sEH inhibitor | BI-1935

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Target protein: 
sEH
Probe Name: 
BI-1935
MOLECULAR WEIGHT [DA]: 
498.5
In stock: 
7390

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.

 

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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 1 / Negative control 2

BI-1935

BI-2049

MW [Da]

498.5

503.5

h-sEH (IC50) [nM]a

7

>3,000

r-sEH (IC50) [nM]b

7

>3,000

sEH_HepG2 [nM]c

<1

n.d.

sEH_RAT FPDR[nM]

7.4

>3,000

CYP 2J2 [µM]

3

5

CYP 2C9 [µM]

1

>20

CYP 2C19 [µM]

10

>30

CYP 3A4 [µM]

>50

>30

CYP 2D6 [µM]

>50

>30

aHuman and rat soluble epoxide hydrolase inhibition

bRat soluble epoxide hydrolase inhibition

cCellular 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 vitro DMPK and CMC parameters

Probe name / Negative control 2

BI-1935

BI-2049

Aqueous solubility @ pH 6.8 [µg/ml]

37

n.d.

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

32

n.d.

CACO efflux ratio

1

n.d.

Hepatocyte clearance [% QH] human / rat

72 / 43

n.d.

Plasma protein binding [%] human / rat

97.7 / 99.1

n.d.

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

MOLECULAR WEIGHT OF NEGATIVE CONTROL [DA]: 
503.5

The molecule BI-2049 can be used as in vitro negative control (IC50 h-sEH >3 µM)

BI-2049, negative control

BI-2049, negative control


Until 21.03.2018 the compound BI-64BS was offered on opnMe.com as in vitro negative control (IC50 h-sEH = >100 µM) which was replaced by BI-2049 which is structurally more similar to BI-1935.

BI-64BS, negative control

Structure of BI-64BS

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

    Taylor S. J., Soleymanzadeh F., Eldrup A. B., Farrow N. A., Muegge I., Kukulka A., Kabcenell A. K., De Lombaert S.

    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

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

  4. Soluble Epoxide Hydrolase Regulates Hydrolysis of Vasoactive Epoxyeicosatrienoic Acids

    Yu Z., Xu F., Huse L. M., Morisseau C., Draper A. J., Newman J. W., Parker C., Graham L., Engler M. M., Hammock B. D., Zeldin D. C., Kroetz D. L.

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

  5. Cardiovascular Therapeutic Aspects of Soluble Epoxide Hydrolase Inhibitors

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

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

    Spector A. A., Fang X., Snyder G. D., Weintraub N. L.

    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

    Larsen B. T., Miura H., Hatoum O. A., Campbell W. B., Hammock B. D., Zeldin D. C., Falck J. R., Gutterman D. D.
    Am. J. Physiol. Heart Circ. Physiol. 2006, 290, H491-499.

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

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

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

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

    Imig J. D., Zhao X., Capdevila J. H., Morisseau C., Hammock B. D.
    Hypertension 2002, 39, 690-694.

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

    Zhao X., Yamamoto T., Newman J. W., Kim I. H., Watanabe T., Hammock B. D., Stewart J., Pollock J. S., Pollock D. M., Imig J. D.
    J. Am. Soc. Nephrol. 2004, 15, 1244-1253.

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

    Smith K. R., Pinkerton K. E., Watanabe T., Pedersen T. L., Ma S. J., Hammock B. D.
    Proc. Natl. Acad. Sci. U S A. 2005, 102, 2186-2191.

  12. Soluble epoxide hydrolase inhibitors: a patent review

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

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