1-(1-Acetyl-piperidin-4-yl)-3-adamantan-1-yl-urea (AR9281) as a potent, selective, and orally available soluble epoxide hydrolase inhibitor with efficacy in rodent models of hypertension and dysglycemia

Article abstract of DOI:10.1016/j.bmcl.2010.12.042

1-(1-Acetyl-piperidin-4-yl)-3-adamantan-1-yl-urea 14a (AR9281), a potent and selective soluble epoxide hydrolase inhibitor, was recently tested in a phase 2a clinical setting for its effectiveness in reducing blood pressure and improving insulin resistance in pre-diabetic patients. In a mouse model of diet induced obesity, AR9281 attenuated the enhanced glucose excursion following an intraperitoneal glucose tolerance test. AR9281 also attenuated the increase in blood pressure in angiotensin-II-induced hypertension in rats. These effects were dose-dependent and well correlated with inhibition of the sEH activity in whole blood, consistent with a role of sEH in the observed pharmacology in rodents.

Full text of DOI:10.1016/j.bmcl.2010.12.042

Bioorganic & Medicinal Chemistry Letters 21 (2011) 983–988
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
1-(1-Acetyl-piperidin-4-yl)-3-adamantan-1-yl-urea (AR9281) as a potent,
selective, and orally available soluble epoxide hydrolase inhibitor with
efficacy in rodent models of hypertension and dysglycemia
Sampath-Kumar Anandan a, , Heather Kay Webb a, Dawn Chen a, Yi-Xin (Jim) Wang a, Basker R. Aavula a,
⇑
Sylvaine Cases a, Ying Cheng a, Zung N. Do a, Upasana Mehra a, Vinh Tran a, Jon Vincelette a,
Joanna Waszczuk a, Kathy White a, Kenneth R. Wong a, Le-Ning Zhang a, Paul D. Jones b, Bruce D. Hammock b,
Dinesh V. Patel a, Randall Whitcomb a, D. Euan MacIntyre a, James Sabry a, Richard Gless a
a Arête Therapeutics, Inc., 7000 Shoreline Court, South San Francisco, CA 94080, United States
b Department of Entomology and UCD Cancer Center, One Shields Avenue, University of California, Davis, CA 95616, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
1-(1-Acetyl-piperidin-4-yl)-3-adamantan-1-yl-urea 14a (AR9281), a potent and selective soluble epoxide
hydrolase inhibitor, was recently tested in a phase 2a clinical setting for its effectiveness in reducing
blood pressure and improving insulin resistance in pre-diabetic patients. In a mouse model of diet
induced obesity, AR9281 attenuated the enhanced glucose excursion following an intraperitoneal glucose
tolerance test. AR9281 also attenuated the increase in blood pressure in angiotensin-II-induced hyperten-
sion in rats. These effects were dose-dependent and well correlated with inhibition of the sEH activity in
whole blood, consistent with a role of sEH in the observed pharmacology in rodents.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 16 November 2010
Revised 4 December 2010
Accepted 7 December 2010
Available online 13 December 2010
Keywords:
sEH inhibitor
AR9281
Efficacy
DIO model
AngII hypertension model
Diabetes
Soluble epoxide hydrolase (sEH, Epxh2) has attracted consider-
able interest over the last decade as a novel pharmaceutical target
primarily for cardiovascular and inflammatory disease as well as
a number of other indications. Considerable effort has been ex-
pended both in academia and the pharmaceutical industry to devel-
op novel, drug-like inhibitors.1 We wish to report the chemical
details and rationale for the selection of the sEH inhibitor, 1-(1-
acetyl-piperidin-4-yl)-3-adamantan-1-yl-urea2 14a (AR9281), as a
candidate for human clinical trials in hypertension and metabolic
syndrome.3 sEH is responsible for the conversion of C18, C20, and
C22 epoxy lipids, including epoxyeicosatrienoic acids (EETs), which
are formed by the monooxygenase epoxidation of arachidonic acid
by CYP2J and CYP2C epoxygenases, to the corresponding dihydr-
oxyeicosatrienoic acids (DHETs). EETs are recognized modulators
of biological function eliciting a range of pharmacological effects,
while the corresponding DHETs are less active.4 Inhibition of sEH
is proposed to stabilize EETs and effectively increase EET concentra-
tions in relevant compartments to produce biological effects. sEH
attracted attention as a potential pharmaceutical target based on
reports of lipid modulatory, anti-hypertensive, cardioprotective, or-
gan protective, and anti-inflammatory effects in a variety of animal
models.5–17 The observed profile of effects suggest that sEH inhibi-
tion should have a beneficial impact on the component processes
and symptoms of metabolic syndrome.5
Prototypical sEH inhibitors, dicyclohexyl urea (DCU) 1 and ada-
mantyl ureido dodecanoic acid (AUDA) 2, are potent enzyme inhib-
itors (DCU IC50 = ca. 52 nM, AUDA IC50 = ca. 3 nM),18 but suffer
from less than optimal physical properties and lack appropriate
pharmacokinetic behavior for drug development.19 Subsequent ef-
forts have involved modification of the lipophilic aliphatic chain of
AUDA on the right hand side (RHS) of the urea primary pharmaco-
phore and introduction of rigid cyclic moieties on both the right
and left hand side (LHS) resulting in compounds with improved
potency and drug-like properties.1 Most of the potent sEH inhibi-
tors published to date contain urea as the primary pharmacophore.
However, Boehringer Ingelheim and Merck have recently reported
potent sEH inhibitors with improved pharmacokinetic behavior
with amide as the primary pharmacophore utilizing rigid, biaryl
and/or spirocyclic moieties as the LHS/RHS portions. Boehringer re-
ports optimization of its amide-based diphenylmethane series for
metabolic stability and reports compound 3 as an optimal com-
pound showing excellent potency and in vitro microsomal stability
resulting in good plasma exposure in rat.20 A second, amide-based
⇑
Corresponding author. Tel.: +1 650 737 4610; fax: +1 510 737 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.2010.12.042

984
S.-K. Anandan et al. / Bioorg. Med. Chem. Lett. 21 (2011) 983–988
series, exemplified by compound 4, is also reported.21 No animal
pharmacology studies are reported for either series. Merck has dis-
closed three structural classes of potent, urea-based inhibitors
exemplified by compounds 5, 6, and 7, as well as a series of non-
urea, non-amide based inhibitors.22,23 However, despite desirable
PK and demonstrated target engagement, compounds 5, 6, and 7
failed to show efficacy in an SHR hypertensive model.22 No results
for AngII-hypertensive rat models were reported by Merck in spite
of this being one of the standard paradigms used in previous sEH
hypertension studies.6,7,9
The synthesis of 14a and its analogs via key intermediates 10
and 11 is shown in Scheme 1. This library approach allows facile
preparation of various LHS and RHS combinations around the pipe-
ridinyl urea nucleus. An additional advantage of this approach is
that it allows urea formation using a nucleophilic amine via inter-
mediate 11 rather than via an isocyanate.24 In some cases, espe-
cially with UV transparent amines such as adamantylamine and
cyclohexylamine, the corresponding symmetrical ureas, for exam-
ple, dicyclohexyl- and bisadamantyl urea, which are unavoidable
O
O
OH
N
H
N
H
N
H
N
H
O
1 DCU
2 AUDA
F
O
Cl
O
N
H
F C
3
N
H
O
N
SO Me
2
CN
SO Me
2
4
3
O
O
N
N
H
N
N
H
O
N
N
O
N
6
O
5
O
OH
Cl
O
N
N
H
7
impurities in the isocyanates, can be almost impossible to remove
efficiently from a reaction product and are potent inhibitors of sEH
in their own right. Urea formation with aryl isocyanates is less
problematic.
One of the many structural variations on sEH inhibitors pub-
lished by the Hammock laboratory involved incorporation of a solu-
bilizing group into one of the cyclohexane rings of DCU 1. The
resulting 4-piperidinyl ureas were reported to be potent sEH inhib-
itors.2 We focused on expanding the SAR around the piperidinyl
urea-based sEH inhibitors 14 and wish to report the details of the
chemistry SAR and the rationale for the selection of one member
of this chemical series, 1-(1-acetyl-piperidin-4-yl)-3-adamantan-
1-yl-urea2 14a (AR9281), as a clinical candidate in hypertension
and metabolic syndrome.3
The readily available N-Boc protected piperidone 8 is reacted
with hydroxyl amine to obtain the corresponding oxime 9 which
is subsequently reduced with Raney nickel to afford the N-Boc
aminopiperidine 10. Treatment of N-Boc-4-piperidineamine 10
with p-nitrobenzene chloroformate affords key intermediate 11.
At this point amine 10 can be treated with an isocyanate to provide
the Boc protected urea 12. This sequence was typically used with
aromatic isocyanates. An alternate procedure was employed for
certain more nucleophilic, UV transparent amines. Reaction of
intermediate 11 with nucleophilic amines at room temperature af-
fords LHS substituted products 12. Less nucleophilic amines, for
example, aromatic amines can also be reacted with 11 but require
elevated reaction temperatures. The Boc group on 12 can then be
removed with TFA to give the corresponding amine intermediate
13. Amine 13 can be treated with various reagents, for example,
O
O
N
N
H
N
H
14a (AR9281)

S.-K. Anandan et al. / Bioorg. Med. Chem. Lett. 21 (2011) 983–988
Boc
985
Boc
Boc
a)
b)
N
N
N
HO
O
N
H2N
8
9
10
R1-NCO
d)
c)
Boc
Boc
O
N
O
R1-NH2
e)
N
R1
p-O2NPh
N
H
N
H
O
N
H
11
12
f)
R
O
O
N
NH
g)
R1
R1
N
H
N
H
N
H
N
H
13
14
Scheme 1. Preparation of piperidinyl ureas 14: (a) NH2OHÁHCl, EtOH, pyridine, reflux, 1 h, 82%; (b) RaNi, MeOH, rt, 4 h, 83%; (c) p-nitrophenyl chloroformate, DCM, 2 h, 87%;
(d) DCM, rt, 12 h, 82%; (e) THF, reflux, 12 h, 85%; (f) TFA, DCM, rt, 12 h, 88%; (g) Ac2O or MeSO2Cl, DCM, rt, 18 h, 70–90%.
activated carboxylic acids or sulfonyl chlorides, to afford the de-
sired substituted piperidinyl urea 14. Representative compounds
are shown in Table 1. An alternate preparation of 14a useful for
large scale preparations has been disclosed in the patent
literature.25
Piperidinyl urea 14a exhibited excellent enzyme and cell-based
assay IC50 values, but the pharmacokinetic profile in rat was less
than ideal. The poor pharmacokinetic behavior was identified as
due to rapid CYP mediated metabolic oxidation at the adamantyl
group in vivo.26 Introduction of electronegative fluorine(s) on the
LHS to circumvent CYP oxidation was investigated, but analogues
with mono fluoro or trifluoro substitution on the adamantyl ring27
(Table 1: 14b, 14c) afforded reduced enzyme potency. A similar
drop in potency with fluorine introduction was also observed with
a cyclohexyl LHS, for example, 14f and 4,4-difluorocyclohexyl ana-
logue 14j. Replacement of the adamantyl group with a 4-trifluoro-
methylphenyl, for example, 14k, or 4-trifluoromethoxyphenyl, for
example, 14m, group gave comparable enzyme and cell-based
Table 1
Enzyme and cell IC50 values, hERG inhibition and oral exposure for selected sEH inhibitors
Compd
R1
R
hsEHa IC50 (nM)
Cellb IC50 (nM)
hERGc% inhibition
Rat AUC24 h (ng h/mL)e
at 30 lM
14a
14b
14c
14d
14e
14f
Adamantyl
COCH3
COCH3
COCH3
COCH3
COCH3
COCH3
8
58
120
25
14
57
—
—
300
120
—
<8d
—
—
—
—
720
—
—
1480
—
—
3-Fluoroadamantyl
3,5,7-Trifluoroadamantyl
4-Methyl[2,2,2]bicyclooctyl
[2,2,1]Cycloheptyl
Cyclohexyl
29
—
14g
14h
14i
14j
14k
14l
14m
14n
14o
14p
14q
14r
14s
Cycloheptyl
COCH3
COCH3
COCH3
COCH3
COCH3
COCH3
COCH3
SO2CH3
SO2CH3
CO(3-pyridyl)
CO(2-pyridyl)
SO2CH(Me)2
SO2CH(Me)2
0.8
13
6.0
185
11
27
270
38
—
98
226
59
3.9
26
6.7
67
13
64
9
7
7840
4-t-Butylcyclohexyl
4,4-Dimethylcyclohexyl
4,4-Difluorocyclohexyl
4-CF3Phenyl
3-CF3Phenyl
4-CF3OPhenyl
Adamantyl
4-CF3Phenyl
4-CFO3Phenyl
Cyclohexyl
1780
f
0.8
—
35
10
—
À2.8
34
57
3.4
13
11
—
13100
19600
—
10
12
1.9
3.7
1.6
6.4
2.9
1.6
640
6850
11300
8320
5890
7300
4-CF3Phenyl
4-CF3OPhenyl
a
b
c
d
e
f
Enzyme activity was determined in duplicate.18
Conversion of 14,15-EET to 14,15-DHET was measured in HUVEC cell.
hERG activity inhibition was determined by a high throughput patch clamp method.
8% at 100 M.
l
Data for PO dosing normalized to 10 mg/kg.
PO data not available; IV showed a very short half life.

986
S.-K. Anandan et al. / Bioorg. Med. Chem. Lett. 21 (2011) 983–988
assay potency and afforded a dramatic improvement in the phar-
macokinetic profile. Unfortunately, replacing the adamantyl group
on the LHS with substituted phenyl had a decidedly negative effect
on hERG channel liability. While 14a showed only 8% hERG chan-
against microsomal epoxide hydrolase or an extended panel of
ca. 150 other enzyme and receptor targets when tested at 10 M.
l
No significant inhibition of drug metabolizing CYP enzymes such
as CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A4, as well as
CYP2J and CYP2C, which are essential for the production of EETs
was noted with 14a. The plasma protein binding of the compound
was modest, ranging from 58% to 61% across multiple species. The
compound was highly permeable across a Caco-2 monolayer.
When administered orally, 14a was well absorbed in various spe-
cies with oral bioavailability ranging from 25% in cynomolgus
monkey to 100% in rat. The oral exposure, as measured by the area
under the plasma concentration–time curve, increased in approxi-
mate proportion to dose up to 2000 mg/kg in rats, 500 mg/kg in
dogs, and 180 mg/kg in cynomolgus monkeys. The compound
had a relatively moderate to high clearance and short half life,
and is eliminated primarily by the oxidative modifications on the
adamantyl ring, in the form of hydroxylated adamantyl
metabolites.
Following the establishment of potency and pharmacokinetic
properties, several compounds from different series as well as
14a were evaluated in an AngII-infused rat model of hypertension.
This model was selected for early pharmacological evaluation due
to the published efficacy of AUDA.7 Compounds were tested at
50 mg/kg, dosed orally twice daily in a suspension in 0.5% carboxy-
methylcellulose, 0.1% Tween 80 in Sprague–Dawley rats that were
induced to be hypertensive by a continuous infusion of 65 ng/min
of AngII. The blood pressure was assessed continuously by telemet-
ric recording. Of the compounds tested, 14a showed superior effi-
cacy in reducing systolic and diastolic blood pressure. Relative to
vehicle control treatment, systolic blood pressure was decreased
by 8–10% (or 14–16 mm Hg) with a more modest effect on diastolic
pressure. This result was confirmed independently in a second
laboratory.28
nel block at 100
lM, both 14k and 14o showed ca. 35% inhibition
at 30 M, which was judged to be unacceptable. A large number of
l
analogues with various electron withdrawing groups, for example,
F, Cl, Br, CF3, CF3O, CHF2O, and CF3CH2, substituted independently
at one or two of the 3, 4, and 5 positions on the aromatic ring to
alter the electronic nature and/or steric requirements of the LHS
aryl system afforded no significant improvement in hERG liability
with the exception of the 3-trifluoromethylphenyl analogue 14l
which shows a significant loss in cell potency. Use of one or more
electron donating groups on the LHS aryl ring or use of a LHS het-
eroaryl ring also gave no improvement in hERG liability and typi-
cally resulted in less effective sEH enzyme inhibition (data not
shown). While most of the examples given in the table contain
N-acetyl as the RHS functionality, additional analogues with an
N-sulfonyl RHS were also prepared. These analogues were, in gen-
eral, more potent than the N-acetyl analogues (e.g., 14n, o vs 14a,
k) but the increase in potency was compromised by decreased oral
exposure. While the methyl sulfonamide analogue 14o had very
similar hERG liability compared to the acetamide analogue 14k,
the isopropyl sulfonamide 14r was found to block the hERG chan-
nel by threefold less. Introduction of aryl or pyridyl rings in the
RHS along with aryl LHS substitution, for example, 14p, gave in-
creased hERG liability. The hERG liability with an aryl RHS series
could be ameliorated by substituting cycloalkyl for aryl on the
LHS as shown in example 14q. While cycloalkyl replacements for
adamantyl LHS (14g–14i) afforded reduced hERG liability, no sig-
nificant improvement in pharmacokinetic profile was observed.
Piperidinyl urea compounds with a cycloalkyl LHS including
adamantyl, for example, 14a, typically showed an oral pharmaco-
kinetic profile that indicated a rapid absorption with a high Cmax
,
Compound 14a was also tested in an SHR rat model of hyper-
tension8 and was found to be moderately efficacious at a dose of
300 mg/kg with a 14% decrease in mean blood pressure, but no ef-
fect was noted at 100 mg/kg. These data are consistent with the re-
cent report22 showing a lack of correlation between potency and
exposure with blood pressure lowering in the SHR model. sEH
inhibitors exert antihypertensive effects in some but not all animal
models of hypertension.28 Collectively, the lack of a robust rela-
tionship between target engagement, exposure, and the pharmaco-
logical endpoint was insufficient to support solely a human
hypertension indication for clinical evaluation of sEH inhibitors.
The hypertension models utilized were based on the literature
precedence for a blood pressure lowering effect of sEH inhibitors
both in AngII-induced hypertension,7 and in SHR.8 Compound
14a was subsequently evaluated in a diet induced-obesity (DIO)
mouse model of aberrant glucose regulation.29 The DIO mouse
model tested the pharmacology of these inhibitors in a model of
insulin resistance with anticipated activity due in part to the vaso-
dilator, lipid modulatory and anti-inflammatory effects of EETs.14
EETs have been shown, to play a role in endothelial cell function
and vascular inflammatory processes, involving modulation of
but rapid metabolism manifested by a short half life and relatively
high oral clearance. Reduction of metabolic liability in non-ada-
mantyl LHS cycloalkyl groups was attempted by introducing steric
hindrance or electron withdrawing fluorine groups. None of these
compounds afforded the desired improvement in pharmacokinetic
profile, although all gave significant reduction in hERG inhibition.
Replacement of the adamantyl group with aryl did result in potent
sEH inhibitors with the desired pharmacokinetic profile but they
all suffered from increased inhibition of hERG activity. Since the
targeted disease states, that is, hypertension and metabolic syn-
drome are chronic indications, it was decided to advance com-
pounds having reasonable PK and extended inhibition of sEH
with minimal risk of cardiovascular toxicity. Compound 14a was
the candidate of choice based on scalable PK, target engagement,
and its consistent efficacy in animal models of hypertension and
diet induced obesity.
Compound 14a is a potent inhibitor with a human sEH enzyme
IC50 value of 8 nM and mouse sEH enzyme IC50 value of 3 nM. The
cell-based human sEH IC50 value was found to be 57 nM consistent
with a ca. 10-fold decrease in potency seen for most of the sEH
inhibitors between isolated enzyme and cell-based assays. In mur-
ine PK/PD experiments, the plasma concentrations of 14a were di-
rectly correlated with the inhibition of sEH activity in the whole
blood, as measured by the hydrolysis rate of 14,15-EET. Plasma
exposure was also directly associated with increases in ratios of
endogenous epoxy-to-dihydroxy lipids. Total EET/DHET and
EpOME/DiHOME (9,10- and 12,13-octadecenoic acid) ratios in
14a-treated wild type mice, where blood sEH activity was inhib-
ited 90%, were similar to those in Ephx deficient mice. An oral dos-
ing schedule of 100 mg/kg BID in mice resulted in an extended
period of 90% or greater inhibition of blood sEH activity. Compound
14a was found to be highly selective with no inhibitory activity
NF-j
B-mediated transcription.30 Vascular inflammation has been
implicated as an important factor in insulin sensitivity.31 EETs
are regulated by sEH,32 and EETs have been shown to modulate
PPARc33 and eNOS.34 The enzymes, PPAR
c and eNOS, are regula-
tors in insulin resistance.35 Thus, sEH inhibition was proposed as
a mechanism by which insulin resistance could be improved in a
model of diet-induced obesity.
The efficacy of 14a was evaluated in DIO male C57Bl/6 mice
with emphasis on the impact of administration of 14a on glucose
excursions following a bolus administration of glucose. C57BL/6
mice were fed a high fat, high fructose diet using Research Diets
45% fat diet, D12451, with administration of high fructose corn

S.-K. Anandan et al. / Bioorg. Med. Chem. Lett. 21 (2011) 983–988
987
Figure 1. Evaluation of 14a (AR9281) in DIO mouse model. Left is the blood glucose levels over time following an intraperitoneal administration in a typical experiment. Right
is the whole blood sEH activity following the last dose of the study.
syrup in the liquid portion of the diet at 0.42 kcal/mL for 6 weeks
prior to initiation of AR9281 administration and throughout
AR9281 administration.29 Accordingly, 14a or vehicle was adminis-
tered via oral gavage at a dose of 100 mg/kg twice a day for an
additional 12 weeks. After 4 weeks treatment, a glucose tolerance
test was conducted by intraperitoneal injection of glucose (2 g/
kg) at 4 h after the dose of 14a. Blood glucose measurements were
taken with a glucometer at time intervals up to 2 h following glu-
cose administration. The vehicle-treated mice had an impaired glu-
cose tolerance evidenced by the blood glucose excursions being in
excess of mice fed normal chow and that the blood glucose concen-
tration was still not restored to the baseline at 2 h after glucose
load (Fig. 1, left). However, in comparison to vehicle-treated ani-
mals, the 14a-treated mice had a lower glucose AUC as well as low-
er maximal glucose excursion. At the end of the study, blood
samples were taken at specific times after the last dose and pro-
cessed to plasma for 14a concentration measurements using LC/
MS/MS and blood sEH activity. Blood sEH activity was defined as
the rate of 14, 15 EET hydrolysis, corrected for non-specific hydro-
lysis in the presence of 5 mM AUDA.29 sEH activity was undetect-
able in whole blood from animals receiving 14a for up to 7 h post
administration. The sEH-catalyzed EET hydrolysis activity contin-
ued to be inhibited by ꢀ70% for 12 h after the last dose, suggesting
that at trough there continued to be significant target inhibition
(Fig. 1, right).29 These results indicate that 14a inhibited sEH activ-
ity and significantly improved glucose tolerance in a DIO mouse
model.
In conclusion we have shown that piperidinyl urea 14a
(AR9281) is a potent sEH inhibitor with excellent selectivity
against other targets. AR9281 was well tolerated in early animal
and human dose range finding toxicology studies.29 AR9281 af-
fords an acceptable half life in mouse for pharmacology testing
with whole blood sEH activity essentially completely inhibited
for up to 7 h post administration and still inhibited by ꢀ70% for
12 h after the last 100 mg/Kg dose. In humans it was shown that
greater than 90% inhibition of blood sEH was possible with once
a day and twice a day dosing.36 Based on the blood pressure low-
ering activity in the AngII-induced hypertension and SHR models
and the more robust activity in the DIO mouse, 14a (AR9281)
was selected for proof of concept studies in a human clinical trial
involving obese patients with stage 1 hypertension and impaired
glucose tolerance.
Acknowledgments
Partial support for P.D.J. and B.D.H. came from NIEHS R01
ES002710. B.D.H. is a George and Judy Marcus Senior Fellow of
the American Asthma Foundation. P.D.J. was supported in part by
an NIH/NHLBI Ruth L. Kirchstein NRSA Grant (F32 HL078096).
References and notes
1. (a) Marino, J. P., Jr. Curr. Top. Med. Chem. 2009, 9, 452; (b) Shen, H. C. Expert Opin.
Ther. Patents 2010, 20, 1.
2. (a) Jones, P. D.; Tsai, H.-J.; Do, Z. N.; Morisseau, C.; Hammock, B. D. Bioorg. Med.
Chem. Lett. 2006, 16, 5212; (b) Rose, T. E.; Morisseau, C.; Liu, J.-Y.; Inceoglu, B.;
Jones, P. D.; Sanborn, J. R.; Hammock, B. D. J. Med. Chem. 2010, 53, 7067.
3.
A randomized, double-blind, placebo-controlled, dose-ranging, exploratory,
28-day study to examine the effects of AR9281 on blood pressure and glucose
tolerance in patients with mild to moderate hypertension and impaired glucose
tolerance. ClinicalTrials.gov, ID NCT00847899.
4. (a) Spector, A. A.; Norris, A. W. Am. J. Physiol. Cell Physiol. 2007, 292, C996; (b)
Lason, B. T.; Gutterman, D. D.; Hatoum, O. A. Eur. J. Clin. Invest. 2006, 36, 293; (c)
Spector, A. A.; Fang, X.; Snyder, G. D.; Weintraub, N. L. Prog. Lipid Res. 2004, 434,
55.
5. (a) De Taeye, B. M.; Morisseau, C.; Coyle, J.; Covington, J. W.; Luria, A.; Yang, J.;
Murphy, S. B.; Friedman, D. B.; Hammock, B. D.; Vaughan, D. E. Obesity 2010, 18,
489; (b) Sodhi, K.; Inoue, K.; Gotlinger, K. H.; Canestraro, M.; Vanella, L.; Kim, D.
H.; Manthati, V. L.; Koduru, S. R.; Falck, J. R.; Schwartzman, M. L.; Abraham, N.
G. J. Pharmacol. Exp. Ther. 2009, 331, 906; (c) Burdon, K. P.; Lehtinen, A. B.;
Langefeld, C. D.; Carr, J. J.; Rich, S. S.; Freedman, B. I.; Herrington, D.; Bowden, D.
W. Diab. Vasc. Dis. Res. 2008, 5, 128; (d) Luo, P.; Chang, H.-H.; Zhou, Y.; Zhang,
S.; Hwang, S. H.; Morisseau, C.; Wang, C.-Y.; Inscho, E. W.; Hammock, B. D.;
Wang, M.-H. J. Pharmacol. Exp. Ther. 2010, 334, 430; (e) Mustafa, S.; Sharma, V.;
McNeill, J. H. Exp. Clin. Cardiol. 2009, 14, e41; (f) Lyer, A.; Fairlie, D. P.; Prins, J.
B.; Hammock, B. D.; Brown, L. Nat. Rev. Endocrinol. 2010, 6, 71; (g) Ohtoshi, K.;
Kaneto, H.; Node, K.; Nakamura, Y.; Shiraiwa, T.; Matsuhisa, M.; Yamasaki, Y.
Biochem. Biophys. Res. Commun. 2005, 331, 347; (h) Webb, H. WO 08058033 A2,
2008.; (i) Larsen, B. T.; Campbell, W. B.; David, D.; Gutterman, D. D. Trends
Pharmacol. Sci. 2007, 28, 32.
6. Jung, O.; Brandes, R. P.; Kim, I.; Schweda, F.; Schmidt, R.; Hammock, B. D.;
Busse, R.; Fleming, I. Hypertension 2005, 45, 759.
7. 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.
8. 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, 87, 992.
9. (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.
10. Dorrance, A. M.; Rupp, N.; Pollock, D. M.; Newman, J. W.; Hammock, B. D.; Imig,
J. D. J. Cardiovasc. Pharmacol. 2005, 46, 842.
11. 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. Natl. Acad. Sci. 2006, 103, 18733.

988
S.-K. Anandan et al. / Bioorg. Med. Chem. Lett. 21 (2011) 983–988
12. (a) Liu, Y.; Webb, H.; Kroetz, D. L. FASEB J. 2008, 22, 479.19.; (b) Parrish, A. R.;
Chen, G.; Burghardt, R. C.; Watanabe, T.; Morisseau, C.; Hammock, B. D. Cell
Biol. Toxicol. 2009, 25, 217.
23. Shen, H. C.; Ding, F. X.; Deng, Q.; Xu, S.; Tong, X.; Zhang, X.; Chen, Y.; Zhou, G.;
Pai, L.-Y.; Alonso-Galicia, M.; Roy, S.; Zhang, B.; Tata, J. R.; Berger, J. P.; Colletti,
S. L. Bioorg. Med. Chem. Lett. 2009, 9, 5716.
13. (a) Zhang, L.-N.; Vincelette, J.; Cheng, Y.; Mehra, U.; Chen, D.; Anandan, S.-K.;
Gless, R.; Webb, H. K.; Wang, Y.-X. Arterioscler. Thromb. Vasc. Biol. 2009, 29,
1265; (b) Ulu, A.; Davis, B. B.; Tsai, H.-J.; Kim, I.-H.; Morisseau, C.; Inceoglu, B.;
Fiehn, O.; Hammock, B. D.; Weiss, R. H. J. Cardiovasc. Pharmacol. 2008, 52, 314.
14. Node, K.; Huo, Y.; Ruan, X.; Yang, B.; Spiecker, M.; Ley, k.; Zeldin, D. C.; Liao, J. K.
Science 1999, 285, 1276.
15. Schmelzer, K. R.; Kubala, L.; Newman, J. W.; Kim, I.-H.; Eiserich, J. P.; Hammock,
B. D. Proc. Natl. Acad. Sci. 2005, 102, 9772.
16. Smith, K. R.; Pinkerton, K. E.; Watanabe, T.; Pedersen, T. L.; Ma, S. J.; Hammock,
B. D. Proc. Natl. Acad. Sci. 2005, 102, 2186.
17. (a) Inceoglu, B.; Jinks, S. L.; Schmelzer, K. R.; Waite, T.; Kim, I.-H.; Hammock, B.
D. Life Sci. 2006, 79, 2311; (b) Inceoglu, B.; Schmelzer, K. R.; Morisseau, C.; Jinks,
S. L.; Hammock, B. D. Prostaglandins Other Lipid Mediat. 2007, 82, 42; (c)
Inceoglu, B.; Jinks, S. L.; Ulu, A.; Hegedus, C. M.; Georgi, K.; Schmelzer, K. R.;
Wagner, K.; Jones, P. D.; Morisseau, C.; Hammock, B. D. Proc. Natl. Acad. Sci.
U.S.A. 2008, 105, 18901.
18. Jones, P. D.; Wolf, N. M.; Morisseau, C.; Whetstone, P.; Hock, B.; Hammock, B. D.
Anal. Biochem. 2005, 343, 66.
19. Kim, I.-H.; Nishi, K.; Tsai, H.-J.; Bradford, T.; Koda, Y.; Watanabe, T.; Morisseau,
C.; Blanchfield, J.; Toth, I.; Hammock, B. D. Bioorg. Med. Chem. Lett. 2007, 15,
312.
24. Kowalski, J. A.; Swinamer, A. D.; Muegge, I.; Eldrup, A. B.; Kukulka, A.; Cywin, C.
L.; De Lombaert, S. Bioorg. Med. Chem. Lett. 2010, 20, 3703.
25. Gless, R. WO2008094862 A1 August 7, 2008.
26. (a) Jia, L.; Noker, P. E.; Coward, L.; Gorman, G. S.; Protopopova, M.;
Tomaszewski, J. E. Br. J. Pharmacol. 2006, 147, 476; (b) Rohde, J. L.;
Pliushchev, M. A.; Sorensen, B. K.; Wodka, D.; Shuai, Q.; Wang, J.; Fung, S.;
Monzon, K. M.; Chiou, W. J.; Pan, L.; Deng, X.; Chovan, L. E.; Ramaiya, A.;
Mullally, M.; Henry, R. F.; Stolarik, D. F.; Imade, H. M.; Marsh, K. C.; Beno, D. W.
A.; Fey, T. A.; Droz, B. A.; Brune, M. E.; Camp, H. S.; Sham, H. L.; Frevert, E. U.;
Jacobson, P. B.; Link, J. T. J. Med. Chem. 2007, 50, 149; (c) Cohen, M. L.;
Bloomquist, W.; Calligaro, D.; Swanson, S. Drug Dev. Res. 1998, 43, 193; (d)
Kajbaf, M.; Rossato, P.; Barnaby, J. R.; Pellegatti, M. Xenobiotica 1998, 28, 167;
(e) Hoffman, H. E.; Gaylord, J. C.; Blaseki, J. W.; Shalaby, L. M.; Whitney, G. C.
Antimicrob. Agents Chemother. 1988, 32, 1699; (f) Fukuda, E. K. Drug Metab.
Dispos. 1988, 16, 773.
27. Vytautas, J. J.; Volkmann, R. A. U.S. Patent 6,057,364 May 2, 2000.
28. Imig, J. D.; Carpenter, M. A.; Shaw, S. Pharmaceuticals 2009, 2, 217.
29. Whitcomb, R.; Chen, D.; Wang, Y.-X.; Anandan, S.-K.; Gless, R.; Webb, H. K.
Diabetes 2009, 58, A165, 612-P.; Wong, K.; Zhang, L.-N.; Vincelette, J.; Chen, D.;
Tran, V.; Mehra, U.; Gless, R.; Anandan, S.-K.; Webb, H. K.; MacIntyre, U.; Wang,
Y.-X. Diabetes 2009, 58, A436, 1698-P.
20. Eldrup, A. B.; Solewymanzadeh, F.; Taylor, S. J.; Muegge, I.; Farrow, N. A.;
Joseph, D.; McKellop, K.; Man, C. C.; Kulkulka, A.; De Lombaert, S. J. Med. Chem.
2009, 52, 5880.
21. Taylor, S. J.; Solewymanzadeh, F.; Eldrup, A. B.; Muegge, I.; Farrow, N. A.;
Kulkulka, A.; Kabcenell, A. K.; De Lombaert, S. Bioorg. Med. Chem. Lett. 2009, 19,
5864.
30. Fang, X.; Kaduce, T. L.; Weintraub, N. L.; VanRollins, M.; Spector, A. A. Circ. Res.
1996, 79, 784.
31. Kim, F.; Pham, M.; Luttrel, I.; Bannerman, D. D.; Tupper, J.; Thaler, J.; Hawn, T.
R.; Rainse, E. W.; Schwartz, M. W. Circ. Res. 2007, 100, 1589.
32. (a) Zeldin, D. C.; Kobayashi, J.; Falck, J. R.; Winder, B. S.; Hammock, B. D.;
Snapper, J. R.; Capdevila, J. H. J. Biol. Chem. 1993, 268, 6402.
22. (a) Shen, H. C.; Ding, F.-X.; Wang, S.; Xu, S.; Chen, H.-S.; Tong, X.; Tong, V.;
Mitra, K.; Kumar, S.; Zhang, X.; Chen, Y.; Zhou, G.; Pai, L.-Y.; Alonso-Galicia, M.;
Chen, X.; Zhang, B.; Tata, J. R.; Berger, J. P.; Colletti, S. L. Bioorg. Med. Chem. 2009,
19, 3398; (b) Shen, H. C.; Ding, F.-X.; Wang, S.; Deng, Q.; Zhang, X.; Chen, Y.;
Zhou, G.; Xu, S.; Chen, H.-S.; Tong, X.; Tong, V.; Mitra, K.; Kumar, S.; Tsai, C.;
Stevenson, A. S.; Pai, L.-Y.; Alonso-Galicia, M.; Chen, X.; Soisson, S. M.; Roy, S.;
Zhang, B.; Tata, J. R.; Berger, J. P.; Colletti, S. L. J. Med. Chem. 2009, 52, 5009; (c)
Shen, H. C.; Ding, F. X.; Deng, Q.; Xu, S.; Chen, H. S.; Tong, X.; Tong, V.; Zhang,
X.; Chen, Y.; Zhou, G.; Pai, L. Y.; Alonso-Galicia, M.; Zhang, B.; Roy, S.; Tata, J. R.;
Berger, J. P.; Colletti, S. L. Bioorg. Med. Chem. Lett. 2009, 19, 5314.
33. Wray, J.; Bishop-Bailey, D. Exp. Physiol. 2008, 93, 148.
34. (a) Wang, D.; Hirase, T.; Nitto, T.; Soma, M.; Node, K. J. Cardiol. 2009, 54, 368;
(b) Chen, R.; Jiang, J.; Xiao, X.; Wang, D. Sci. China C. Life Sci. 2005, 48, 495.
35. Rizzo, N. O.; Maloney, E.; Pham, M.; Luttrell, I.; Wessells, H.; Tateya, S.; Daum,
G.; Handa, P.; Schwartz, M. W.; Kim, F. Arterioscler. Thromb. Vasc. Biol. 2010, 30,
758.
36. Chen, D.; Whitcomb, R.; MacIntyre, E.; Tran, V.; Do, Z. N.; Sabry, J.; Patel, D. V.;
Anadan, S. K.; Gless, R.; Webb, H. K. J. Clin. Pharmacol., accepted for publication.