Unsymmetrical non-adamantyl N,N′-diaryl urea and amide inhibitors of soluble expoxide hydrolase

Article abstract of DOI:10.1016/j.bmcl.2009.05.102

Incorporation of an adamantyl group in prototypical soluble expoxide hydrolase (sEH) inhibitors afforded improved enzyme potency. We explored replacement of the adamantyl group in unsymmetrical ureas and amides with substituted aryl rings to identify equipotent and metabolically stable sEH inhibitors. We found that aryl rings, especially those substituted in the para position with a strongly electron withdrawing substituent, afforded enzyme IC₅₀ values comparable to the adamantyl compounds in an ether substituted, unsymmetrical N,N′-diaryl urea or amide scaffold.

Full text of DOI:10.1016/j.bmcl.2009.05.102

Bioorganic & Medicinal Chemistry Letters 19 (2009) 4259–4263
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Unsymmetrical non-adamantyl N,N0-diaryl urea and amide inhibitors of soluble
expoxide hydrolase
*
Sampath-Kumar Anandan , Heather K. Webb, Zung N. Do, Richard D. Gless
Arete Therapeutics, Inc., 3912 Trust Way, Hayward, CA 94545, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Incorporation of an adamantyl group in prototypical soluble expoxide hydrolase (sEH) inhibitors afforded
improved enzyme potency. We explored replacement of the adamantyl group in unsymmetrical ureas
and amides with substituted aryl rings to identify equipotent and metabolically stable sEH inhibitors.
We found that aryl rings, especially those substituted in the para position with a strongly electron with-
drawing substituent, afforded enzyme IC50 values comparable to the adamantyl compounds in an ether
substituted, unsymmetrical N,N0-diaryl urea or amide scaffold.
Received 7 April 2009
Accepted 22 May 2009
Available online 30 May 2009
Keywords:
sEH inhibitors
Non-adamantyl
Unsymmetrical urea
Ó 2009 Elsevier Ltd. All rights reserved.
Epoxides of arachidonic acids (epoxyeicosatrienoic acids or
EETs) are known modulators of biological processes such as vaso-
dilation in a range of vascular beds.1 Soluble expoxide hydrolase
(sEH) metabolizes EETs to the corresponding diols (dihydroxyei-
cosatrienoic acids or DHETs) by catalyzing the addition of water
to the epoxide moiety.2 Metabolism of EETs to DHETs by sEH often
leads to reductions in beneficial biological effects.3 Hence, inhibi-
tion of sEH leading to elevated levels of EETs has been proposed
as a new therapeutic target for a number of disease indications
including diabetes,4 hypertension,5 stroke,6 and inflammatory
diseases.7 AR9281, an sEH inhibitor from Arete Therapeutics, is
presently in a Phase 2 clinical trial program for the potential treat-
ment of type 2 diabetes mellitus.
O
N
R
P1
O
1
Linker
L2
Linker
L1
R
P3
P1
P2
Primary
Pharmacophore
Secondary
Pharmacophore
Tertiary
Pharmacophore
The most potent sEH inhibitors reported to date contain a urea or
amide as the central or ‘primary’ pharmacophore (Fig. 1).8 We have
recently reported potent sEH inhibitors containing the hydroxya-
mide moiety as a replacement for urea.9 Early animal studies with
prototype sEH inhibitors such as dicyclohexyl urea (DCU) or ada-
mantyldodecylurea(ADU)were hampered bypooraqueoussolubil-
ity. Incorporation of a solubilizing group at the end of the extended
alkyl chain afforded adamantyl ureido dodecanoic acid (AUDA).
Although AUDA was found to be more soluble than ADU or DCU, it
was still problematic to formulate for in vivo studies.10 Subse-
quently, introduction of polar functionality such as an ether, ester,
oramide asa ‘secondary’pharmacophore ca. 7.5 Åfromthe‘primary’
pharmacophore was found to afford improved aqueous solubility
and pharmacokinetic properties.11 Recent reports describe potent
sEH inhibitors based on conformationally rigid structures with
Figure 1. Pharmacophore model.
better pharmacokinetic profiles.12 Non-adamantyl R groups have
been reported with aliphatic L1 linkers.13
Although incorporation of adamantyl as the R group afforded
superior enzyme potency in prototypical sEH inhibitors,14 adaman-
tane rings can be readily metabolized in vivo to give rise to a
variety of inactive, hydroxylated adamantyl derivatives.15 Hence,
we explored replacement of the adamantyl group with various
substituted aryls to elucidate the SAR as well as to identify meta-
bolically more stable compounds. The aryl ether scaffold 1 was
selected as a convenient platform for the comparison of the effect
of various R groups on potency since compounds with both urea
and amide as the ‘primary’ pharmacophore P1 could be prepared
from a common amino precursor. Scaffold 1 also affords a reduc-
tion in the number of rotatable bonds seen in prototypical sEH
inhibitors such as ADU or AUDA and incorporates both a secondary
ether pharmacophore as well as a pendant morpholine as a tertiary
pharmacophore for increased solubility.11
* Corresponding author. Tel.: +1 510 300 1870; fax: +1 510 785 7061.
E-mail address: skumar@aretetherapeutics.com (S.-K. Anandan).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.05.102

4260
S.-K. Anandan et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4259–4263
O
O
a)
O
N
HO
N
S
O
O
2
3
X
X
O
3
b)
c)
H2N
OH
O
N
H
OH
4 (X = H)
5 (X = F)
6 (X = H)
7 (X = F)
X
X
O
d)
O
N
H
O
N
H2N
O
N
O
O
8 (X = H)
9 (X = F)
10 (X = H)
11 (X = F)
RCH2COOH
f)
RNCO
e)
X
X
O
O
R
R
N
H
N
H
O
N
N
O
N
H
O
O
14 (X = H)
15 (X = F)
12 (X = H)
13 (X = F)
Scheme 1. General synthetic scheme for the preparation of ureas and amides. Reagents and conditions: (a) MsCl, Et3N, DCM, 0 °C–rt, 3 h, 96%; (b) Boc2O, THF, reflux, 18 h,
95%; (c) CsCO3, DMF, 55 °C, 3 days, 82%; (d) 10% H3PO4, conc. HCl, rt, 2 h, 92%; (e) CHCl3, rt, 2–3 days, 60–83%; (f) EDCI, HOBT, DMAP, CHCl3, 19 h, rt, 50–65%.
The general synthetic route for the preparation of urea and
amide variations of scaffold 1 is shown in Scheme 1. Mesylation
of N-(3-hydroxypropyl)-morpholine 2 resulted in mesylate 3.
Reaction of the Boc protected phenol intermediates 6 and 7 with
mesylate 3 gave arylether intermediates 8 and 9. Removal of the
Boc group yielded the required amines 10 and 11 which upon
treatment with isocyanate gave the urea ether analogs 12 and
13. Reaction of amines 10 and 11 with the appropriate acid
resulted in amide ether analogs 14 and 15.
Synthesis of para substituted aryl urea analogs 19 and amide
analogs 20 was carried out using similar chemistry (Scheme 2) as
that used for the synthesis of the meta substituted analogs 12
and 14. Treatment of phenol 16 with mesylate 3 resulted in Boc
protected aniline 17 which was subsequently deprotected to afford
the required aniline intermediate 18. Aniline 18 on reaction with
either isocyanate or acid resulted in urea ether analogs 19 or amide
ether analogs 20.
Cyclohexylethers 25 and 26 were prepared as isomeric mixtures
starting from 3-aminocyclohexanol 22 as shown in Scheme 3.
Aminocyclohexanol 22 on treatment with either isocyanate or acid
resulted in urea 23 or amide 24 which upon reaction with
bromomorpholine 21, obtained by reacting N-(3-hydroxypropyl)-
morpholine 2 with carbon tetrabromide in the presence of triphen-
ylphosphine, yielded the desired urea ether analogs 25 or amide
ether analogs 26.
Enzyme IC50 values against human sEH for compounds in both
the urea and amide series 12–15 are shown in Tables 1 and 2. Use
of an aryl ring as the R group, especially one substituted in the para
position with a strongly electron withdrawing group, such as tri-
fluoromethyl or chlorine, affords enzyme IC50 values comparable
to the adamantyl group with CF3 < Cl < CF3O < F. Substitution at
the para position appears to have the largest effect. While potency
correlates reasonably well with the substituent Hammett
r value,
it is not clear whether this effect is due to the inductive effect of
the substituent or the lipophilicity of the binding site, that is, the
more electron donating substituents tend to be the more polar.
The presence of a polar, basic group as or on the aromatic ring,
for example, 3-pyridyl (12p or 14p) or 3-dimethylamino (12o),
gives a substantial loss in potency. Substitution at the ortho posi-
tion even by a small electronegative substituent such as fluorine
gives a loss in potency (e.g., 12g, 12h), while 2,6-disubstitution
with a bulkier group (e.g., 12m) gives a dramatic decrease in
potency. This latter result is likely due to steric hindrance near
the sEH catalytic site.
As a primary pharmacophore, urea, in general, was found to be
consistently more potent than amide across a range of R groups
with one notable exception. Adamantyl urea 12c is only slightly
more potent than adamantyl amide 14c while all other amides pre-
pared are ca. 5–50-fold less potent than the corresponding ureas.
The difference in activity between amide and the corresponding
urea with various R groups became more pronounced, especially
in less potent compounds. Replacement of the aryl L1 ligand with
1,3-cyclohexyl, for example, urea 25 and amide 26 (Table 2), does
not appear to offer any advantage in potency and introduces the
additional complexities of chiral and cis/trans isomers as well as
the potential for metabolic liability. Replacement of adamantyl
with cyclohexyl as the R group gave enzyme potencies approach-
ing that of adamantyl in the urea (12b vs 12c) but not in the amide
series (14b vs 14c). Substitution of t-butyl for adamantyl (12a vs
12c) as the R group gives dramatically reduced potency.

S.-K. Anandan et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4259–4263
4261
O
O
N
OH
O
O
3
a)
O
N
H
O
N
H
16
17
b)
O
O
N
O
O
N
RCH2COOH
d)
O
R
N
H
H2N
20
18
RNCO
c)
O
O
N
O
R
N
H
N
H
19
Scheme 2. General synthetic scheme for the preparation of ureas and amides. Reagents and conditions: (a) CsCO3, DMF, 55 °C, 2 days, 99%; (b) 4 M HCl/dioxane, rt, 1 h, 98%;
(c) DCM, rt, 18 h, 55–75%; (d) EDCI, HOBT, DMAP, DCM, rt, 18 h, 50–65%.
O
O
a)
Br
N
HO
N
2
21
RCH2COOH
d)
O
O
RNCO
b)
R
R
N
H
N
H
OH
N
H
OH
H2N
OH
24
22
23
21
c)
21
c)
O
O
R
R
N
N
H
N
H
O
N
H
O
N
O
O
25
26
Scheme 3. General synthetic scheme for the preparation of ureas and amides. Reagents and conditions: (a) Ph3P, CBr4, THF, rt, 18 h, 87%; (b) DMF, rt, 1.5 h, 91%; (c) NaH, DMF,
rt, 20 h, 58–70%; (d) EDCI, HOBT, DMAP, DMF, rt, 3 h, 50–65%.
Since inserting an electron withdrawing substituent in the R
group para to the urea nitrogen led to increased potency, a similar
strategy was investigated in the linker L1. Placing a fluoro substitu-
ent at the para position of L1 in the urea or amide series 12 and 14
resulted in a new series of compounds 13 and 15. Incorporation of
fluorine typically enhances the metabolic stability of an aryl ring as
well as of an ether side chain at the ortho position leading to
improved pharmocokinetics.17 Enzyme IC50 values for the fluoro-
aryl ureas 13 and amides 15 are summarized in Table 2. The
potency for the fluorophenyl urea compounds 13 appear, in general,
to be comparable to that of the desfluoro analogs 12 with the pos-
sible exception of 13e which is about threefold less potent. Amides
in the L1-fluoro series 15 with different R groups were found to be
about threefold less potent compared to desfluoro analogs 14.
The enzyme IC50 values for the para substituted urea and
amide analogs 19 and 20 are presented in Table 3. The regio-
chemistry of the ether attachment was found to have no signif-
icant effect on the relative potency. Both the meta substituted
(12 and 14) and para substituted (19 and 20) series gave compa-
rable potency. The urea analogs 19 are typically more potent
than the amide analogs 20 again except where R is adamantyl.
Replacement of the 1,4-substitued aryl ring at L1 with 1,4-cyclo-

4262
S.-K. Anandan et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4259–4263
Table 1
Table 4
Enzyme IC50 Valuesa for compounds 12 and 14
AUC and Cmax values for selected compounds
Compd
R
P1
L1
IC50 (nM)
Compd
R
P1
AUC0–24 h
(ng h/mL)
Cmax
(ng/mL)
12a
12b
12c
12d
12e
12f
12g
12h
12i
t-Butyl
Cyclohexyl
Adamantyl
Phenyl
NHCONH
NHCONH
NHCONH
NHCONH
NHCONH
NHCONH
NHCONH
NHCONH
NHCONH
NHCONH
NHCONH
NHCONH
NHCONH
NHCONH
NHCONH
NHCONH
CH2CONH
CH2CONH
CH2CONH
CH2CONH
CH2CONH
CH2CONH
CH2CONH
CH2CONH
CH2CONH
CH2CONH
1,3-Ph
1,3-Ph
1,3-Ph
1,3-Ph
1,3-Ph
1,3-Ph
1,3-Ph
1,3-Ph
1,3-Ph
1,3-Ph
1,3-Ph
1,3-Ph
1,3-Ph
1,3-Ph
1,3-Ph
1,3-Ph
1,3-Ph
1,3-Ph
1,3-Ph
1,3-Ph
1,3-Ph
1,3-Ph
1,3-Ph
1,3-Ph
1,3-Ph
1,3-Ph
1040
3.9
0.8
38
14
12b
Cyclohexyl
Phenyl
NHCONH
NHCONH
NHCONH
NHCONH
NHCONH
NHCONH
NHCONH
CH2CONH
CH2CONH
NHCONH
NHCONH
131
3570
491
3
8
9
753
0
57
102
1570
123
3
5
6
218
0
48
12d
12e
12f
12i
4-Fluorophenyl
3,4-Difluoro
4-Trifluoromethylphenyl
4-Chlorophenyl
3,4-Methylenedioxyphenyl
Adamantyl
4-Fluorophenyl
Cyclohexyl
4-Trifluoromethylphenyl
4-Fluorophenyl
3,4-Difluorophenyl
2,4-Difluorophenyl
2,4,6-Trifluorophenyl
4-Trifluoromethylphenyl
3-Trifluoromethylphenyl
4-Trifluoromethoxyphenyl
4-Chlorophenyl
2,6-Dichlorophenyl
3,4-Methylenedioxyphenyl
3-Dimethylaminophenyl
3-Pyridyl
t-Butyl
Cyclohexyl
Adamantyl
4-Fluorophenyl
3,4-Difluorophenyl
4-Trifluoromethylphenyl
4-Trifluoromethoxyphenyl
4-Chlorophenyl
3-Pyridyl
3,4-Methylenedioxyphenyl
11
121
1880
1
13.8
8
12l
12n
14c
14e
19b
19i
12j
12k
12l
863
1050
669
263
2
12m
12n
12o
12p
14a
14b
14c
14e
14f
14i
14k
14l
14p
14q
10,000
33
240
5000
1550
28
meta substituted ether compounds 12 exhibited a broad range of
oral exposure values (AUC), however the more potent inhibitors
containing electron withdrawing substituent on the aromatic ring
(e.g., 12f, 12i, and 12l) gave lower exposure. LC/MS/MS of plasma
samples indicated that the primary route of metabolism involved
hydroxylation of the morpholine ring18 and cleavage of the
aromatic ether. The best exposure was seen with the unsubstituted
phenyl analog 12d. Both the para substituted ether analogs 19b
and 19i exhibited superior exposure to the meta substituted ethers
12b and 12i. The amide analogs 14c and 14e were found to have
lower exposure than the urea analogs.
2.5
550
321
55
43
116
14,000
365
a
IC50 values for all sEH inhibitors were determined using a fluorescent assay.16
In conclusion, we have explored the SAR of the left hand side R
group in the aryl ether scaffold 1 and shown that aryl rings bearing
4-CF3, 4-Cl, and 4-CF3O afford enzyme potency comparable to that
afforded by the adamantyl group. We have identified a number of
potent urea and amide analogs with improved pharmacokinetics
over prototypical sEH inhibitors. Further work is in progress to
evaluate sEH inhibitors 12d, 12n, 19b, and 19i, which exhibit good
exposure, in animal efficacy models of type 2 diabetes.
Table 2
Enzyme IC50 Valuesa for compounds 13, 15, 25, and 26
Compd
R
P1
L1
IC50 (nM)
13b
13c
13d
13e
13i
13k
13l
15c
15i
Cyclohexyl
Adamantyl
Phenyl
NHCONH
NHCONH
NHCONH
NHCONH
NHCONH
NHCONH
NHCONH
CH2CONH
CH2CONH
CH2CONH
NHCONH
CH2CONH
1,3-Ph-4-F
1,3-Ph-4-F
1,3-Ph-4-F
1,3-Ph-4-F
1,3-Ph-4-F
1,3-Ph-4-F
1,3-Ph-4-F
1,3-Ph-4-F
1,3-Ph-4-F
1,3-Ph-4-F
1,3-Cyclohexyl
1,3-Cyclohexyl
6.5
0.8
81
4-Fluorophenyl
4-Trifluoromethylphenyl
4-Trifluoromethoxyphenyl
4-Chlorophenyl
Adamantyl
4-Trifluoromethylphenyl
4-Trifluoromethoxyphenyl
Adamantyl
40
1.3
0.8
4.8
6.6
156
145
2.5
5.2
References and notes
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Exp. Ther. 2008, 1, 108. 145102.
15k
25c
26c
2. Morisseau, C.; Hammock, B. D. Annu. Rev. Pharmacol. Toxicol. 2005, 45, 311.
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Hypertension 2005, 45, 759; (b) Chiamvimonvat, N.; Ho, C.-M.; Tsai, H.-J.;
Hammock, B. D. J. Cardiovasc. Pharm. 2007, 50, 225.
Adamantyl
a
IC50 values for all sEH inhibitors were determined using a fluorescent assay.16
6. (a) Dorrance, A. M.; Rupp, N.; Pollock, D. M.; Newman, J. W.; Hammock, B. D.;
Imig, J. D. J. Cardiovasc. Pharm. 2005, 46, 842; (b) Zhang, W.; Koerner, I. P.;
Noppens, R.; Grafe, M.; Tsai, H. -J.; Morisseau, C.; Luria, A.; Hammock, B. D.;
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7. (a) Schmelzer, K. R.; Kubala, L.; Newman, J. W.; Kim, I. -H.; Eiserich, J. P.;
Hammock, B. D. Proc. Nat. Acad. Sci. 2005, 102, 9772; (b) Imig, J. D.; Zhao, X.;
Zaharis, C. Z.; Olearczyk, J. J.; Pollock, D. M.; Newman, J. W.; Kim, I.-H.;
Watanabe, T.; Hammock, B. D. Hypertension 2005, 46, 975.
hexyl is reported to afford comparable enzyme IC50 values for
the urea series when R is adamantyl.11
Pharmacokinetics of selected urea analogs 12 and 19 and amide
analog 14 were evaluated in healthy male Sprague Dawley rats fol-
lowing oral administration of compound at 5 mg/Kg (Table 4). The
8. (a) Kim, I. –H.; Morisseau, C.; Watanabe, T.; Hammock, B. D. J. Med. Chem. 2004,
47, 2110; (b) Kim, I.-H.; Heirtzler, F. R.; Morisseau, C.; Nishi, K.; Hammock, B. D.
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Table 3
Enzyme IC50 Valuesa for compounds 19 and 20
Compd
R
P1
L1
IC50 (nM)
19b
19c
19d
19i
19k
19l
20c
20d
20i
20k
20l
Cyclohexyl
Adamantyl
Phenyl
4-Trifluoromethylphenyl
4-Trifluoromethoxyphenyl
4-Chlorophenyl
Adamantyl
NHCONH
NHCONH
NHCONH
NHCONH
NHCONH
NHCONH
CH2CONH
CH2CONH
CH2CONH
CH2CONH
CH2CONH
1,4-Ph
1,4-Ph
1,4-Ph
1,4-Ph
1,4-Ph
1,4-Ph
1,4-Ph
1,4-Ph
1,4-Ph
1,4-Ph
1,4-Ph
5.4
1.3
39
0.8
0.8
1.5
1.3
870
54
Phenyl
4-Trifluoromethylphenyl
4-Trifluoromethoxyphenyl
4-Chlorophenyl
42
140
14. Morisseau, C.; Goodrow, M. H.; Newman, J. W.; Wheelock, C. E.; Dowdy, D. L.;
Hammock, B. D. Biochem. Pharmacol. 2002, 63, 1599.
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a
IC50 values for all sEH inhibitors were determined using a fluorescent assay.16

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