sEH inhibitor | BI-1935

Target protein: 
sEH
Probe Name: 
BI-1935
In stock: 
2791

Chemical structure

2D Structure of BI1935

Highlights

BI-1935 is a potent and selective small molecule inhibitor of Soluble epoxide hydrolase (sEH). In a biochemical h-sEH binding assay it shows an IC50 of 7 nM and is also highly active in a cellular Hep G2-DHET assay format (IC50 < 1 nM). BI-1935 can also be used in vivo and showed a dose dependent effect on mean arterial pressure blood pressure in Dahl salt sensitive rats. It also shows good selectivity against hCYP epoxygenases 2J2/2C9/2C19 and IL-2.

3D structure of BI-1935

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Target information

The enzyme Soluble epoxide hydrolase (sEH) is involved in the metabolism of chemical mediators originated from arachidonic acid.2,3 sEH catalyzes the hydrolysis of epoxyeicosatrienoic acids (EETs) which is derived from oxidation of arachidonic acid by CYP2J & CYP2C to the corresponding dihydroxyeicosatrienoic acids (DHETs). Inhibition of sEH is expected to increase EETs levels and thereby potentiating in vivo pharmacological effects which include anti-inflammatory and vasodilatory properties. Selective inhibition of Soluble epoxide hydrolase has been invoked to account for the antihypertensive effect of dicyclohexyl urea in the spontaneously hypertensive rat.4,5 EETs elicit a vasodilatory response by acting as an endothelium derived hyperpolarizing factor that mediates vasodilatation through the stimulation of calcium-activated potassium channels in smooth muscle cells.6,7,8 Selective sEH inhibitors have also shown beneficial effects in an angiotensin II-dependent model of hypertension in the Sprague–Dawley rat,9 and protective action in models of hypertension induced renal damage and failure.10 An sEH inhibitor significantly decreased the total bronchoalveolar lavage cell number in tobacco smoke-exposed rats, with significant reductions noted in neutrophils, alveolar macrophages, and lymphocytes in a rat model of airway inflammation.11 These reports suggest that inhibition of sEH represents a potential method for the treatment of inflammatory and cardiovascular diseases.1

Human sEH in complex with a pyrazole agonist (PDB code: 3OTQ)

Human sEH in complex with a pyrazole agonist (PDB code: 3OTQ)

In-Vitro Activity

Probe name / Negative control

BI-1935

BI-64BS

MW [Da]

498.5

388.9

h-sEH (IC50) [nM]a

7

>100,000

r-sEH (IC50) [nM]b

7

-

sEH_HepG2 [nM]c

<1

-

sEH_RAT FPDR[nM]

7.4

-

CYP 2J2 [µM]

3

-

CYP 2C9 [µM]

1

-

CYP 2C19 [µM]

10

-

CYP 3A4 [µM]

>50

-

CYP 2D6

>50

-

IL-2 [µM]

 

-

a Human and rat soluble epoxide hydrolase inhibition

b Rat soluble epoxide hydrolase inhibition

c Cellular assay for inhibition of sEH in human Hep G2 Cells, ELISA readout

In-vitro DMPK parameters

Probe name

BI-1935

Solubility @ pH 6.8 [µg/ml]

37

CACO permeability @ pH 7.4 [*10-6 cm/s]

32

CACO efflux ratio

1

Human hepatocyte clearance [%QH] human / rat

72

43

Plasma protein binding [%] human / rat

97.7

99.1

In-vivo DMPK parameters

Molecule name

BI-1935

tmax [h]b

2.7

Cmax [µM]b

3.6

AUC0–inf [nMh]b

30582

F [%]b

85

CL [ml/min/kg]a

2.9

Vss [l/kg]a

0.5

MRT [h]

3

AUC0–inf [nMh]a

14463

Pharmacokinetic parameters of BI-1935 in rats:

aiv (1.2 mg/kg)

bpo fasted (3 mg/kg)

Negative control

The molecule BI-64BS can be used as in vitro negative control (IC50 h-sEH = >100 µM)

BI-64BS, negative control

BI-64BS, negative control

Selectivity

A Boehringer Ingelheim in-house screen of BI-1935 against hCYP epoxygenases 2J2/2C9/2C19 and IL-2 showed >100fold selectivity (> 1µM for all).
A Eurofins-Panlabs® panel was measured against 67 targets (please refer to supplementary data). 61/67 < 20% Inhibition @ 10 µM, 5/67 < 80% Inhibition @ 10 µM, Thromboxane Synthase 96% inhibition @ 10 µM (IC50 = 0.132 µM). 5LO (5-Lipoxygenase) 66% inhibition @ 10 µM (IC50 = 5.92 µM).

Molecule name

BI-1935

Cerep®

No

Eurofins-Panlabs®

Yes

Invitrogen®

No

DiscoverX®

No

Dundee

No

Download selectivity data: 

reference molecules

For a review on sEH inhibitors please refer to reference 12

Summary

BI-1935 is a potent and selective small molecule inhibitor of Soluble epoxide hydrolase (sEH). In a biochemical binding assay h-sEH it shows an IC50 of 7 nM and is also highly active in a cellular Hep G2-DHET assay format (IC50 < 1 nM).

Supplementary data

References

  1. Design and synthesis of substituted nicotinamides as inhibitors of soluble epoxide hydrolase

    Steven J. Taylor, Fariba Soleymanzadeh, Anne B. Eldrup, Neil A. Farrow, Ingo Muegge, Alison Kukulka, Alisa K. Kabcenell, Stephane De Lombaert

    Bioorg. Med. Lett. 2009, 19, 5864-5868.

  2. Cytochrome P450 and Vasular Homeostasis

    Ingrid Fleming

    Circ. Res. 2001, 89, 753-762.

  3. Action of epoxyeicosatrienoic acids on cellular function

    Arthur A. Spector, Andrew W. Norris
    Am. J. Physiol. Cell Physiol. 2007, 292, C996-1012.

  4. Soluble Epoxide Hydrolase Regulates Hydrolysis of Vasoactive Epoxyeicosatrienoic Acids

    Zhigang Yu, Fengyun Xu, Linn M. Huse, Christophe Morisseau, Alison J. Draper, John W. Newman, Carol Parker, LeRae Graham, Marguerite M. Engler, Bruce D. Hammock, Darryl C. Zeldin, Deanna L. Kroetz

    Circ. Res. 2000, 24, 992-998.

  5. Cardiovascular Therapeutic Aspects of Soluble Epoxide Hydrolase Inhibitors

    John D. Imig
    Cardiovasc. Drug Rev. 2006, 24, 169-88.

  6. Epoxyeicosatrienoic acids (EETs): metabolism and biochemical function

    Athur A. Spector, Xiang Fang, Gary D. Snyder, Neal L. Weintraub

    Prog. Lipid Res. 2004, 43, 55-90.

  7. Epoxyeicosatrienoic and dihydroxyeicosatrienoic acids dilate human coronary arterioles via BK(Ca) channels: implications for soluble epoxide hydrolase inhibition

    Brandon T. Larsen, Hiroto Miura, Ossama A. Hatoum, William B. Campbell, Bruce D. Hammock, Darryl C. Zeldin, John R. Falck, David D. Gutterman
    Am. J. Physiol. Heart Circ. Physiol. 2006, 290, H491-499.

  8. Seubert Epoxyeicosatrienoic acid prevents postischemic electrocardiogram abnormalities in an isolated heart model

    S.N. Batchu, E. Law, D.R. Brocks, J.R. Falck, J.M

    J. Mol. Cell. Cardiol. 2009, 46, 67-74.

  9. Soluble Epoxide Hydrolase Inhibition Lowers Arterial Blood Pressure in Angiotensin II Hypertension

    John D. Imig, Xueying Zhao, Jorge H. Capdevila, Christophe Morisseau, Bruce D. Hammock
    Hypertension 2002, 39, 690-694.

  10. Soluble Epoxide Hydrolase Inhibition Protects the Kidney from Hypertension-Induced Damage

    Xueying Zhao, Tatsuo Yamamoto, John W. Newman, In-Hae Kim, Takaho Watanabe, Bruce D. Hammock, Janet Stewart, Jennifer S. Pollock, David M. Pollock, John D. Imig
    J. Am. Soc. Nephrol. 2004, 15, 1244-1253.

  11. Attenuation of tobacco smoke-induced lung inflammation by treatment with a soluble epoxide hydrolase inhibitor

    Kevin R. Smith, Kent E. Pinkerton, Takaho Watanabe, Theresa L. Pedersen, Seung Jin Ma, and Bruce D. Hammock
    Proc. Natl. Acad. Sci. U S A. 2005, 102, 2186-2191.

  12. Soluble epoxide hydrolase inhibitors: a patent review

    Hong C. Shen
    Expert Opin. Ther. Pat. 2010, 20, 941-956.