Synthesis and structure-activity relationship of piperidine-derived non-urea soluble epoxide hydrolase inhibitors

Article abstract of DOI:10.1016/j.bmcl.2012.11.084

A series of potent amide non-urea inhibitors of soluble epoxide hydrolase (sEH) is disclosed. The inhibition of soluble epoxide hydrolase leads to elevated levels of epoxyeicosatrienoic acids (EETs), and thus inhibitors of sEH represent one of a novel approach to the development of vasodilatory and anti-inflammatory drugs. Structure-activities studies guided optimization of a lead compound, identified through high-throughput screening, gave rise to sub-nanomolar inhibitors of human sEH with stability in human liver microsomal assay suitable for preclinical development.

Full text of DOI:10.1016/j.bmcl.2012.11.084

Bioorganic & Medicinal Chemistry Letters 23 (2013) 417–421
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and structure–activity relationship of piperidine-derived
non-urea soluble epoxide hydrolase inhibitors
Stevan Pecic a, Svetlana Pakhomova b, Marcia E. Newcomer b, Christophe Morisseau c, Bruce D. Hammock c,
Zhengxiang Zhu a, Alison Rinderspacher a, Shi-Xian Deng a,
⇑
a Department of Medicine, Columbia University, 650 W 168th Street, BB1029, New York, NY 10032, USA
b Department of Biological Sciences, Louisiana State University, Baton Rouge, LA 70803, USA
c Department of Entomology and UCD Cancer Center, University of California, 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:
A series of potent amide non-urea inhibitors of soluble epoxide hydrolase (sEH) is disclosed. The inhibi-
tion of soluble epoxide hydrolase leads to elevated levels of epoxyeicosatrienoic acids (EETs), and thus
inhibitors of sEH represent one of a novel approach to the development of vasodilatory and anti-inflam-
matory drugs. Structure–activities studies guided optimization of a lead compound, identified through
high-throughput screening, gave rise to sub-nanomolar inhibitors of human sEH with stability in human
liver microsomal assay suitable for preclinical development.
Received 27 September 2012
Revised 12 November 2012
Accepted 20 November 2012
Available online 1 December 2012
Keywords:
Published by Elsevier Ltd.
Soluble epoxide hydrolase
Non-urea inhibitors
Hypertension
Human liver microsomes stability
Soluble epoxide hydrolase (sEH) is a bifunctional homodimeric
enzyme with hydrolase and phosphatase activity detected in vari-
ous species ranging from plants to mammals.1 In humans it is
mostly located in liver, kidney, intestinal and vascular tissues.2
The sEH enzyme is selective for aliphatic epoxides of fatty acids,
and one of the most important substrates is epoxyeicosatrienoic
acid (EET).3 EETs are one of the metabolic derivatives of arachi-
donic acid.4 The epoxygenase CYP2 enzymes catalyse the epoxyda-
tion of olefin bonds of arachidonic acid generating EETs.5 EETs
exhibit vasodilatory effects in various arteries6,7 and possess
anti-inflammatory properties.8 sEH mediates the addition of water
to EETs, converting them to the corresponding diols—dihydroxyei-
cosatrienoic acids (DHETs), which show abolished or diminished
biological activity. The inhibition of this enzyme, therefore may
represent a promising therapeutic strategy since it would lead to
elevated levels of EETs, which could then have beneficial therapeu-
tic effects on blood pressure and inflammation.9
Amides, carbamates and thioureas have been evaluated as alter-
native pharmacophores in an attempt to improve physical proper-
ties of urea-based inhibitors.10,11 In this report we disclose our
efforts towards designing novel non-urea, amide-based inhibitors
of sEH.
Previously we identified through high-throughput screening
(HTS)14 several hits with a low micromolar to low nanomolar po-
tency. A majority of these compounds were urea-based inhibitors.
However, several were non-ureas and among them the most po-
tent was the derivative of isonipecotic acid, with substantial activ-
ity of 20 nM. Our initial SAR studies15 led to discovery of
compound 1 with an IC50 of 7.9 nM (Fig. 1). Based on its potent
inhibition of sEH activity, we continued our evaluation of the
right-hand side (2,4,6-trimethylphenyl ring) of 1, and this follow-
up SAR study revealed compound 2, with an IC50 of 1.6 nM.16
Herein we report modifications of the left-hand side of non-
urea inhibitor 2. In particular, we were focused on the replacement
The most explored sEH inhibitors to date are urea-based com-
pounds and numerous structure–activity relationship (SAR) stud-
ies led to discovery of several potent urea-based sEH inhibitors
with IC50s in the lower nanomolar range.10,11 However, the urea-
based inhibitors often suffer from poor solubility and stability,
which hinders their pharmacological use in vivo.12,13
O
O
N
H
N
H
N
N
S
S
O
O
O
O
1
IC50 = 7.9 nM
2
IC50 = 1.6 nM
⇑
Corresponding author. Tel.: +1 212 305 1152; fax: +1 212 305 3475.
E-mail address: sd184@columbia.edu (S.-X. Deng).
Figure 1. Chemical structures of non-urea inhibitors.
0960-894X/$ - see front matter Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.bmcl.2012.11.084

418
S. Pecic et al. / Bioorg. Med. Chem. Lett. 23 (2013) 417–421
towards the large deep pocket that opens toward solvent, which
allows access for further structural modifications ( Fig. 2). We
therefore hypothesized that the left-hand segment in 1 could be
optimized to further improve the potency of this group of non-urea
sEH inhibitors.
Scheme 1 outlines the synthetic route used to form the left-
hand side library of non-urea amide sEH inhibitors. Sulfonamide
5 was prepared from two commercially available starting materi-
als, methyl isonipecotate
3 and 2,4-dimethylbenzenesulfonyl
chloride 4. Saponification of this methyl ester with LiOH afforded
acid 6. EDC peptide coupling reactions of 6 with various commer-
cially available amines provided analogs 7–1 to 7–46.
A sensitive fluorescent based assay was employed to determine
IC50 values of these sEH inhibitors. In short, cyano(2-meth-
oxynaphthalen-6-yl)methyl trans-(3-phenyloxyran-2-yl) methyl
carbonate (CMNPC) was used as the fluorescent substrate. Human
sEH (1 nM) was incubated with the inhibitor for 5 min in pH 7.0
Bis–Tris/HCl buffer (25 mM) containing 0.1 mg/mL of BSA at
30 °C prior to substrate introduction ([S] = 5 lM). Activity was
determined by monitoring the appearance of 6-methoxy-2-naph-
thaldehyde over 10 min by fluorescence detection with an excita-
tion wavelength of 330 nm and an emission wavelength of
465 nm. Reported IC50 values are the average of the three repli-
cates with at least two datum points above and at least two below
20
Figure 2. The active site of the hydrolase domain of human sEH complexed with 1.
The Fo–Fc electron density map is contoured at 3r. Hydrogen bonds are indicated by
the IC50
.
In Table 1 are summarized the biological results.
Previous studies on urea-based inhibitors containing piperidine
moiety have shown that the hydrophobic cycloalkyl groups on the
left-hand side of the molecules are positively correlated with
inhibitory potency.17 Among this set of analogs we identified sev-
eral inhibitors possessing improved or similar potency comparing
to the lead compound 2, specifically compound 7–10 showed an
IC50 of 0.4 nM, the most potent amide non-urea sEH inhibitor re-
ported to date. Replacement of cycloalkyl ring with a more com-
pact phenyl ring (compound 7–12), resulted in 15-fold drop in
potency against the human sEH. However, introduction of the phe-
nyl ring allowed us access to electronically and sterically diverse
structures, and as well attachment of various polar groups, which
could in turn improve physical and pharmacokinetic properties.
Placement of fluorine or bromine in the ortho position did not sig-
nificantly change the potency of the non-urea inhibitors (7–13 and
7–15), while chlorine and methyl group decreased the potency for
10 and 30-fold, respectively (7–14 and 7–16).
dashes. The structure reveals that the 2,4,6-trimethylphenyl group is directed into
the hydrophobic environment, whereas the cycloheptyl moiety is exposed toward
the solvent. Coordinates of the complex deposited as 4HAI with the Protein Data
Bank. The image was produced using PYMOL.
of the cycloheptyl moiety of the 2, following the SAR reported by
Rose et al.17, and guided by docking model of the previously re-
ported protein-inhibitor complex and X-ray cocrystal structure of
human sEH and 1.
The X-ray crystallographic structure of human sEH and an
inhibitor 4-(3-cyclohexylureido)-carboxylic acid complex (PDB
code: 1ZD3) revealed the catalytic pocket and key structural fea-
tures required to inhibit sEH enzyme. Two tyrosine (Tyr383 and
Tyr466) and one aspartic acid (Asp335) residues, located in the
hydrolase catalytic pocket of sEH, are involved in degradation of
EET—tyrosine residues act as hydrogen bond donors to promote
the epoxide ring opening by Asp335.18,19 The urea group of 4-(3-
cyclohexylureido)-carboxylic acid fits in the hydrolase catalytic
pocket and the carbonyl oxygen of the urea moiety is engaged in
a hydrogen bond interaction with Tyr381 and Tyr466 while the
N–H acts as a hydrogen bond donor to Asp335 The co-crystal struc-
ture of 1 and human sEH was determined (See Supplementary
data) to guide the design of more potent inhibitors. Our close
examination of the structure revealed that the amide moiety of 1
is positioned in the same fashion as the urea group in urea-based
inhibitors, where the amide moiety, instead of urea group, is
involved in hydrogen bonding with tyrosine and aspartic acid
residues in the catalytic pocket of sEH. We noticed that the 2,4,6-
trimethylphenyl ring on the right-hand side of this inhibitor occu-
pies the smaller of the two lipophilic pockets in the sEH active site,
while the cycloheptyl moiety on the left-hand side is directed
Polar hydroxyl group in ortho position showed clear negative ef-
fect on potency in non-urea based compounds (7–17). Although
the para substitution is generally tolerated, placement of polar sub-
stituents resulted in less potent inhibitors.
Placement of methoxy group in para position (compound 7-18)
did not significantly changed the potency comparing to compound
7-12, while introduction of hydroxyl group in the same position
(compound 7-19 can be observed as a metabolite of 7-18) led to
two fold decreased potency presumably because of unfavorable
electron character and increased polarity. Similar results, but with
more drastically change in potency can be observed based on
results for methyl ester compound 7-21 and its corresponding car-
boxylic acid compound 7-22. We synthesized the 4-trifluorometh-
oxyphenyl analog 7-23, since it has been reported previously that
O
O
SO2Cl
O
N
O
O
N
O
O
N
O
S
S
S
a
b
c
H
N
O
O
N
H
3
R
O
OH
O
4
5
6
7-1 to 7-46
Scheme 1. Reagents and condition: (a) Et3N, CH2CL2, rt 24 h; 89% (b) LiOH, THF/H2O, rt, 24 h; 91% (c) R-NH2, EDC, DMAP, CH2CL, rt, 24 h; 65–92%.

S. Pecic et al. / Bioorg. Med. Chem. Lett. 23 (2013) 417–421
419
Table 1
The biological results for sulfonamide analogs 7–1 to 7–46
O
N
O
S
H
N
R
O
a,b
Compound
R
IC50 (nM)
Compound
R
IC50 (nM)
7-1
18
7-24
4.6
29
7-2
7-3
6900
5.2
7-25
7-26
102
41
7-4
7-5
263
5.8
7-27
7-28
N
Boc
2.8
7-6
7-7
1.7
1.1
7-29
7-30
6.9
8.7
F
Cl
7-8
0.6
1.2
0.4
7-31
7-32
7-33
20
25
20
Br
7-9
O
OH
7-10
HO
O
O
7-11
7-12
8.5
23
7-34
7-35
17
12
HOOC
O
F3CO
O2N
H2N
O
7-13
20
7-36
43
N
N
7-14
7-15
250
30
7-37
7-38
6.7
N
O
O
S
O
F3C
1.6
F3C
F3C
7-16
7-17
640
7-39
7-40
290
F
2200
45
Cl
Br
(continued on next page)

420
S. Pecic et al. / Bioorg. Med. Chem. Lett. 23 (2013) 417–421
Table 1 (continued)
a,b
Compound
R
IC50 (nM)
Compound
R
IC50 (nM)
78
Cl
F3C
7-18
25
7-41
Cl
Cl
Cl
Cl
7-19
7-20
7–21
55
6.0
13
7-42
7-43
7-44
8.3
2.3
23
N
N
N
N
7-22
110
5.2
7-45
7-46
0.6
O
HOOC
O
O
O
O
7-23
30,000
O
O
a
Reported IC50 values are the average of three replicates. The fluorescent assay as performed here has a standard error between 10% and 20% suggesting that differences of
two fold or greater are significant.
b
t-AUCB that has an IC50 between 1 and 2 nM was used as positive control.
this moiety is more metabolically stable replacement for cycloalkyl
rings.12 We observed fourfold increase in potency for this com-
pound compared with compound 7-12, thus it was selected for fur-
ther pharmacokinetic studies. Interestingly, the analog 7-24,
showed five fold increased activity comparing to phenyl compound
7-12, despite the presence of the high polarity nitro functionality.
The metabolic stability for this inhibitor was evaluated as well.
We also introduced a basic nitrogen (piperidine and morpholine
rings in para position; analogs 7-25, 7-26 and 7-27) in order to al-
low formulation of the inhibitor as a salt. These modifications did
not improve the potency, similar to other polar substituents in this
position. On the other hand, the inhibition potencies increased
when small non-polar para or meta substituents were added (7-
28, 7-29, 7-30 and 7-31). Since it has been known that halogens
can enhance polarity and decrease the rate of metabolism degrada-
tion due to their electron withdrawing effect on the aromatic ring,
we decided to prepare a set of analogs containing various halogens
in different position on the left-hand side phenyl moiety. The
fluorinated, chlorinated and brominated para-phenyl compounds
(7-32, 7-33 and 7-34, respectively) did not show significant
improvement in activity compared to compound 7-12. Placement
of two chlorine atoms in meta, and meta and para positions showed
a twofold and threefold lower IC50 against human sEH enzyme,
7-35 and 7-37, respectively.
Future rational optimization of these meta, para disubstituted
halogens might yield additional more potent compounds. Inclusion
of 2-naphthalene on the left side of the molecule 7-38 resulted in
high potency against the human enzyme, which is already shown
in recent literature,17 thus, we decided to test in vitro metabolic
profile for this compound. We tried to introduce a nitrogen in this
moiety in order to improve physical properties and the ease of
formulation. Various aminoquinolines were attached via different
position to central non-urea moiety. 5-Aminoquinoline derivative
7-39 led to five fold lower potency against sEH, 3-aminoquinoline
derivative 7-40 showed 30-fold diminished potency, while 6- and
8-aminoquinoline analogs 7-41 and 7-42, led to even more
drastically decreased potency, 50-fold and 180-fold, respectively.
The poor performance of aminoquinolines returned our attention
to 2-naphthalene moiety, where we tried to introduce polar group
in position 6. Methylester analog 7-43 showed slight decrease in
activity, while corresponding carboxylic acid 7-44 had 15-folds
lower inhibition then the 2-naphthalene analog. Interestingly,
3,4-methylenedioxybenzene analog 7-45 led us to discovery of
subnano molar potent inhibitor of human sEH enzyme.
The selected non-urea sEH inhibitors were profiled in human
liver microsomal assay22 as a predictor of in vivo oxidative metab-
olism (Table 2). Our results from this assay indicated that although
compounds with hydrophobic cycloalkyl substituents on the
right-side of the non-urea piperidine scaffold such as cyclohexyl,
methylcyclohexyl, cycloheptyl, cyclooctyl or adamantyl were more
potent inhibitors of sEH, compared to compounds with aromatic
moiety, these compounds showed poor metabolic profile in human
liver microsomal assay. Evaluation of the in vitro metabolic stabil-
ity for aromatic compounds revealed intermediate metabolic
profiles for compounds with para-substitution (compounds 7-23
and 7-24), with the exception of the carboxylic acid derivative
7-44, which demonstrated excellent in vitro metabolic stability
in human liver microsomes.
In summary, our structure–activity relationship of the lead 2 re-
veals some particular structural requirements to the left-hand side
part of the piperidine amide-based sEH inhibitors. A varying degree
of bulky, nonpolar cycloalkyl rings are well tolerated in this region
by target enzyme. In contrast, proper substitution on the phenyl
ring is crucial for attaining good potency, emphasizing the impor-
tance of the small nonpolar groups and halogens in para position as
a recognition element for sEH, suggesting that left-hand side phe-
nyl is in a relatively close proximity to a several hydrophobic res-
idues located in the large, non-polar pocket of sEH that opens
towards solvent, and probably participating in a p-stacking inter-
action with them. The above observations are corroborated by
the costructure of 1 with sEH.
While low nanomolar and sub-nanomolar potencies were
achieved, the majority of tested inhibitors in this non-urea based
series were still not as stable in human liver microsome assay as

S. Pecic et al. / Bioorg. Med. Chem. Lett. 23 (2013) 417–421
421
Table 2
Stability in human liver microsomes (t1/2) for selected compounds
b
b
Compound
hLMa t1/2 (min)
CLint,
(mL/min/kg)
Compound
hLMa t1/2 (min)
CLint,
(mL/min/kg)
app
app
2
5.5
14
14
2.4
3.7
11
46
220
90
90
520
340
120
28
7-24
7-37
7-38
7-42
7-44
7-45
180
25
36
8.7
220
36
7.0
50
35
140
5.6
35
7-3
7-6
7-9
7-11
7-20
7-23
a
Data represents averages of duplicate determination. hLMt1/2 is the half life in human liver microsomes.
b
CLint,
is apparent intrinsic clearance
app
some other non-urea sEH inhibitors previously reported.21 How-
ever, compound 7-4423 showed good stability and it will be further
explored in various in vivo experiments. Our future work will focus
as well on possible combinations of these data obtained from this
SAR study and combinations of related fragments that would be
used for future design of highly potent inhibitors with improved
pharmacokinetic profiles.
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Acknowledgments
14. AID:1026; Pubchem 2008.
15. Xie, Y.; Liu, Y.; Gong, G.; Smith, D. H.; Yan, F.; Rinderspacher, A.; Feng, Y.; Zhu,
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C.; Hammock, B. D.; Landry, D. W. Bioorg. Med. Chem. Lett. 2009, 19, 2354.
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Hammock, B. D. J. Med. Chem. 2010, 53, 7067.
18. Gomez, G. A.; Morisseau, C.; Hammock, B. D.; Christianson, D. W. Biochemistry
2004, 43, 4716.
19. Gomez, G. A.; Morisseau, C.; Hammock, B. D.; Christianson, D. W. Protein Sci.
2006, 15, 58.
20. Jones, P. D.; Wolf, N. M.; Morisseau, C.; Whetstone, P.; Hock, B.; Hammock, B. D.
Anal. Biochem. 2005, 343, 66.
21. Taylor, S. J.; Soleymanzadeh, F.; Eldrup, A. B.; Farrow, N. A.; Muegge, I.;
Kukulka, A.; Kabcenell, A. K.; De Lombaert, S. Bioorg. Med. Chem. Lett. 2009, 19,
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22. In vitro human liver microsomal metabolic stability: Microsomal stability was
assessed in pooled human liver microsomes (Celsis, Edison, NJ). All reactions
were carried out for 90 min at 37 °C in an NADPH-generating system consisting
of glucose 6-phosphate, glucose 6-phosphate dehydrogenase, and NADP+
(Sigma, St., Louis, MO). Positive control incubations proceeded with 7-
ethoxycoumarin as the substrate. Reactions were terminated by adding
methanol. The mixtures were centrifuged and the supernatants were
evaporated. The residues were reconstituted in mobile phase (85% ACN; 15%
H2O) and subjected to LC/MS analysis.
This work was supported in part by NIEHS R01 ES002710 and
NIH R01 HL 107887 (MEN). Preliminary structural work was per-
formed at the Center for Advanced Microstructures and Devices
(Baton Rouge), funded in part by the Louisiana Governors’ Biotech-
nology Initiative. The work includes research conducted at the
Advanced Photon Source on the Northeastern Collaborative Access
Team beamlines, which are supported by grants from the National
Center for Research Resources (5P41RR015301-10) and the Na-
tional Institute of General Medical Sciences (8 P41 GM103403-
10) from the National Institutes of Health. Use of the Advanced
Photon Source, an Office of Science User Facility operated for the
U.S. Department of Energy (DOE) Office of Science by Argonne Na-
tional Laboratory, was supported by the U.S. DOE under Contract
No. DE-AC02-06CH11357. We thank Dr. David Neau for assistance
with data collection. BDH is a George and Judy Senior fellow of the
American Asthma Foundation.
Supplementary data
23. Analytical data for the representative compounds. Compound 7–10: 1H NMR
(400 MHz, CDCl3): d 7.78–7.76 (d, J = 8 Hz, 1H) 7.09 (s, 1H), 7.07 (s, 1H), 3.96–
3.89 (m, 1H), 3.71–3.66 (d, J = 9.6 Hz, 2H), 2.69 (t, J = 12 Hz, 2H), 2.55 (s, 3H),
2.35 (s, 3H), 2.10–2.03 (m, 1H), 1.86–1.82 (d, J = 10.8 Hz, 2H), 1.79–1.68 (m,
4H), 1.66–1.42 (m, 14H); 13C NMR (100 MHz, CDCl3) d 172.5, 143.7, 138.1,
133.7, 133.1, 130.6, 126.8, 49.6, 44.9, 43.0, 32.8, 28.8, 27.5, 25.9, 24.1, 21.6,
20.8; ESI-MS (M++H): 407; Compound 7–44: 1H NMR (400 MHz, DMSO-d6): d
10.27 (s, 1H), 8.45 (s, 1H), 8.34 (s, 1H), 7.99–7.97 (d, J = 9.2 Hz, 1H), 7.88–7.85
(d, J = 10 Hz, 1H), 7.82–7.80 (d, J = 8.8, 1H), 7.68–7.66 (d, J = 8.4 Hz, 1H), 7.61–
7.59 (d, J = 8.4 Hz, 1H), 7.24 (s, 1H) 7.20–7.18 (d, J = 7.6 Hz, 1H), 3.65–3.62 (d,
J = 12.4 Hz, 2H), 2.67 (t, J = 11.6 Hz, 2H), 2.53 (s, 3H), 2.35 (s, 3H), 1.92–1.90 (d,
J = 11.2 Hz, 2H), 1.69–1.59 (dd, J = 11.6 and 9.2 Hz, 2H); 13C NMR (100 MHz,
DMSO-d6) d 173.8, 168.0, 143.9, 139.5, 137.7, 136.3, 134.2, 134.0, 133.4, 131.0,
130.7, 130.5, 129.3, 127.4, 127.2, 121.2, 115.5, 115.2, 45.1, 28.7, 21.6, 21.5,
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2012.11.
084.
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