Biologically active ester derivatives as potent inhibitors of the soluble epoxide hydrolase

Article abstract of DOI:10.1016/j.bmcl.2012.07.074

Substituted ureas with a carboxylic acid ester as a secondary pharmacophore are potent soluble epoxide hydrolase (sEH) inhibitors. Although the ester substituent imparts better physical properties, such compounds are quickly metabolized to the correspondi

Full text of DOI:10.1016/j.bmcl.2012.07.074

Bioorganic & Medicinal Chemistry Letters 22 (2012) 5889–5892
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Biologically active ester derivatives as potent inhibitors of the soluble
epoxide hydrolase
In-Hae Kim , Kosuke Nishi , Takeo Kasagami à, Christophe Morisseau, Jun-Yan Liu, Hsing-Ju Tsai,
⇑
Bruce D. Hammock
Department of Entomology and UC Davis Comprehensive Cancer Center, University of California, One Shields Avenue, Davis, CA 95616, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Substituted ureas with a carboxylic acid ester as a secondary pharmacophore are potent soluble epoxide
hydrolase (sEH) inhibitors. Although the ester substituent imparts better physical properties, such com-
pounds are quickly metabolized to the corresponding less potent acids. Toward producing biologically
active ester compounds, a series of esters were prepared and evaluated for potency on the human
enzyme, stability in human liver microsomes, and physical properties. Modifications around the ester
function enhanced in vitro metabolic stability of the ester inhibitors up to 32-fold without a decrease
in inhibition potency. Further, several compounds had improved physical properties.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 15 May 2012
Revised 18 July 2012
Accepted 23 July 2012
Available online 2 August 2012
Keywords:
sEH
sEH inhibitors
Substituted urea–ester derivatives
Metabolic stability
Epoxyeicosatrienoic acids (EETs), which are metabolites of ara-
chidonic acid by cytochrome P450 epoxygenases, have important
roles in the regulation of hypertension,1–6 inflammation,7–11 and
other cardiovascular related diseases.12,13 Recently a role in modu-
lating pain was also reported.14 However, metabolism of EETs (1)
to their corresponding hydrated products (2) by soluble epoxide
hydrolase (sEH) generally reduces these biological activities
(Fig. 1).1 Both in vitro and in vivo studies have demonstrated that
the anti-hypertensive and cardio protective effects mediated by
the EETs are reversely dependent on the extent of sEH hydrolysis
of the EETs.2–4,6–8,13,15 Thus, maintaining the in vivo concentration
of EETs through sEH inhibition is a promising therapeutic pathway
to treat cardiovascular and other diseases. Urea, amide, and carba-
mate compounds substituted with hydrophobic groups are very
potent and stable inhibitors of sEH with significant biological activ-
ities in both in vitro and in vivo models.3,4,16 However, poor phys-
ical properties of the early compounds, such as low solubilities and
high melting points, likely result in limited in vivo availability.17
The addition of a polar functional group on specific positions of
sEHI
sEH
O
O
OH
OH
HO
OH
O
14,15-EET
14,15-DHET
2
1
Figure 1. Metabolism of biologically active EETs (1; e.g., 14,15-EET) to the less
active DHETs (2; e.g., 14,15-DHET) by sEH. The sEH converts a variety of lipid
epoxides to their corresponding diols. The sEHIs act by blocking this enzyme,
increasing the in vivo concentrations of EETs which have direct actions on
hypertension, inflammation, and pain. EET, epoxyeicosatrienoic acid; DHET,
dihydroxyeicosatrienoic acid; sEHI, soluble epoxide hydrolase inhibitor.
one of the urea-substitution is effective in increasing solubility in
either water or organic solvents, and also in improving in vivo
availability while maintaining the inhibition potency on the target
enzyme.18–21 Among a variety of polar functional groups explored
previously, ester functionalities located on the fifth atom from the
urea function were found to be among the most suitable polar
groups for making potent inhibitors with improved physical prop-
erties.18 However, as expected, the ester functionality is rapidly
hydrolyzed both in vitro and in vivo producing the corresponding
short chain acid metabolite that has dramatically reduced inhibi-
tion potency on the human sEH.20 Although rapid enzymatic
hydrolysis of the ester compound is not favorable for high in vivo
efficacy, it offers some advantage. First, alcohol moieties of ester
Abbreviations: sEH, soluble epoxide hydrolase; EET, epoxyeicosatrienoic acid;
EDCI, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide; DMAP, 4-dimethyl-
pyridine.
⇑
Corresponding author. Tel.: +1 530 752 7519; fax: +1 530 752 1537.
E-mail address: bdhammock@ucdavis.edu (B.D. Hammock).
Present address: Department of Applied Bioscience, Faculty of Agriculture, Ehime
University, 3-5-7 Tarumi, Matsuyama, Ehime 790-8566, Japan.
à
Present address: Drug Development Service Segment, Mitsubishi Chemical
Medience Corporation, 14-1 Sunayama Kamisu-shi, Ibaraki 314-0255, Japan.
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.07.074

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I.-H. Kim et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5889–5892
HO
O
(A)
O
O
d
O
O
a
OH
O
O
N
H
N
H
N
H
N
H
O
O
3
O
9
7
(b, c)
a
O
O
O
R1
O
N
N
N
N
H
H
H
H
O
R
O
CN
4: R= H,
R1= n-Butyl
5: R= Methyl, R1= n-Butyl
6: R= Ethyl, R1= n-Butyl
8: R= H,
R1= (2-Ethoxyethoxy)methyl
(B)
O
O
a
OH
O
R1
N
H
N
H
N
H
N
H
10
O
O
R
11: R= H,
R1= n-Butyl
12: R= Ethyl, R1= n-Butyl
13: R= Phenyl, R1= (2-Ethoxyethoxy)methyl
Scheme 1. Syntheses of 4-(3-adamantan-1-yl-ureido)-butyric acid or -cyclohexanecarboxylic acid derivatives. Reagents and conditions: (a) EDCI, DMAP, a corresponding
alcohol (2-hexanol for compound 5, 3-heptanol for compounds 6 and 12, and diethylene glycol monoethyl ether for compounds 8 and 13) in MC or 1-bromopentane for
compounds 4 and 11 in DMF, rt; (b) pentanal, TMSCN, ZnI, chloroform, rt/3 N HCl; (c) coupling of compound 3 with the product of reaction; (b) by using EDCE/DMAP in MC, rt;
(d) 2-ethoxyethanol, NaH, DMF, rt.
groups can be rapidly altered to explore binding properties of the
right hand side of the inhibitors such as those shown in Scheme 1.
Second, the introduction of a secondary pharmacophore roughly
7–8 Å from the urea or amide carbonyl of the primary pharmaco-
phore often improves solubility while retaining high po-
tency.18,21–23 Finally, to date the urea inhibitors of the sEH
appear highly selective with low toxicity. The epoxy-lipids stabi-
lized by these inhibitors have numerous biological activities.
Although the activities of the epoxy-lipids are so far found to be
beneficial, it may be important to direct the activities to individual
tissues. Administering short acting compounds may be also impor-
tant for the treatment of pulmonary inflammation by inhalation.
Thus for these latter two approaches it is important to develop es-
ters of varying metabolic stability with increasing stability for clas-
sical systemic administration and decreasing stability for short
term or local effects.24 In the present study, we explored structural
modifications of urea–ester inhibitors toward altering the enzy-
matic stability of the ester function in an in vitro metabolic system
while maintaining sEH inhibition potency and appropriate physical
properties.
prepared by the reaction of 2-ethoxyethanol with 2-phenyloxirane,
was coupled with compound 3 in the above same method as that
used for the preparation of compound 7 to afford compound 9 in
48% yield. Scheme 1(B) shows syntheses of derivatives with a
cyclohexyl linker (10–13) between the urea and ester pharmaco-
phores.21 Compound 10, which was prepared from the coupling
Table 1
Inhibition of human sEH by 4-(3-adamantan-1-yl-ureido)-butyric acid derivatives
O
O
N
H
N
H
R
O
Compound
R
Human sEH IC50 (nM)a
3
4
H
684
10
5
6
4
4
Compound 3, which was prepared as previously reported,18,21
was coupled with a corresponding alcohol by using 1-[3-(dimeth-
ylamino)propyl]-3-ethylcarbodiimide (EDCI) in the presence of 4-
dimethylaminopyridine (DMAP) in dichloromethane to afford
compounds 5, 6, and 8 or was alkylated with 1-bromopentane in
the presence of K2CO3 in DMF to afford compound 4 in a range of
64–95% yield (Scheme 1(A)). For the synthesis of cyanoalkyl ester
(7), 1-pentanal was first reacted with trimethylsilyl cyanide in
the presence of zinc iodide in chloroform at 0 °C, followed by
hydrolysis with an aqueous solution of 3 N HCl (80%). The resulting
cyanohydrin intermediate was then coupled with compound 3 by
using EDCI and DMAP in dichloromethane to provide 7 in 70%
yield. In addition, ethoxyethanol with a phenyl group, which was
7
8
12
67
CN
O
O
O
O
9
4
a
Human sEH (0.96 nM) was incubated with inhibitors for 5 min in 25 mM Bis–
Tris/HCl buffer (200 L; pH 7.0) at 30 °C before fluorescent substrate introduction
([S] = 5 M). Results are averages of three separate measurements. The fluorescent
l
l
assay as performed here has a standard error between 10% and 20%, suggesting that
differences of 2-fold or greater are significant.

I.-H. Kim et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5889–5892
5891
of 1-adamantyl isocyanate with 3-aminocyclohexanoic acid, was
alkylated or coupled with a corresponding bromide or alcohol in
the same reaction condition as that used for the preparation of
compounds 4–9 in Scheme 1(A) to give target compounds 11–13
in 65–95% yield.21
carboxylic acid was synthesized as seen in compound 10 in Table 2,
further reduced inhibition was exhibited. This indicates that a
short chain acid attached to the urea function like urea–cyclo-
hexylcarboxylic acid is a poor inhibitor and substitution of the acid
could also result in potent compounds. When cyclohexylcarboxylic
acid esters were prepared as seen in Table 2, as expected, a dra-
matic improvement in inhibition on the target human enzyme
was observed in compound substituted with a pentyl group (11).
The incorporation of an ethyl group (12) on the alpha carbon of
the alcohol moiety of the pentyl ester 11 provided a highly potent
inhibitor, as well. A diethyleneglycol group with a phenyl also
made a potent inhibitor (13), although it was less potent than com-
pounds 11 or 12. The results in Table 2 imply that alkylation of the
acid function of urea–cyclohexylcarboxylic acid (10) is effective for
producing highly potent inhibitors like butyrate derivatives in
Table 1.
In general, liphophilicity of compounds causes limited solubility
in water, which probably affects in vivo efficacy of com-
pounds.17,21,25 In addition, the stability of the crystals of com-
pounds, indicated by their high melting points, leads to a general
lack of solubility even in organic solvents. These poor physical
properties result in undesirable pharmacokinetic properties and
difficulty in compound formulation in either an aqueous or oil
base. We examined physical properties of the above potent deriv-
atives in Tables 1 and 2. As seen in Table 3, butyric acid (3) and the
corresponding ester derivatives (4 and 6) had very low solubility in
water, while dramatic improvement in solubility was observed in
diethylene glycol compounds (8 and 9). Similar increase in solubil-
ity was obtained in cyclohexylcarboxylic acid ester with a diethyl-
ene glycol group (13). The diethylene glycol derivatives (8, 9, and
13) also possessed much lower melting points in comparison with
the acids (3 and 10) or other ester compounds (4, 6, and 12). This
result indicates that hydrophilic alcohol moiety of the ester func-
tion of compounds 9 and 13 is highly beneficial for improving
physical properties while producing potent inhibition. In order to
see in vitro metabolism of the urea-ester compounds we used hu-
man liver microsomes, which contain various kinds of enzymes
such as esterases, amidases, and cytochrome P450s playing a pri-
mary role in drug metabolism. When compounds 3 and 10 were
Five derivatives (5–9) were prepared to first explore the modi-
fication effect of the alcohol moiety of the ester function of com-
pound
4 on inhibition potency. As shown in Table 1, the
incorporation of a methyl group (5) on the alpha carbon of the alco-
hol moiety showed a 2.5-fold improvement in inhibition potency
compared to compound 4. An ethyl group (6) substituted on the al-
pha carbon of compound 4 exhibited a similar enhancement in po-
tency, indicating that an alkyl substituent on the alpha position is
effective for improving potency. On the other hand, the introduc-
tion of a cyano group (7) induced a 3-fold decrease in inhibition
potency in comparison with that of methyl (5) or ethyl (6) groups.
This suggests that hydrophobic alkanes are better than a polar
group to be incorporated on the alpha carbon of the alcohol moiety
of the ester function for enhanced inhibition potency. In a previous
report, we demonstrated that diethylene glycol groups attached to
hydrophobic urea inhibitors are useful for improving water solubil-
ity and bioavailability without a loss in inhibition potency.21 Two
derivatives with a diethylene glycol group (8 and 9) were prepared
to investigate whether the polar ethylene glycol group affects inhi-
bition potency of urea–ester compounds. As illustrated by com-
pound 8, attachment of a diethylene glycol resulted in a 7- to 17-
fold reduction in inhibition when compared to those of non-substi-
tuted (4) and alkyl substituted compounds (5 and 6). However,
interestingly, a big improvement in inhibition was obtained by
incorporating a phenyl group (9) on the alpha carbon of the alcohol
moiety of compound 8, which was as potent as that of the alkyl
derivatives (5 and 6). This further indicates that a hydrophobic
substituent on the alpha carbon of the ester function is highly
effective to lead to potent urea–butyrate compounds as inhibitors
of the human sEH. As described, the corresponding acid compound
(3) of butyrate derivatives in Table 1 was poor as an inhibitor of the
human enzyme. In addition, when a corresponding cyclohexyl-
Table 2
Inhibition of human sEH by 3-(3-adamantan-1-yl-ureido)-cyclohexylcarboxylic acid
derivatives
Table 3
Physical properties and in vitro metabolic stability of 4-(3-adamantan-1-yl-ureido)-
butyric acid or -cyclohexylcarboxylic acid derivatives
Compound Structure
Human
sEH
Compound
Solubility in watera
g/mL)
Mp (°C)
Stabilityb
IC50 (nM)a
(
l
(% remaining)
O
3
4
6
8
7
2
3
165
114
72
Oil
Oil
>250
124
oil
97
<1
4
10
14
95
10
32
OH
O
10
11
12
1160
N
H
N
H
O
878
89
9
O
10
12
13
NDc
1
2
3
N
N
H
H
41
O
a
O
An excess of the test compound was added to a vial containing sodium phos-
phate buffer, 0.1 M pH 7.4 (1 mL), and a suspension of the mixture was equilibrated
during 1 h of sonication and 24 h of shaking, followed by centrifugation. The water
supernatant was analyzed by LC–MS/MS. A regression curve for each compound
was obtained from five standard stock solutions by using LC–MS/MS. Then, the
absolute amount of each compound was calculated.19
O
N
H
N
H
O
O
O
O
b
N
N
O
Human liver microsomal protein (0.125 mg) was incubated with a solution of
13
9
H
H
O
test compound under a NADPH generating system. Incubation mixture was shaken
at 37 °C for 60 min. The absolute quantity of parent compounds remaining after the
incubation was analyzed by LC–MS/MS and was converted to a percentage. The
corresponding acid metabolites (3 and 10) of ester compounds were analyzed in all
determinations (data not shown). The results given are averages of triplicate
independent analyses.
a
Human sEH (0.96 nM) was incubated with inhibitors for 5 min in 25 mM Bis–
Tris/HCl buffer (200 L; pH 7.0) at 30 °C before fluorescent substrate introduction
([S] = 5 M). Results are averages of three separate measurements. The fluorescent
assay as performed here has a standard error between 10% and 20%, suggesting that
differences of 2-fold or greater are significant.
l
l
c
Not-determined because the crystal of compound 10 was not dissolved in water
which seems to be due to the high melting point (>250 °C).

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I.-H. Kim et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5889–5892
tested for microsomal incubation, >95% of the parent acids were
determined. This implies that the adamantylurea–acid structure
of compounds 3 and 10 are stable under the incubation conditions
and the human liver microsomal incubation is useful to investigate
relative in vitro metabolic stability of urea–ester compounds. As
expected, pentyl ester of butyric acid (4) was all metabolized to
the corresponding butyric acid (3) in the incubation. On the other
hand, a little increased stability was shown in compound 6 with an
ethyl branch on the alpha carbon of the ester function. Further,
diethylene glycol compounds (8 and 9) had >2.5-fold improved
metabolic stability compared to compound 6, suggesting that a po-
lar alcohol moiety of the ester function is more effective for
improving the ester stability over a hydrophobic alkyl group. Inter-
estingly, cyclohexylcarboxylic acid ester derivatives (12 and 13)
exhibited much higher metabolic stability than the corresponding
butyric acid esters (6 and 9). Comparing both compounds with an
ethyl branch on the alpha carbon (6 and 12) a 2.5-fold increase in
stability was observed in the cyclohexane derivative (12). Approx-
imately a 2-fold improved stability was also shown in compound
13 compared to that of the corresponding ethyleneglycol butyric
acid ester (9), indicating that sterically rigid cyclohexane linker
present between the urea primary pharmacophore and the ester
secondary pharmacophore is highly effective for increasing the es-
ter stability. The results in Table 3 showed that solubility and sta-
bility of urea–ester compounds are varied up to 390-fold and 32-
fold, respectively, through incorporation of a substituent and/or
modification in the linker structure.
Acknowledgments
This work was supported in part by NIEHS Grant R01 ES02710,
NIEHS Center for Environmental Health Sciences P30 ES05707,
NIH/NIEHS Superfund Basic Research Program P42 ES04699, NIH/
NHLBI R01 HL59699-06A1, and UCDMC Translational Technology
Research Grant. B.D.H. is a George and Judy Marcus Senior Fellow
of the American Asthma Foundation.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2012.07.
074.
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