Design, synthesis and biological evaluation of potent FAAH inhibitors

Article abstract of DOI:10.1016/j.bmcl.2016.04.004

A new series of 3-carboxamido-5-aryl-isoxazoles was designed, synthesized and evaluated for their biological activity. Different pharmacomodulations have been explored and the lipophilicity of these compounds was assessed. Investigation of the in vitro bi

Full text of DOI:10.1016/j.bmcl.2016.04.004

Bioorganic & Medicinal Chemistry Letters 26 (2016) 2701–2705
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design, synthesis and biological evaluation of potent FAAH inhibitors
Wei Tuo, Natascha Leleu-Chavain, Amélie Barczyk, Nicolas Renault, Lucas Lemaire, Philippe Chavatte,
⇑
Régis Millet
ICPAL, Univ. Lille, Inserm, U995-LIRIC-Lille Inflammation Research International Center, 3 rue du Professeur Laguesse BP83, F-59006 Lille, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 26 February 2016
Revised 1 April 2016
Accepted 3 April 2016
Available online 23 April 2016
A new series of 3-carboxamido-5-aryl-isoxazoles was designed, synthesized and evaluated for their bio-
logical activity. Different pharmacomodulations have been explored and the lipophilicity of these com-
pounds was assessed. Investigation of the in vitro biological activity led to the identification of 5
compounds as potent FAAH inhibitors, their good FAAH inhibition capacity is probably correlated with
their suitable lipophilicity. Specifically, compound 25 showed similar inhibition potency against FAAH
in comparison with URB597, one of the most potent FAAH inhibitor known to date.
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
FAAH inhibitor
AEA
PEA
Cannabinoid receptors
PPAR-
a
Fatty acid ethanolamines (FAEs), belong to
a
class of
electrophilic carbonyl group of the substrate, which is accompa-
nied by the formation of an acyl-enzyme adduct and the release
of ethanolamine.7,8 The inhibition of FAAH may result in the
decrease of AEA hydrolysis and therefore the elevation of AEA
levels, associated with analgesic and anti-inflammatory
activities.9–12
Trifluoromethyl ketones and fluorophosphates were the first
generation FAAH inhibitors identified. They showed good in vitro
FAAH inhibition potency, but most of them exhibited poor selectiv-
ity for FAAH over other serine hydrolases (such as the triacylglyc-
erol hydrolase and the membrane-associated hydrolase
KIAA1363).9–12 Over the past decade, research on FAAH inhibitors
has been significantly developed. Numerous selective FAAH inhibi-
tors have been identified. Generally, according to the different
interaction mechanisms, FAAH inhibitors can be classified as cova-
lent reversible inhibitors, such as OL-13513,14 (Fig. 1), covalent irre-
versible inhibitors, such as URB59715,16 (Fig. 1), or non-covalent
reversible inhibitors, such as compound 1 disclosed by Abbott17
(Fig. 1) and compound 2 synthesized by Amgen18 (Fig. 1). OL-
lipid-derived mediators and include: saturated FAEs such as
palmitoylethanolamine (PEA), monounsaturated FAEs such as oleoy-
lethanolamine (OEA), and polyunsaturated FAEs such as
anandamide (AEA). Over the last decade, FAEs have been identified
to induce a wide range of biological responses through several
endogenous receptors. Typically, AEA relieves inflammation and
pain by stimulating cannabinoid receptors CB1/CB21 and PEA exerts
anti-inflammatory and analgesic activities via the peroxisome pro-
liferator-activated receptor
a (PPAR-a
).2,3 Hence, during recent
decades, regulation of the AEA/PEA signaling through the inhibi-
tion of relevant biodegradation enzymes has been considered as
a potent therapeutic approach to exert anti-nociceptive and anti-
inflammatory effects.
Fatty acid amide hydrolase (FAAH), a membrane-bound serine
hydrolase, is responsible for the principal degradation of AEA.4,5
Its binding site comprises three functional channels: a membrane
access channel, an acyl-chain binding channel, and a cytosolic port
channel, which are relevant to the transport of the substrate to the
catalytic site, the accommodation of the acyl chain during catalysis,
and the removal of the leaving group after hydrolysis, respec-
tively.6 Especially, the substrate is surrounded by the catalytic triad
(Ser241-Ser217-Lys142)7,8 and the oxyanion hole residues (includ-
ing Ser241, Gly240, Gly239, and Ile238)6 during the hydrolysis. The
nucleophilic hydroxyl group of the Ser241 interacts with the
135, an a-ketoheterocycle, has been discovered in 2004 as a cova-
lent, selective, and reversible FAAH inhibitor with an IC50 of
2 nM.13 Especially, its carbonyl group has been demonstrated to
interact with the Ser241 of the catalytic triad accompanied by
the formation of an enzyme–substrate tetrahedral intermediate.13
Additionally, the pyridine group of OL-135 has been identified to
form H-bonds with the Lys142 and the Thr236, which is favorable
for the interaction between OL-135 and FAAH.19,20 URB597, a rep-
resentative carbamate-based selective FAAH inhibitor, was identi-
fied to irreversible bind to FAAH accompanied by the generation of
⇑
Corresponding author. Tel.: +33 3 20 96 49 06; fax: +33 3 20 96 43 74.
E-mail address: regis.millet@univ-lille2.fr (R. Millet).
http://dx.doi.org/10.1016/j.bmcl.2016.04.004
0960-894X/Ó 2016 Elsevier Ltd. All rights reserved.

2702
W. Tuo et al. / Bioorg. Med. Chem. Lett. 26 (2016) 2701–2705
N
O
N
O
O
O
N
H
O
NH2
OL-135
URB597
Covalent and reversible inhibitor
Covalent and irreversible inhibitor
O
N
N
O
S
O
O
N
O
N
S
N
N
N
NH
S
1
2
Non-covalent and reversible inhibitor
Non-covalent and reversible inhibitor
Figure 1. Structures of representative FAAH inhibitors.
pharmacomodulations were carried out on this series.22 The
O
O
replacement of the benzodioxol ethyl group appended to the car-
boxamide function by an adamant-1-yl group and the substitution
of the terminal phenyl ring by a pentoxy group led to a substantial
increase of FAAH inhibitory efficacy (4, IC50 = 8 nM, Fig. 2). Com-
pound 4 produced anti-inflammatory effect in a dextran sulfate
sodium (DSS)-induced acute colitis model in mice.22
In this context, a novel series of compounds based on this inter-
esting scaffold was designed. The replacement of the phenyl moi-
ety of compound 4 by a pyridine group or the introduction of
different aromatic substituents instead of the pentoxy group at
the para position of the phenyl ring is supposed to optimize physic-
ochemical parameters (such as LogP).
O
O
NH
O
O
NH
N
N
O
4
3
Figure 2. Structures of previously synthesized FAAH inhibitors 3 and 4.
The target compounds were obtained in five steps. The Claisen
condensation of aromatic ketones 5 and 6 with diethyl oxalate in
the presence of sodium ethanolate afforded b-diketoesters 7
(47%) and 8 (39%), respectively. It has been demonstrated that
these b-diketoesters are in their enol form, which is probably due
to the formation of an internal hydrogen bond.23–25 Then, cycliza-
tion reaction was performed to convert compounds 7 and 8 into 5-
aryl isoxazole-3-carboxylates 9 (78%) and 10 (71%) by addition of
hydroxylamine hydrochloride in ethanol at reflux. Furthermore,
a carbamylated-enzyme adduct. To date, URB597 is considered as
one of the most potent FAAH inhibitors with an IC50 of 4.6 nM.15,16
As previously reported by our research group, 3-carboxamido-
5-arylisoxazole has been regarded as an interesting scaffold for
developing FAAH inhibitors.21,22 Typically, compound 3 (IC50 = 88 nM,
Fig. 2) displayed a potent FAAH inhibitory capacity in vitro and
produced protective efficacy on a 2,4,6-trinitrobenzene sulfonic
acid (TNBS)-induced colitis mouse model.21,22 Recently, different
O
O
O
OH
O
(b)
O
(a)
N
O
O
Br
X
Br
X
Br
X
5-6
7-8
9-10
O
OH
O
O
O
NH
NH
(e)
(c)
(d)
N
O
N
N
O
B
r
X
R
X
Br
N
X
15-43
13-14
11-12
N
X = CH, N. R =
R'
O
Scheme 1. Synthesis of N-(adamantan-1-yl)-5-aryl isoxazole-3-carboxamides 15–43. Reagents and conditions: (a) Diethyl oxalate, sodium ethanolate, ethanol, reflux 6 h,
39–47%. (b) Hydroxylamine hydrochloride, ethanol, reflux, 2 h, 71–78%. (c) Sodium hydroxide, 95% ethanol, rt, overnight, 95–98%. (d) HBTU, HOBt, DIEA, 1-adamantanamine
hydrochloride, DCM, rt, 12 h, 53–67%. (e) Aryl boronic acid or boronic acid pinacol ester, potassium carbonate, tetrakis (triphenylphosphine) palladium(0), DMF, H2O, MW,
100 °C, 30 min, 76–89%.

W. Tuo et al. / Bioorg. Med. Chem. Lett. 26 (2016) 2701–2705
2703
saponification into 5-aryl isoxazole-3-carboxylate carboxylic acids
11 (98%) and 12 (95%) was carried out, followed by amidification
with 1-adamantanamine hydrochloride to achieve to precursor
compounds 13 (67%) and 14 (53%). Finally, a tetrakis (triph-
enylphosphine)palladium(0)-catalyzed Suzuki reaction with differ-
ent aromatic boronic acids or boronic acid pinacol esters afforded
N-(adamantan-1-yl)-5-aryl isoxazole-3-carboxamide derivatives
15–43 with good yields (76–89%) (Scheme 1).
The N-(adamantan-1-yl)-5-aryl isoxazole-3-carboxamides 15–
43 and reference compounds (4 and URB597) were assessed for
their ability to inhibit the hydrolysis of 7-amino-4-methyl cou-
marin-arachidonamide (AMC-AA), a fluorescent FAAH substrate,
by human recombinant FAAH (expressed in SF21 cells) after a
15 min preincubation with 4 U/mL of enzyme at 37 °C in Tris buffer
pH 9.26 All the compounds were firstly screened at the concentra-
5 compounds demonstrated a good activity against FAAH with
IC50 values in a submicromolar range. Nevertheless, when replac-
ing the phenyl ring appended to the isoxazole by a pyridinyl ring
(37–43), a decrease of activity was observed. Indeed, these com-
pounds manifested less than 25% FAAH inhibition. Moreover, com-
pounds with a pyridinyl group (19), a quinolinyl group (34) or a
furanyl group (35) on the phenyl ring manifested slight inhibition
activity against FAAH from 17% to 31% inhibition. When the sub-
stituent on the terminal phenyl ring is bearing at the 2-position
(20, 47% inhibition), a slight decrease of inhibitory activity was
observed in comparison with the corresponding 3-substituted
derivative 21 (58% inhibition). The FAAH inhibitory capacity of
the molecules was almost completely lost when the substituent
is bearing at the 4-position. For instance, compounds 16, 22, 27,
and 31 were determined to exert less than 25% inhibition of FAAH.
Additionally, biphenyl derivatives bearing a carbamoyl substituent
either at 3-position (17) or at 4-position (18) were determined to
show no obvious activity towards FAAH (<15%). Furthermore, the
introduction of an additional methoxy group at the 4-position of
compound 21 led to a sharp decrease of inhibitory capacity from
58% to 14% (23). Surprisingly, the introduction of a third methoxy
tion of 10 lM. The half maximal inhibitory concentrations (IC50)
were determined for compounds exhibiting a specific inhibition
superior to 50% for FAAH.
As illustrated in Table 1, among all synthesized compounds,
biphenyl derivatives 15, 21, 25, 26, and 28 with substitutions at
the 3-position possessed the best FAAH inhibitory capacity. These
Table 1
Percentage of FAAH inhibition at 10
lM, half-maximum inhibitory concentration (IC50) towards human recombinant FAAH and cytotoxicity on HT29 and HEK293 cells at 10 lM
of compounds 15–43, and reference compounds 4 and URB597
O
O
NH
N
R
X
a
Compounds
X
R
FAAH % inhibition
FAAH IC50
(lM)
HT29 % inhibition
HEK293 % inhibition
at 10
lM
at 10
lM
at 10 lM
4
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
N
Pentoxy
3-Acetylphenyl
4-Acetylphenyl
3-Carbamoylphenyl
4-Carbamoylphenyl
Pyridin-4-yl
2-Methoxyphenyl
3-Methoxyphenyl
79
56
18
11
10
17
47
58
15
14
42
64
69
16
63
41
49
24
44
23
22
31
18
23
22
13
20
23
12
10
98
0.46 (0.008)b
0.59 0.02
N.D.c
1
4
0
0
1
2
0
0
7
6
0
0
N.D.c
16
5
3
4
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
URB597
9
25
20
2
29
32
0
38
20
93
89
54
23
47
37
24
12
9
14
18
5
1
1
10
3
0
0.72 0.04
4-Methoxyphenyl
3,4-Dimethoxyphenyl
3,4,5-Trimethoxyphenyl
3-Cyanophenyl
0.24 0.07
0.83 0.08
3-(Morpholinomethyl)Phenyl
4-(Morpholinomethyl)phenyl
3-(4-Methyl-1-piperazinylmethyl)phenyl
4-(4-Methyl-1-piperazinylmethyl)phenyl
3-(Morpholine-4-carbonyl)phenyl
4-(Morpholine-4-carbonyl)phenyl
3-(4-Methyl-1-piperazinylcarbonyl)phenyl
4-(4-Methyl-1-piperazinylcarbonyl)phenyl
Quinolin-3-yl
Furan-2-yl
3,4-(Methylenedioxy)phenyl
phenyl
3-Acetylphenyl
4-Acetylphenyl
0
1.13 0.06
97
90
10
0
55
24
0
0
0
0
0
0
14
0
0
0
N
N
N
N
N
N
3-Carbamoylphenyl
Pyridin-4-yl
4-(Morpholine-4-carbonyl)phenyl
4-(4-Methyl-1-piperazinylcarbonyl)phenyl
0.26 0.07
0
a
IC50 values were obtained after a 15 min preincubation with the enzyme by a fluorogenic assay. Data represent the mean SEM of three experiments performed in
duplicate.
b
Data from Ref. 22. Evaluated for the ability to inhibit the hydrolysis of [3H]-AEA by a recombinant human FAAH (expressed in Escherichia coli).
N.D. means not determined.
c

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W. Tuo et al. / Bioorg. Med. Chem. Lett. 26 (2016) 2701–2705
Table 2
Calculated CLogP values of 10 representative compounds bearing a 3-substituted phenyl ring
Compounds
15
17
21
25
26
28
30
32
38
40
CLogPa
5.73
4.80
6.21
5.72
6.04
6.60
4.92
5.48
4.58
3.71
a
CLogP was calculated by SYBYL-X 2.0 (Tripos).
7.000
6.500
6.000
5.500
5.000
4.500
4.000
3.500
80
70
60
50
40
30
20
10
0
3.000
26
25
28
21
15
30
32
38
40
17
Compounds
CLogP
Activity
Figure 3. Lipophilicity–activity relationships of 10 representative compounds bearing a 3-substituted phenyl ring.
group at the 5-position of the terminal phenyl ring of compound 23
brought about an obvious recovery of inhibitory potency to 42%
(24). Moreover, the replacement of the methylene function
appended to the terminal phenyl ring of compounds 26 (69% inhi-
bition) and 28 (63% inhibition) by a carbonyl function led to a sub-
stantial attenuation of the inhibitory activity to 49% (30) and 44%
(32), respectively. Overall, a phenyl group is more favorable than
other aromatic groups (such as pyridinyl, quinolinyl, and furanyl
groups) for the design of FAAH inhibitors. Substituents at position
3 are more favorable than substituents at position 4. Specifically,
acetyl, morpholinomethyl, cyano, methoxy, and 4-methyl-1-piper-
azinylmethyl substituents are preferred rather than a carbamoyl
An investigation of the lipophilicity–activity relationships of
compounds with substituents at the 3-position on the terminal
phenyl ring was performed. Lipophilicity is an important property
in drug discovery and the prediction of bioavailability.27 The loga-
rithm of the octanol/water partition coefficient (LogP) is widely
used to assess the lipophilicity of molecules. In terms of different
calculation rules, LogP values can be calculated by atomic methods
(such as ALogP and XLogP), which consider the contribution of
each atom; fragmental methods (such as CLogP, ACD/LogP and
KowWIN), which consider the contribution of each small fragment
in a molecule; or property-based methods (such as MLogP), which
is based on the three-dimensional (3D) structures of the molecules
and topological approaches.27 Actually, CLogP was identified to
display more accurate prediction of LogP in a wide range of 108
compounds, in comparison with ACD/LogP and KowWIN,28 Hence,
LogP values of our compounds were calculated by CLogP method
(Table 2). As represented in Figure 3, our 5 most potent FAAH inhi-
bitors (15, 21, 25, 26, and 28) possessed high CLogP values ranging
from 5.5 to 6.6. Conversely, compounds with a low FAAH inhibitory
capacity (17, 30, 32, 38, and 40) possessed CLogP values below 5.5.
This result indicates that compounds with substituents at the 3-
position of the terminal phenyl ring conferring higher LogP values
(such as acetyl, methoxy, and cyano group) showed better FAAH
inhibition potency. Hence, the low inhibitory capacity of com-
pound 17 (CLogP = 4.80) with a carbamoyl group might be attrib-
uted to its weak lipophilicity. The replacement of the methylene
linker of compounds 26 (CLogP = 6.04) and 28 (CLogP = 6.60) with
a carbonyl linker (30, CLogP = 4.92, 32, CLogP = 5.48) and the
replacement of the phenyl ring of compound 15 (CLogP = 5.73)
by a pyridine ring (38, CLogP = 4.58) led to a substantial attenua-
tion of the FAAH inhibitory activity probably because of the
decrease of lipophilicity.
group. Notably, compound 15 (IC50 = 0.59
FAAH inhibitory capacity in comparison with compound
(IC50 = 0.46 M), a previously identified potent FAAH inhibitor in
lM) possessed similar
4
l
our group. The replacement of the acetyl group of compound 15
by a cyano group (25) brought about an impressive improvement
of inhibitory potency against FAAH. Compound 25 is approxi-
mately 2 times more potent against FAAH than compounds 4 and
15. This compound manifests a moderate efficacy (maximum effect
that a drug can produce, 64% inhibition at 10
but a good potency (amount required to produce a given effect,
IC50 = 0.24 M). It shows a similar inhibitory potency against FAAH
lM concentrations)
l
than the positive control URB597 (IC50 = 0.26
lM), one of the most
potent FAAH inhibitors to date.
Cytotoxicity of these compounds was determined at 10 lM
using a cell proliferation assay on human colorectal adenocarci-
noma cells HT29 and human embryonic kidney cells HEK293. This
test is based on a colorimetric method, which measures the activity
of cellular enzymes that reduce the tetrazolium dye (MTS, uncol-
ored) to its insoluble formazan giving a purple color. This assay
measures cellular metabolic activity via NADPH-dependent cellu-
lar oxidoreductase enzymes and reflects, under defined conditions,
the number of viable cells. No cytotoxicity was observed for our
new compounds on HT29 cells except for compounds with a piper-
azinyl moiety (28, 29, 32, and 33). These 4 compounds inhibited
also proliferation of HEK293 cells.
In conclusion, a series of new 3-carboxamido-5-aryl-isoxazoles
was designed, synthesized and screened for their inhibitory
potency against FAAH. Their cytotoxicity was determined and their
lipophilicity was calculated. Compounds bearing a 3-substituted
biphenyl moiety with high LogP values displayed a good inhibitory

W. Tuo et al. / Bioorg. Med. Chem. Lett. 26 (2016) 2701–2705
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2705
percentage against FAAH. Compound 25 was identified as a potent
FAAH inhibitor devoid of cytotoxicity on HT29 and HEK293 cells.
Its good biological activity is probably due to its suitable lipophilic-
ity. This compound possesses a FAAH inhibitory potency compara-
ble to URB597, one of the most potent FAAH inhibitor identified to
date.
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Wei TUO is financially supported by China Scholarship Council.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2016.04.
004.
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