Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT7WVHI)

• DTT Name: Soluble epoxide hydrolase (EPHX2)
• Synonyms: Bifunctional epoxide hydrolase 2
• Gene Name: EPHX2
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Ether bond hydrolase
• UniProt ID: HYES_HUMAN
• TTD ID: T35734
• Sequence:
  MTLRAAVFDLDGVLALPAVFGVLGRTEEALALPRGLLNDAFQKGGPEGATTRLMKGEITL
  SQWIPLMEENCRKCSETAKVCLPKNFSIKEIFDKAISARKINRPMLQAALMLRKKGFTTA
  ILTNTWLDDRAERDGLAQLMCELKMHFDFLIESCQVGMVKPEPQIYKFLLDTLKASPSEV
  VFLDDIGANLKPARDLGMVTILVQDTDTALKELEKVTGIQLLNTPAPLPTSCNPSDMSHG
  YVTVKPRVRLHFVELGSGPAVCLCHGFPESWYSWRYQIPALAQAGYRVLAMDMKGYGESS
  APPEIEEYCMEVLCKEMVTFLDKLGLSQAVFIGHDWGGMLVWYMALFYPERVRAVASLNT
  PFIPANPNMSPLESIKANPVFDYQLYFQEPGVAEAELEQNLSRTFKSLFRASDESVLSMH
  KVCEAGGLFVNSPEEPSLSRMVTEEEIQFYVQQFKKSGFRGPLNWYRNMERNWKWACKSL
  GRKILIPALMVTAEKDFVLVPQMSQHMEDWIPHLKRGHIEDCGHWTQMDKPTEVNQILIK
  WLDSDARNPPVVSKM
• 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.
• KEGG Pathway:
  Arachidonic acid metabolism (hsa00590)
  Metabolic pathways (hsa01100)
  Peroxisome (hsa04146)
• Reactome Pathway:
  Biosynthesis of maresins (R-HSA-9018682)
  Peroxisomal protein import (R-HSA-9033241)
  Synthesis of epoxy (EET) and dihydroxyeicosatrienoic acids (DHET) (R-HSA-2142670)

Molecular Interaction Atlas (MIA) of This DTT

2 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
AR9281	DMJHA6Q	Hypertension	BA00-BA04	Phase 2	[1]
GSK2256294	DM7FN12	Chronic obstructive pulmonary disease	CA22	Phase 1	[2]

104 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
1,3-DIPHENYLUREA	DMI4H05	Discovery agent	N.A.	Investigative	[3]
1-(1-Adamantyl)-3-(1-propionylpiperidin-4-yl)urea	DM7G2AB	Discovery agent	N.A.	Investigative	[4]
1-(1-Propionylpiperidin-4-yl)-3-m-tolylurea	DMAZR9C	Discovery agent	N.A.	Investigative	[4]
1-(1-Propionylpiperidin-4-yl)-3-o-tolylurea	DMUH59X	Discovery agent	N.A.	Investigative	[4]
1-(1-Propionylpiperidin-4-yl)-3-p-tolylurea	DMWUBI4	Discovery agent	N.A.	Investigative	[4]
1-(3-(3-morpholinopropoxy)phenyl)-3-phenylurea	DM3EBFS	Discovery agent	N.A.	Investigative	[5]
1-(3-Chloro-phenyl)-3-(4-hydroxy-decyl)-urea	DMC5PI4	Discovery agent	N.A.	Investigative	[6]
1-(3-Chloro-phenyl)-3-cyclohexyl-urea	DM1VLMC	Discovery agent	N.A.	Investigative	[6]
1-(4-(3-morpholinopropoxy)phenyl)-3-phenylurea	DMYIK9W	Discovery agent	N.A.	Investigative	[5]
1-adamantan-1-yl-3-((R)-1-phenyl-ethyl)-urea	DMRJSG7	Discovery agent	N.A.	Investigative	[7]
1-adamantan-1-yl-3-(1-benzyl-piperidin-4-yl)-urea	DMNXU1O	Discovery agent	N.A.	Investigative	[8]
1-adamantan-1-yl-3-(1-butyl-piperidin-4-yl)-urea	DMAJC42	Discovery agent	N.A.	Investigative	[8]
1-adamantan-1-yl-3-(1-ethyl-piperidin-4-yl)-urea	DMY1Z2X	Discovery agent	N.A.	Investigative	[8]
1-adamantan-1-yl-3-(1-propyl-piperidin-4-yl)-urea	DM2K7TX	Discovery agent	N.A.	Investigative	[8]
1-adamantan-1-yl-3-(2-heptyloxyethyl)urea	DMRIYX9	Discovery agent	N.A.	Investigative	[9]
1-Adamantan-1-yl-3-(2-hydroxy-phenyl)-urea	DMJ8ZS6	Discovery agent	N.A.	Investigative	[10]
1-adamantan-1-yl-3-(2-hydroxyethyl)urea	DMDO9YM	Discovery agent	N.A.	Investigative	[9]
1-Adamantan-1-yl-3-(2-methoxy-phenyl)-urea	DMRBVFO	Discovery agent	N.A.	Investigative	[10]
1-adamantan-1-yl-3-(3-hexyloxypropyl)urea	DMGEXOZ	Discovery agent	N.A.	Investigative	[9]
1-Adamantan-1-yl-3-(3-hydroxy-phenyl)-urea	DM8SEJP	Discovery agent	N.A.	Investigative	[10]
1-adamantan-1-yl-3-(3-hydroxypropyl)urea	DMZX72E	Discovery agent	N.A.	Investigative	[9]
1-Adamantan-1-yl-3-(3-methoxy-phenyl)-urea	DMHAS3G	Discovery agent	N.A.	Investigative	[10]
1-Adamantan-1-yl-3-(4-hydroxy-decyl)-urea	DMHKG89	Discovery agent	N.A.	Investigative	[6]
1-Adamantan-1-yl-3-(4-hydroxy-phenyl)-urea	DMUPAR1	Discovery agent	N.A.	Investigative	[10]
1-adamantan-1-yl-3-(4-hydroxybutyl)urea	DM53G1V	Discovery agent	N.A.	Investigative	[9]
1-Adamantan-1-yl-3-(4-methoxy-phenyl)-urea	DMMBYOD	Discovery agent	N.A.	Investigative	[10]
1-adamantan-1-yl-3-(4-pentyloxybutyl)urea	DM3RE2D	Discovery agent	N.A.	Investigative	[9]
1-adamantan-1-yl-3-(4-pentyloxycylclohexyl)urea	DMUZ3OS	Discovery agent	N.A.	Investigative	[9]
1-adamantan-1-yl-3-(5-butoxypentyl)urea	DMEDQVX	Discovery agent	N.A.	Investigative	[9]
1-adamantan-1-yl-3-(5-hydroxypentyl)urea	DMV6824	Discovery agent	N.A.	Investigative	[9]
1-adamantan-1-yl-3-(6-hydroxyhexyl)urea	DMOX5MC	Discovery agent	N.A.	Investigative	[9]
1-adamantan-1-yl-3-(6-propyloxyhexyl)urea	DMO1L3I	Discovery agent	N.A.	Investigative	[9]
1-Adamantan-1-yl-3-decyl-urea	DMLD2G3	Discovery agent	N.A.	Investigative	[6]
1-Adamantan-1-yl-3-phenyl-urea	DMCFKX0	Discovery agent	N.A.	Investigative	[10]
1-adamantan-1-yl-3-piperidin-4-yl-urea	DMTNPBH	Discovery agent	N.A.	Investigative	[8]
1-adamantan-1-yl-3-piperidin-4-ylmethyl-urea	DMGPIL0	Discovery agent	N.A.	Investigative	[8]
1-adamantan-1-yl-3-[4-(4-fluorophenoxy)butyl]urea	DMXRHKQ	Discovery agent	N.A.	Investigative	[1]
1-Cycloheptyl-3-(1-propionylpiperidin-4-yl)urea	DMA2607	Discovery agent	N.A.	Investigative	[4]
1-Cyclohexyl-3-(1-propionylpiperidin-4-yl)urea	DMAZYCD	Discovery agent	N.A.	Investigative	[4]
1-Cyclohexyl-3-(4-methoxy-phenyl)-urea	DMESUD7	Discovery agent	N.A.	Investigative	[6]
1-Cyclohexyl-3-phenethyl-urea	DMH9O6V	Discovery agent	N.A.	Investigative	[6]
1-Cyclohexyl-3-phenyl-urea	DM9K8HA	Discovery agent	N.A.	Investigative	[6]
1-Octyl-3-(1-propionylpiperidin-4-yl)urea	DM9OJ7T	Discovery agent	N.A.	Investigative	[4]
1-Phenyl-3-(1-propionylpiperidin-4-yl)urea	DMCHOFK	Discovery agent	N.A.	Investigative	[4]
12-(3-Adamantan-1-yl-ureido)-dodeca noic acid	DM84YCI	Discovery agent	N.A.	Investigative	[11]
12-(3-n-Hexylureido)dodec-8(Z)-enoic acid	DM0F3SR	Discovery agent	N.A.	Investigative	[12]
12-(3-n-Pentylureidooxy)dodec-8(Z)-enoic acid	DMAFNXZ	Discovery agent	N.A.	Investigative	[12]
13-(3-n-Pentylthioureido)tridec-8(Z)-enoic Acid	DMIY9DB	Discovery agent	N.A.	Investigative	[12]
13-(3-n-Pentylureido)tridec-5(Z)-enoic acid	DM0NRJG	Discovery agent	N.A.	Investigative	[12]
13-(3-n-Pentylureido)tridec-8(E)-enoic acid	DM17DY6	Discovery agent	N.A.	Investigative	[12]
13-(3-n-Pentylureido)tridec-8-ynoic acid	DM9VDOG	Discovery agent	N.A.	Investigative	[12]
13-(3-Pentyluredo)tridec-8(Z)-enoic acid	DM3I6PS	Discovery agent	N.A.	Investigative	[12]
13-(5-n-Pentylfuran-2-yl)tridec-8(Z)-enoic acid	DM8HRTC	Discovery agent	N.A.	Investigative	[12]
13-(N-Isopropylheptanamido)tridec-8(Z)-enoic acid	DMXK6D2	Discovery agent	N.A.	Investigative	[12]
13-(N-Methyl-n-heptnamido)tridec-8(Z)-enoic acid	DM689TH	Discovery agent	N.A.	Investigative	[12]
13-(n-Pentylcarbamoyloxy)tridec-8(Z)-enoic acid	DMSF3C8	Discovery agent	N.A.	Investigative	[12]
13-n-Heptanamidotridec-5-ynoic acid	DMRVQCB	Discovery agent	N.A.	Investigative	[12]
13-n-Heptanamidotridec-8(Z)-enoic acid	DM0LGWJ	Discovery agent	N.A.	Investigative	[12]
14-(n-Hexylamino)-14-oxotetradec-8(Z)-enoic acid	DM5NFB6	Discovery agent	N.A.	Investigative	[12]
16-(3-Ethylureido)hexadec-11(Z)-enoic acid	DMCHMNF	Discovery agent	N.A.	Investigative	[12]
2-Adamantan-1-yl-N-decyl-acetamide	DMJAUH0	Discovery agent	N.A.	Investigative	[6]
2-Cyclohexyl-N-(4-methoxy-phenyl)-acetamide	DMF6PMU	Discovery agent	N.A.	Investigative	[6]
2-Cyclohexyl-N-phenethyl-acetamide	DM89CLH	Discovery agent	N.A.	Investigative	[6]
2-Cyclohexyl-N-phenyl-acetamide	DMBJUP5	Discovery agent	N.A.	Investigative	[6]
3-(3-Adamantan-1-yl-ureido)-benzoic acid	DMT0M94	Discovery agent	N.A.	Investigative	[10]
4,4-Diphenyl-N-(pyridin-3-yl)-butyramide	DMM0H9Y	Discovery agent	N.A.	Investigative	[13]
4-(3-Adamantan-1-yl-ureido)-benzoic acid	DMKUAEY	Discovery agent	N.A.	Investigative	[10]
4-(3-cyclohexylureido)butanoic acid	DMXFLMK	Discovery agent	N.A.	Investigative	[3]
6-amino-N-(2,4-dichlorobenzyl)nicotinamide	DMEHG2F	Discovery agent	N.A.	Investigative	[14]
6-amino-N-(3,3-diphenylpropyl)nicotinamide	DMYI5GU	Discovery agent	N.A.	Investigative	[14]
6-{[(CYCLOHEXYLAMINO)CARBONYL]AMINO}HEXANOIC ACID	DM1G7P9	Discovery agent	N.A.	Investigative	[3]
9-(3-n-Pentylureido)non-4(Z)-enoic acid	DMUIRS1	Discovery agent	N.A.	Investigative	[12]
9-(3-n-Pentylureido)non-4-ynoic acid	DMJYMFE	Discovery agent	N.A.	Investigative	[12]
Cis-1-adamantan-1-yl-3-(4-hydroxycyclohexyl)urea	DMP3F0D	Discovery agent	N.A.	Investigative	[1]
Cis-1-adamantan-1-yl-3-(4-methoxycyclohexyl)urea	DM8NX3Q	Discovery agent	N.A.	Investigative	[1]
Dodecanoic acid adamantan-1-ylamide	DM6TIQX	Discovery agent	N.A.	Investigative	[6]
EXRD-4605	DMY96KO	Hypertension	BA00-BA04	Investigative	[15]
Methyl 14-(3-n-butylureido)tetradec-8(Z)-enoate	DMV1AL5	Discovery agent	N.A.	Investigative	[12]
Methyl 4-(3-cyclohexylureido)butanoate	DM9S210	Discovery agent	N.A.	Investigative	[16]
Methyl 6-(3-cyclohexylureido)hexanoate	DM9BPQ1	Discovery agent	N.A.	Investigative	[16]
N,N'-dicyclohexyl-urea	DMLVMJH	Discovery agent	N.A.	Investigative	[1]
N-(3,3-Diphenyl-propyl)-2-pyridine-3-ylacetamide	DM4PTR3	Discovery agent	N.A.	Investigative	[13]
N-(3,3-Diphenyl-propyl)-isonicotinamide	DMOXR4K	Discovery agent	N.A.	Investigative	[13]
N-(3,3-diphenyl-propyl)-nicotinamide	DMDYZ9K	Discovery agent	N.A.	Investigative	[13]
N-(3-Chloro-phenyl)-2-cyclohexyl-acetamide	DME6IKT	Discovery agent	N.A.	Investigative	[6]
N-(3-Phenyl-propyl)-nicotinamide	DMA7X62	Discovery agent	N.A.	Investigative	[13]
N-(4,4-Diphenyl-butyl)-nicotinamide	DM086VJ	Discovery agent	N.A.	Investigative	[13]
N-(biphenyl-3-yl)benzo[d]isoxazol-3-amine	DM2ZQBS	Discovery agent	N.A.	Investigative	[17]
N-(biphenyl-4-yl)benzo[d]isoxazol-3-amine	DML10NT	Discovery agent	N.A.	Investigative	[17]
N-(naphthalen-1-yl)benzo[d]isoxazol-3-amine	DM2CBNG	Discovery agent	N.A.	Investigative	[17]
N-(naphthalen-2-yl)benzo[d]isoxazol-3-amine	DM2NHVX	Discovery agent	N.A.	Investigative	[17]
N-adamantyl-N'-cyclohexylurea	DMZ43N1	Discovery agent	N.A.	Investigative	[1]
N-benzyl-6-(3,3,3-trifluoropropoxy)nicotinamide	DM7NHRV	Discovery agent	N.A.	Investigative	[14]
N-Cyclohexyl-2-(4-methoxy-phenyl)-acetamide	DM8HS0B	Discovery agent	N.A.	Investigative	[6]
N-Cyclohexyl-2-phenyl-acetamide	DM15MQT	Discovery agent	N.A.	Investigative	[6]
N-Cyclohexyl-4-phenyl-butyramide	DM2COR5	Discovery agent	N.A.	Investigative	[6]
N-Cyclohexyl-N'-(4-Iodophenyl)Urea	DMPSYRW	Discovery agent	N.A.	Investigative	[18]
N-Cyclohexyl-N'-(Propyl)Phenyl Urea	DMYF243	Discovery agent	N.A.	Investigative	[3]
N-Cyclohexyl-N'-Decylurea	DM17G82	Discovery agent	N.A.	Investigative	[3]
N-[(CYCLOHEXYLAMINO)CARBONYL]GLYCINE	DMHNR36	Discovery agent	N.A.	Investigative	[3]
N-[3,3-Bis-(4-fluorophenyl)-propyl]-benzamide	DMKPYEU	Discovery agent	N.A.	Investigative	[13]
N-[3,3-Bis-(4-fluorophenyl)-propyl]-nicotinamide	DMIP8AK	Discovery agent	N.A.	Investigative	[13]
Trans,trans-1,3-bis-(4-hydroxycyclohexyl)urea	DMHD1XM	Discovery agent	N.A.	Investigative	[1]
[4-(3-Adamantan-1-yl-ureido)-phenyl]-acetic acid	DMNCAE9	Discovery agent	N.A.	Investigative	[10]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Chronic obstructive pulmonary disease	CA23	Lung tissue	8.78E-01	-0.1	-0.27
Chronic obstructive pulmonary disease	CA23	Small airway epithelium	4.40E-02	-0.18	-0.42

The Drug-Metabolizing Enzyme (DME) Role of This DTT

• DTT DME Name: Bifunctional epoxide hydrolase 2 (EPHX2) DME Info
• Gene Name: EPHX2

1 Investigative Drug(s) Metabolized by This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Myrisglycerol-phosphate	DMVMHTC	N. A.	N. A.	Investigative	[19]

References

• [1] Orally bioavailable potent soluble epoxide hydrolase inhibitors. J Med Chem. 2007 Aug 9;50(16):3825-40.
• [2] In vitro and in vivo characterization of a novel soluble epoxide hydrolase inhibitor. Prostaglandins Other Lipid Mediat. 2013 Jul-Aug;104-105:25-31.
• [3] The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
• [4] 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.
• [5] 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.
• [6] Optimization of amide-based inhibitors of soluble epoxide hydrolase with improved water solubility. J Med Chem. 2005 May 19;48(10):3621-9.
• [7] Solid-phase combinatorial approach for the optimization of soluble epoxide hydrolase inhibitors. Bioorg Med Chem Lett. 2006 Nov 15;16(22):5773-7.
• [8] Synthesis and SAR of conformationally restricted inhibitors of soluble epoxide hydrolase. Bioorg Med Chem Lett. 2006 Oct 1;16(19):5212-6.
• [9] 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.
• [10] Salicylate-urea-based soluble epoxide hydrolase inhibitors with high metabolic and chemical stabilities. Bioorg Med Chem Lett. 2009 Mar 15;19(6):1784-9.
• [11] 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.
• [12] 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.
• [13] Structure-based optimization of arylamides as inhibitors of soluble epoxide hydrolase. J Med Chem. 2009 Oct 8;52(19):5880-95.
• [14] Design and synthesis of substituted nicotinamides as inhibitors of soluble epoxide hydrolase. Bioorg Med Chem Lett. 2009 Oct 15;19(20):5864-8.
• [15] 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.
• [16] Peptidyl-urea based inhibitors of soluble epoxide hydrolases. Bioorg Med Chem Lett. 2006 Oct 15;16(20):5439-44.
• [17] 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.
• [18] How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
• [19] Role of soluble epoxide hydrolase phosphatase activity in the metabolism of lysophosphatidic acids. Biochem Biophys Res Commun. 2012 Mar 23;419(4):796-800.