Exploration of secondary and tertiary pharmacophores in unsymmetrical N,N′-diaryl urea inhibitors of soluble epoxide hydrolase

Article abstract of DOI:10.1016/j.bmcl.2010.03.074

The impact of various secondary and tertiary pharmacophores on in vitro potency of soluble epoxide hydrolase (sEH) inhibitors based on the unsymmetrical urea scaffold 1 is discussed. N,N′-Diaryl urea inhibitors of soluble epoxide hydrolase exhibit subtle variations in inhibitory potency depending on the secondary pharmacophore but tolerate considerable structural variation in the second linker/tertiary pharmacophore fragment.

Full text of DOI:10.1016/j.bmcl.2010.03.074

Bioorganic & Medicinal Chemistry Letters 20 (2010) 2740–2744
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Exploration of secondary and tertiary pharmacophores in unsymmetrical
N,N0-diaryl urea inhibitors of soluble epoxide hydrolase
*
Sampath-Kumar Anandan , Richard D. Gless
Arête Therapeutics, Inc., 7000 Shoreline Court, South San Francisco, CA 94080, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The impact of various secondary and tertiary pharmacophores on in vitro potency of soluble epoxide
hydrolase (sEH) inhibitors based on the unsymmetrical urea scaffold 1 is discussed. N,N0-Diaryl urea
inhibitors of soluble epoxide hydrolase exhibit subtle variations in inhibitory potency depending on
the secondary pharmacophore but tolerate considerable structural variation in the second linker/tertiary
pharmacophore fragment.
Received 18 February 2010
Revised 17 March 2010
Accepted 17 March 2010
Available online 19 March 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
sEH inhibitor
N,N0-Unsymmetrical diaryl urea
Metabolic syndrome
Epoxyeicosatrienoic acids (EETs), which elicit a range of biolog-
ical effects,1 are formed by the monooxygenase epoxidation of ara-
chidonic acid by CYP2J and CYP2C epoxygenases. Soluble epoxide
hydrolase (sEH) converts these epoxides to the corresponding, less
active diols by addition of a molecule of water across the epoxide.
Thus, inhibition of sEH is proposed to stabilize, and hence increase
EET concentrations to produce biological effects. Soluble epoxide
hydrolase inhibitors have been evaluated in a range of animal
models, and lipid modulatory,2 anti-hypertensive,3 glucoregulato-
ry,4 cardioprotective,5 organ protective,6 and anti-inflammatory7
effects have been reported. These pre-clinical observations suggest
that sEH inhibition may be of therapeutic benefit in treating cer-
tain of the risk factors of metabolic syndrome.8 An sEH inhibitor,
AR9281, is currently completing a phase 2 clinical trial for the
treatment of type 2 diabetes mellitus and hypertension.9
The prototypical sEH inhibitors contained a urea as the primary
pharmacophore, which is proposed to mimic the endogenous
epoxide ligand with a similar binding motif, flanked by two lipo-
philic groups.10 These compounds, for example, dicyclohexyl urea
(DCU), cyclohexyl dodecyl urea (CDU), adamantyl dodecyl urea
(ADU), and adamantyl ureido dodecanoic acid (AUDA) are potent
inhibitors of the sEH enzyme, but are less than optimal from a
physical property standpoint.11 Subsequent elaboration, primarily
by the Hammock group, led to additional refinement of the phar-
macophore model with the addition of secondary and tertiary
pharmacophores, P2 and P3 (Fig. 1).12–14 The details of the various
aspects of this model have been well delineated,15 and it is note-
worthy that the great majority of published sEH inhibitors are
structurally consistent with this model.16
Various secondary pharmacophores have been described in the
sEH inhibitor literature, and an evaluation of both secondary and
tertiary pharmacophores have been presented for N-adamantyl,
N0-alkyl ureas derived from CDU and AUDA12,14 as well as for
N-adamantyl, N0-aryl ureas.15 However, there is no systematic dis-
cussion of the impact of various secondary and tertiary pharmaco-
phores on enzyme inhibitory potency in more rigid N,N0-diaryl urea
systems. The aryl urea scaffold 1 with an amide as a secondary
pharmacophore was selected as a convenient platform for the com-
parison of the impact of the second linker/tertiary pharmacophore
combination L2P3 on enzyme inhibition.
L2
O
P2
P3
R
N
H
N
H
1
A series of N-adamantyl, N0-aryl ureas as well as the analogous
N,N0-diaryl ureas were prepared to confirm the equivalency of ada-
mantyl and trifluoromethylphenyl as the R group with respect to
inhibitory potency prior to evaluation of various L2P3 combinations.
The L2P3 region of the pharmacophore model is not necessarily re-
quired for activity and has been shown to be useful primarily as a
‘solubilizing’ group.11,12 A variety of functional groups appear to
be acceptable as the tertiary pharmacophore P3 when it is suffi-
ciently distant from P1 since it may actually lie in the solvent sphere
outside the sEH binding site.10 Acidic, basic, and neutral fragments
* Corresponding author. Tel. +1 650 737 4610; fax: 510 737 4681.
E-mail address: anandan30@yahoo.com (S.-K. Anandan).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.03.074

S.-K. Anandan, R. D. Gless / Bioorg. Med. Chem. Lett. 20 (2010) 2740–2744
2741
Linker
Linker
L1
N
L2
N
R
N
N
N
N
H
P3
P1
P2
f
h
k
g
Primary
Pharmacophore
Secondary
Pharmacophore
Tertiary
Pharmacophore
O
O
N
Figure 1. Pharmacophore model.
N
N
N
H
N
H
N
(Figs. 2–4) were explored as the second linker/tertiary pharmaco-
phore L2P3 to determine their impact on inhibitory potency. The
amide secondary pharmacophore was then replaced with a sulfon-
amide or sulfone functionality in selected examples, and the impact
on enzyme inhibition of these secondary pharmacophores was
compared with results obtained with an ether secondary pharmaco-
phore in a similar system.17
The general synthetic approach used to prepare the desired
inhibitors with an amide as the secondary pharmacophore is pre-
sented in Scheme 1. Accordingly, 3- or 4-nitrobenzoic acid chloride
2 was treated with the appropriate L2P3 amine to obtain the amide
3. The nitro functionality of 3 was then reduced with iron and
ammonium formate to the corresponding amine 4. Treatment of
amine 4 with isocyanate then afforded the corresponding urea 5.
Typically, urea formation was conducted in a polar solvent such
as DMF at 60–85 °C. The corresponding fluoroaryl analogs 6 were
obtained using a similar synthetic sequence as that employed for
the preparation of the desfluoro analogs 5.
j
i
Figure 3. Basic L2P3 fragments.
O
N
H
O
N
N
O
N
O
l
m
n
Figure 4. Neutral L2P3 fragments.
ration of various second linker/tertiary pharmacophore L2P3 are
shown in Table 1.
Examination of the enzyme IC50 values for compounds with
amide as the secondary pharmacophore, P2, shows consistent supe-
riority in potency with para substitution on the aromatic L1 linker.
This effect is more pronounced with less potent compounds. The
exceptions to this observation occur either with very potent com-
pounds (e.g., 5h) or with L2P3 fragments having rigid or bulky func-
tionality (e.g., 5u). R may be either cycloalkyl or a substituted
aromatic ring. Cyclic and fused polycyclic rings as the R group afford
potent inhibitors with adamantyl affording more potency than
cyclohexyl (5n vs 5m). Replacement of the potentially metabolically
labile alkyl R group with substituted aromatic moieties confirmed
the SAR seen previously,17 namely, potency increasing with substi-
tution at the para position of the aromatic ring with
CF3 ꢀ CF3O > Cl > F > H (5o–s, 5v–z). A cyclohexyl ring as R exhibited
potency comparable to 4-chlorophenyl (5m vs 5q) while adamantyl
afforded potency comparable to the 4-trifluoromethylphenyl group
(5f vs 5h and 5n vs 5r) especially with the para isomer.
For molecules containing an acidic L2P3 fragment (a–e), more
lipophilic or extended L2 linkers that displace the polar functional-
ity further from the lipophilic P1 binding site afford better potency.
Even a subtle change such as replacing an amide NH with NMe
(e.g., 5a vs 5b) or, assuming equivalent potency for the adamantyl
and trifluoromethylphenyl groups as R, inserting oxygen in an alkyl
chain (e.g., 5c vs 5d) has a negative impact on potency. The less
acidic aromatic acid analogs 5e were found to be generally more
potent than the aliphatic acid analogs (5a–d).
Molecules containing a basic L2P3 fragment (f–k) exhibit a sim-
ilar trend to that noted with the acidic L2P3 fragments, namely
longer or more lipophilic L2 linkers which displace the amine func-
tionality further from the lipophilic P1 binding site in general afford
better potency. Increasing lipophilicity also trends to somewhat
more potent inhibitors, for example, 5h versus 5j and 5i versus
5k. Reducing the polarity (basicity) either by incorporating the
amine nitrogen into aromatic ring (e.g., 5t) or in a morpholine ring
system (5l vs 5r) affords more potent compounds. Molecules con-
taining a neutral L2P3 fragment (l–n) exhibit similar trends to those
noted with the acidic and basic L2P3 fragments with the more lipo-
philic moieties again affording better potency.
The synthesis of unsymmetrical diaryl urea inhibitors with sul-
fonamide as the secondary pharmacophore was carried out accord-
ing to Scheme 2 starting with 3- or 4-nitrobenzenesulfonyl
chloride. The sulfonyl chloride 7, on treatment with appropriate
amine followed by hydrogenation of the nitro group using palla-
dium on charcoal, afforded the required amine 8. Treatment of
amine 8 with various aryl isocyanates resulted in the desired sul-
fonamide analog 9.
The general synthetic protocol for the preparation of sEH inhib-
itors with sulfone as the secondary pharmacophore is presented in
Scheme 3. The 3- or 4-nitrobenzenethiol 10 was treated with
1-bromo-3-chloropropane followed by reduction of the nitro group
to give the amino intermediate 11 which on treatment with vari-
ous aryl isocyanates resulted in chloro intermediate 12. Oxidation
of the thio functionality of intermediate 12 followed by reacting
with morpholine afforded the desired sulfone analogs 13.
The general structure activity relationships observed for scaf-
fold 1 are shown in Fig. 5. The relative impact of L2P3 fragments
on potency against the sEH enzyme are color coded with
green > yellow > orange > red. Fragments shown in green typically
afforded more potent compounds, while fragments shown in red,
the least. Enzyme IC50 values for selected examples from the explo-
O
O
O
H
N
H
N
N
OH
OH
OH
b
c
a
O
H
N
OH
OH
O
O
d
e
Figure 2. Acidic L2P3 fragments.

2742
S.-K. Anandan, R. D. Gless / Bioorg. Med. Chem. Lett. 20 (2010) 2740–2744
O
O
O
L2P3 Fragment
a)
b)
Cl
L2P3
L2P3
O2N
O2N
H2N
O
X
X
X
2
3
4
O
X
R-N=C=O
c)
X
O
L2P3
R
N
H
L2P3
R
N
H
N
H
N
H
O
meta-5, X = H
meta-6, X = F
para-5, X = H
para-6, X = F
Scheme 1. Preparation of amides. Reagents and conditions: (a) K2CO3, ACN, 60–85 °C, 12 h, 70–90%; (b) Fe/HCOONH4, toluene/H2O, 70–80 °C, 6–12 h, 40–70%; (c) DMF, 60–
80 °C, 12 h, 70–90%.
O
S
O
S
O
a)
b)
O
L2P3 Fragment
+
L2P3
Cl
O2N
H2N
7
8
R-N=C=O
c)
O
S
O
O
L2P3
R
N
H
N
H
9
Scheme 2. Preparation of sulfonamides. Reagents and conditions: (a) TEA, DCM, 3 h, 30–50%; (b) Pd/C, MeOH, rt, 12 h, 75–80%; (c) toluene, 12 h, 60 °C, 60–70%.
R-N=C=O
a)
b)
SH
c)
Cl
Br
Cl
+
S
Cl
O2N
H2N
10
11
O
S
O
O
d, e)
O
O
S
N
R
R
N
N
H
N
H
N
H
H
12
13
Scheme 3. Preparation of sulfones. Reagents and conditions: (a) NaOH, EtOH, rt 12 h, 71%; (b) RaNi, MeOH, rt, 3 h, 77%; (c) DCM, rt, 3 h, 50%; (d) m-CPBA, DCM, rt, 1 h, 50%; (e)
morpholine, ACN, 80 °C, 3 h, 40%.
Introduction of fluorine in the L1 phenyl linker in either the 3
position (6-para series) or the 4 position (6-meta series) appears
to afford a slight improvement in potency against the enzyme
(Table 1). It is not clear whether this is due to an electronic effect
on the urea NH or just an electronic effect decreasing the polarity
of the adjacent P2 amide moiety in the same fashion noted above in
the replacement of a P2 amide NH with an amide N-alkyl.17
Having explored the effect of structural variations in the L2P3
portion of the molecule with amide as the secondary pharmaco-
phore, we then explored the effect of substituting the amide sec-
ondary pharmacophore with sulfonamide or sulfone in selected
examples of scaffold 1. Enzyme IC50 values for selected sulfona-
mides and sulfones are presented in Table 2.
hibit superior enzyme inhibitory potency in comparison to the
corresponding meta substituted analogs (Table 1). This is in distinct
contrast with compounds with ether as the secondary pharmaco-
phore in which both the para substituted and meta substituted ser-
ies give comparable enzyme potencies.17 It would be reasonable to
postulate that this difference can be ascribed to increased
flexibility in the ether series or possibly the more polar character
of an amide, especially given that tertiary amides generally appear
to be more active than secondary amides. In the case of the meta
amide series, the polar amide may be infringing on the lipophilic
region in the enzyme near the P1 binding site, while in the para
amide series, the amide may be sufficiently distant.12a Although
the data set is small, it appears that compounds with sulfonamide
or sulfone as the secondary pharmacophore are significantly more
potent than the compounds with amide as the secondary pharma-
Compounds containing an amide as the secondary pharmaco-
phore at the para position on the L1 aromatic ring consistently ex-

S.-K. Anandan, R. D. Gless / Bioorg. Med. Chem. Lett. 20 (2010) 2740–2744
2743
N
N
N
N
f
O
N
g
h
l
CF3O
CF3
N
O
N
H
O
N
H
N
H
H
N
O
N
N
O
O
N
H
m
n
i
j
C
N
H
H2
H
N
O
N
O
N
H
N
O
H
N
Cl
R
P1
L1
P2
L2P3
N
k
O
O
H
N
OH
(N)
a
O
O
F
H
N
N
OH
OH
F
F
b
c
O
H
H
N
OH
OH
O
O
d
e
Figure 5. General SAR for P1 ureas and amides.
Table 1
IC50 valuesa for sEH inhibitors with amide as the secondary pharmacophore
Entry
Compound
R
L2P3
para Isomer IC50 (nM)
meta Isomer IC50 (nM)
1
2
3
4
5
6
7
8
9
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
5r
Adamantyl
Adamantyl
4-Trifluoromethylphenyl
Adamantyl
4-Trifluoromethylphenyl
Adamantyl
a
b
c
d
e
f
f
f
f
g
g
h
i
i
i
i
i
i
i
490
200
19
80
20
12
160
14
7
800
230
120
130
27
36
—
12
—
15
—
68
280
62
2800
—
130
22
—
4-Fluorophenyl
4-Trifluoromethylphenyl
4-Trifluoromethoxyphenyl
4-Trifluoromethylphenyl
4-Trifluoromethoxyphenyl
4-Trifluoromethylphenyl
Cyclohexyl
Adamantyl
Phenyl
4-Fluorophenyl
4-Chlorophenyl
4-Trifluoromethylphenyl
4-Trifluoromethoxyphenyl
4-Trifluoromethylphenyl
4-Chlorophenyl
Phenyl
4-Fluorophenyl
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
2
4
48
19
3
320
140
16
1
5s
5t
2
8
j
k
l
l
l
18
47
—
—
49
9
5u
5v
5w
5x
5y
5z
5aa
5ab
6a
6b
6c
6d
6e
6f
235
251
170
18
5
4
3
54
4
—
19
—
2
11
2
4-Chlorophenyl
4-Trifluoromethylphenyl
4-Trifluoromethoxyphenyl
4-Trifluoromethylphenyl
Adamantyl
4-Trifluoromethylphenyl
4-Chlorophenyl
4-Trifluoromethylphenyl
4-Chlorophenyl
4-Trifluoromethylphenyl
4-Chlorophenyl
l
l
—
—
m
n
f
h
h
i
i
l
l
110
16
760
—
38
18
—
6g
4-Trifluoromethylphenyl
8
a
IC50 determinations were done using a fluorescence assay.18

2744
S.-K. Anandan, R. D. Gless / Bioorg. Med. Chem. Lett. 20 (2010) 2740–2744
Table 2
IC50 valuesa for sEH inhibitors with sulfonamide and sulfone as the secondary pharmacophore
Entry
Compound
R
L2P3
para Isomer IC50 (nM)
meta Isomer IC50 (nM)
1
2
3
4
5
9a
9b
9c
13a
13b
4-Trifluoromethylphenyl
4-Trifluoromethylphenyl
4-Trifluoromethylphenyl
phenyl
g
i
l
—
—
5
3
1
54
1
3
1
1
100
1
4-Trifluoromethylphenyl
a
IC50 determinations were done using a fluorescence assay.18
5. Xu, D.; Li, N.; He, Y.; Timofeyev, V.; Lu, L.; Tsai, H.-J.; Kim, I.-H.; Tuteja, D.;
Mateo, R. K. P.; Singapuri, A.; Davis, B. B.; Low, R.; Hammock, B. D.;
Chiamvimonvat, N. Proc. Nat. Acad. Sci. 2006, 103, 18733.
cophore (Table 2). The examples prepared with sulfonamide as the
secondary pharmacophore are sufficiently active that it is difficult
to discern a significant difference in enzyme potency in the para
and meta substituted series. However, the para and meta sulfone
isomers appear to exhibit the same potency relationship as that
noted with compounds with amide as the secondary pharmaco-
phore. It is clear from these data that a variety of secondary phar-
macophores can be employed to prepare very potent sEH
inhibitors.
6. (a) 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; (b) Imig, J. D. Am. J. Physiol. Renal Physiol. 2005, 289, F496; (c)
Dorrance, A. M.; Rupp, N.; Pollock, D. M.; Newman, J. W.; Hammock, B. D.; Imig,
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7. (a) Node, K.; Huo, Y.; Ruan, X.; Yang, B.; Spiecker, M.; Ley, K.; Zeldin, D. C.; Liao,
J. K. Science 1999, 285, 1276; (b) Schmelzer, K. R.; Kubala, L.; Newman, J. W.;
Kim, I.-H.; Eiserich, J. P.; Hammock, B. D. Proc. Nat. Acad. Sci. 2005, 102, 9772; (c)
Smith, K. R.; Pinkerton, K. E.; Watanabe, T.; Pedersen, T. L.; Ma, S. J.; Hammock,
B. D. Proc. Nat. Acad. Sci. 2005, 102, 2186.
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10. Morisseau, C.; Goodrow, M. H.; Newman, J. W.; Wheelock, C. E.; Dowdy, D. L.;
Hammock, B. D. Biochem. Pharmacol. 2002, 63, 1599.
11. Kim, I.-H.; Nishi, K.; Tsai, H.-J.; Bradford, T.; Koda, Y.; Watanabe, T.; Morisseau,
C.; Blanchfield, J.; Toth, I.; Hammock, B. D. Biorg. Med. Chem. Lett. 2007, 15, 312.
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47, 2110; (b) Kim, I.-H.; Heirtzler, F. R.; Morisseau, C.; Nishi, K.; Tsai, H.-J.;
Hammock, B. D. J. Med. Chem. 2005, 48, 3621; (c) Li, H.-Y.; Jin, Y.; Morisseau, C.;
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Tsai, H.-J.; Do, Z. N.; Morisseau, C.; Hammock, B. D. Biorg. Med. Chem. Lett. 2006,
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Potent N,N0-diaryl urea sEH inhibitors incorporating several sec-
ondary pharmacophores and a variety of second linker/tertiary
pharmacophore L2P3 fragments have been prepared. Potent inhib-
itors with potentially metabolically stable, substituted aromatic R
groups and potency equivalent to adamantyl analogs have been
identified. Soluble epoxide hydrolase inhibitors containing urea
and amide primary pharmacophores exhibit subtle variations in
enzyme inhibitory potency based on the secondary pharmaco-
phore but tolerate considerable structural variation in the second
linker/tertiary pharmacophore L2P3 fragment. In general, more
lipophilic, nonpolar fragments afford the most potent inhibitors.
Further work is in progress to find optimum pharmacophore and
linker combinations that afford the desired potency, solubility,
selectivity, and appropriate pharmacokinetic properties.
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18. Fluorescence assays were carried out using 12-(3-adamantan-1-yl-
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