GSK-2256294

Investigational

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C21H24F3N7O
Molecular Weight	447.4568
Optical Activity	UNSPECIFIED
Defined Stereocenters	2 / 2
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

CNC1=NC(N[C@H]2CCC[C@H](C2)C(=O)NCC3=CC=C(C=C3C(F)(F)F)C#N)=NC(C)=N1

InChI

InChIKey=LQHDJQIMETZMPH-ZBFHGGJFSA-N

InChI=1S/C21H24F3N7O/c1-12-28-19(26-2)31-20(29-12)30-16-5-3-4-14(9-16)18(32)27-11-15-7-6-13(10-25)8-17(15)21(22,23)24/h6-8,14,16H,3-5,9,11H2,1-2H3,(H,27,32)(H2,26,28,29,30,31)/t14-,16+/m1/s1

HIDE SMILES / InChI

Molecular Formula	C21H24F3N7O
Molecular Weight	447.4568
Charge	0
Count	MOL RATIO 1 MOL RATIO (average)

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	2 / 2
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description

GSK-2256294 is a potent, reversible, tight binding inhibitor of isolated recombinant human sEH (soluble epoxide hydrolase) (IC50 = 27 pM; t1/2 = 121 min) and displays potent inhibition against the rat (IC50 = 61 pM) and murine (IC50 = 189 pM) orthologs of sEH. GSK-2256294A also displays potent cellular inhibition (IC50 = 0.66 nM) of sEH in an assay developed using a cell line transfected with the human sEH enzyme. GSK-2256294 was well-tolerated and demonstrated sustained inhibition of sEH enzyme activity. These data support further investigation in patients with endothelial dysfunction or abnormal tissue repair, such as diabetes, wound healing or COPD. GSK-2256294 is in phase I clinical trials for the treatment of COPD.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Epoxide hydratase 4	Inhibitor 8,297		27.0 pM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Pulmonary disease, chronic obstructive 3	Primary		Phase I 428	Unknown

C_max

Value	Dose	Analyte	Population
1223 ng/mL	20 mg single, oral	GSK-2256294 plasma	Homo sapiens
1455 ng/mL	18 mg 1 times / day multiple, oral	GSK-2256294 plasma	Homo sapiens
321 ng/mL	6 mg single, oral	GSK-2256294 plasma	Homo sapiens
559 ng/mL	10 mg single, oral	GSK-2256294 plasma	Homo sapiens
689 ng/mL	6 mg 1 times / day multiple, oral	GSK-2256294 plasma	Homo sapiens
836 ng/mL	12 mg single, oral	GSK-2256294 plasma	Homo sapiens

AUC

Value	Dose	Analyte	Population
11464 ng × h/mL	20 mg single, oral	GSK-2256294 plasma	Homo sapiens
15774 ng × h/mL	18 mg 1 times / day multiple, oral	GSK-2256294 plasma	Homo sapiens
2741 ng × h/mL	6 mg single, oral	GSK-2256294 plasma	Homo sapiens
5267 ng × h/mL	10 mg single, oral	GSK-2256294 plasma	Homo sapiens
5801 ng × h/mL	6 mg 1 times / day multiple, oral	GSK-2256294 plasma	Homo sapiens
6680 ng × h/mL	12 mg single, oral	GSK-2256294 plasma	Homo sapiens

T_1/2

Value	Dose	Analyte	Population
41.4 h	20 mg single, oral	GSK-2256294 plasma	Homo sapiens
25 h	6 mg single, oral	GSK-2256294 plasma	Homo sapiens
42.7 h	10 mg single, oral	GSK-2256294 plasma	Homo sapiens
19.3 h	12 mg single, oral	GSK-2256294 plasma	Homo sapiens

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 1,587	inhibitor 1,767	inhibitor 1,852

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
	P-gp 1,537

Drug as perpetrator

Show entries

Target	Modality	Activity
CYP2D6 1,891	inhibitor 3,277	inconclusive [IC50 21.3174 uM]
CYP2C9 1,819	inhibitor 3,277	no
CYP3A4 1,925	inhibitor 3,277	yes [IC50 9.5221 uM]

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Drug as victim

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Target	Modality	Activity	Metabolite	Clinical evidence
P-gp 1,537	substrate 3,367	no

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Sourcing

Sourcing

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Vendor/Aggregator	ID	URL
001 Chemical	DY34458	https://www.001chemical.com/chem/search?q=DY34458
1PlusChem LLC	1P008U49	https://www.1pchem.com/search?query=1P008U49
Axon MedChem	2220	https://www.axonmedchem.com/product/2220
BLD Pharm	BD629930	http://www.bldpharm.com/search/Search.html?keyword=BD629930
Chem Scene	CS-5395	http://www.chemscene.com/goproductList/searchProductList?productObj=CS-5395

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PubMed

Title	Date	PubMed
No data available in table

Patents

Sample Use Guides

In Vivo Use Guide

GSK-2256294 capsules will be administered as once daily as single dose 2 mg, 6 mg, 15 mg in Cohort 1 and 15 mg, 40 mg, 100 mg in Cohort 2. GSK-2256294 capsules will be administered once or twice daily (cohorts 3 and 4) at the dose determined from the data from Cohort 1 and 2.

Route of Administration: Oral

In Vitro Use Guide

GSK-2256294 displays potent cellular inhibition (IC50 = 0.66 nM) of sEH in an assay developed using HEK-293 cells transfected with the human sEH enzyme.

Substance Class	Chemical
Record UNII	L33EX3XR0T
Record Status	`Validated (UNII)`
Record Version

Show entries

Name

Type

Language

GSK-2256294

Code

English

CYCLOHEXANECARBOXAMIDE, N-((4-CYANO-2-(TRIFLUOROMETHYL)PHENYL)METHYL)-3-((4-METHYL-6-(METHYLAMINO)-1,3,5-TRIAZIN-2-YL)AMINO)-, (1R,3S)-

Systematic Name

English

GSK2256294

Code

English

GSK-2256294A

Code

English

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Code System

Code

Type

Description

CAS

1142090-23-0

PRIMARY

PUBCHEM

59448236

PRIMARY

SMS_ID

300000042357

PRIMARY

FDA UNII

L33EX3XR0T

PRIMARY

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Related Record

Type

Details


					JEH09DQZ6V

BIFUNCTIONAL EPOXIDE HYDROLASE 2

TARGET -> INHIBITOR

Amount:

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Related Record

Type

Details


					L33EX3XR0T

GSK-2256294

ACTIVE MOIETY

Amount:

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SMILES

InChI

Originator

Approval Year

Targets

Conditions

Cmax

AUC

T1/2

Overview

OverviewOther

Drug as perpetrator​

Drug as victim

Sourcing

PubMed

Patents

Sample Use Guides

C_max

T_1/2

Drug as perpetrator