel soluble epoxide hydrolase inhibitor. Prostaglandins Other Lipid Mediat. 2013 Jul-Aug;104-105:25-31.

REF 5

The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.

REF 6

1-Aryl-3-(1-acylpiperidin-4-yl)urea inhibitors of human and murine soluble epoxide hydrolase: structure-activity relationships, pharmacokinetics, a... J Med Chem. 2010 Oct 14;53(19):7067-75.

REF 7

Unsymmetrical non-adamantyl N,N'-diaryl urea and amide inhibitors of soluble expoxide hydrolase. Bioorg Med Chem Lett. 2009 Aug 1;19(15):4259-63.

REF 8

Optimization of amide-based inhibitors of soluble epoxide hydrolase with improved water solubility. J Med Chem. 2005 May 19;48(10):3621-9.

REF 9

Solid-phase combinatorial approach for the optimization of soluble epoxide hydrolase inhibitors. Bioorg Med Chem Lett. 2006 Nov 15;16(22):5773-7.

REF 10

Synthesis and SAR of conformationally restricted inhibitors of soluble epoxide hydrolase. Bioorg Med Chem Lett. 2006 Oct 1;16(19):5212-6.

REF 11

1,3-disubstituted ureas functionalized with ether groups are potent inhibitors of the soluble epoxide hydrolase with improved pharmacokinetic prope... J Med Chem. 2007 Oct 18;50(21):5217-26.

REF 12

Salicylate-urea-based soluble epoxide hydrolase inhibitors with high metabolic and chemical stabilities. Bioorg Med Chem Lett. 2009 Mar 15;19(6):1784-9.

REF 13

Discovery of a highly potent, selective, and bioavailable soluble epoxide hydrolase inhibitor with excellent ex vivo target engagement. J Med Chem. 2009 Aug 27;52(16):5009-12.

REF 14

14,15-Epoxyeicosa-5,8,11-trienoic acid (14,15-EET) surrogates containing epoxide bioisosteres: influence upon vascular relaxation and soluble epoxi... J Med Chem. 2009 Aug 27;52(16):5069-75.

REF 15

Structure-based optimization of arylamides as inhibitors of soluble epoxide hydrolase. J Med Chem. 2009 Oct 8;52(19):5880-95.

REF 16

Peptidyl-urea based inhibitors of soluble epoxide hydrolases. Bioorg Med Chem Lett. 2006 Oct 15;16(20):5439-44.

REF 17

Design and synthesis of substituted nicotinamides as inhibitors of soluble epoxide hydrolase. Bioorg Med Chem Lett. 2009 Oct 15;19(20):5864-8.

REF 18

A strategy of employing aminoheterocycles as amide mimics to identify novel, potent and bioavailable soluble epoxide hydrolase inhibitors. Bioorg Med Chem Lett. 2009 Oct 1;19(19):5716-21.

REF 19

How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.

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