1-Aryl-2-((6-aryl)pyrimidin-4-yl)amino)ethanols as competitive inhibitors of fatty acid amide hydrolase

Article abstract of DOI:10.1016/j.bmcl.2014.01.064

A series of 1-aryl-2-(((6-aryl)pyrimidin-4-yl)amino)ethanols have been found to be competitive inhibitors of fatty acid amide hydrolase (FAAH). One member of this class, JNJ-40413269, was found to have excellent pharmacokinetic properties, demonstrated robust central target engagement, and was efficacious in a rat model of neuropathic pain.

Full text of DOI:10.1016/j.bmcl.2014.01.064

Bioorganic & Medicinal Chemistry Letters 24 (2014) 1280–1284
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
1-Aryl-2-((6-aryl)pyrimidin-4-yl)amino)ethanols as competitive
inhibitors of fatty acid amide hydrolase
⇑
John M. Keith , Natalie Hawryluk, Richard L. Apodaca, Allison Chambers, Joan M. Pierce, Mark Seierstad,
James A. Palmer, Michael Webb, Mark J. Karbarz, Brian P. Scott, Sandy J. Wilson, Lin Luo,
Michelle L. Wennerholm, Leon Chang, Michele Rizzolio, Sandra R. Chaplan, J. Guy Breitenbucher
Janssen Pharmaceutical Companies of Johnson & Johnson, 3210 Merryfield Row, San Diego, CA 92121, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 1-aryl-2-(((6-aryl)pyrimidin-4-yl)amino)ethanols have been found to be competitive inhibi-
tors of fatty acid amide hydrolase (FAAH). One member of this class, JNJ-40413269, was found to have
excellent pharmacokinetic properties, demonstrated robust central target engagement, and was effica-
cious in a rat model of neuropathic pain.
Received 26 December 2013
Revised 15 January 2014
Accepted 21 January 2014
Available online 31 January 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Fatty acid amide hydrolase (FAAH)
Enzymes
Crystal structure
Endo-cannabinoids
Analgesia
1
Me
The discovery and cloning of two cannabinoid receptors CB1
O
2
and CB2 in the early 1990s facilitated the development of a ratio-
OH
HO
HO
H
N
H
nale for the analgesic effects of cannabis preparations containing
H
D
9-THC and its derivatives. The subsequent discovery of ananda-
Me
Me
O
Me
mide (AEA)3 (Fig. 1), an endogenous agonist of both CB1 and CB2
receptors with analgesic properties, and fatty acid amide hydrolase
(FAAH),5 the enzyme which hydrolyzes AEA, suggested a means of
engaging the cannabinoid system without the use of exogenous
4
Me
9
Anandamide (AEA)
O
Δ -THC
O
agonists such as
D
9-THC.
HO
N
H
N
Unfortunately, AEA is not drug-like due to its poor physico-
chemical properties and rapid metabolism (T1/2 on the order of a
few minutes)6 by FAAH to give ethanolamine and arachidonic acid.
Furthermore, the synthesis and metabolism of AEA is localized,
thus preventing the appearance of the side-effects (the so-called
cannabinoid tetrad)7 associated with global CB1 agonism. Indeed,
systemic administration of AEA gives rise to side-effects reminis-
H
Me
N-Oleoylethanolamide (OEA)
D
9-THC and endogenous substrates of FAAH.
Me
N-Palmitoylethanolamide (PEA)
Figure 1. Structures of
have anti-inflammatory properties and exert analgesic effects
through a non-cannabinoid pathway,10 while OEA appears to be in-
volved in regulating satiety,11 whereas the similar oleamide (OA),
another substrate of FAAH, is an important contributor to sleep
induction.12
cent of those observed with the use of
D
9-THC.8 The potential ben-
efit to inhibiting the FAAH enzyme is that it should lead to
localized increases in AEA and likely avoid the aforementioned
side-effects of general CB1 activation.
While FAAH very efficiently degrades AEA, it also breaks down
several other ethanolamides including N-palmitoylethanolamide
(PEA), N-oleoylethanolamide (OEA) and others.9 PEA is known to
Numerous groups have reported the preparation and pharma-
cological testing of FAAH inhibitors (Fig. 2). Boger’s group de-
scribed several series of highly potent
a
-keto heterocycles.13
Piomelli14 disclosed carbamate based inhibitors as did Sanofi.15
Pfizer,16 Takeda17 and Janssen18 have disclosed phenyl and hetero-
aryl urea inhibitors of FAAH. All of these compounds are quite po-
tent and are thought to form covalent bonds with Ser 241 within
⇑
Corresponding author. Tel.: +1 858 784 3275.
E-mail address: jkeith@its.jnj.com (J.M. Keith).
http://dx.doi.org/10.1016/j.bmcl.2014.01.064
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.

J. M. Keith et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1280–1284
1281
O
O
O
N
H2N
O
N
H
O
N
OL-135
covalent/reversible
URB597
covalent/irreversible
N
N
O
CF3
O
N
N
S
Me
S
N
N
N
H
H
N
Me
O
N
H
O
O
SA-47
PF-04457845
covalent/irreversible
covalent /irreversible
O
N
O
O
H
N
N
N
H
N
N
O
S
S
N
N
Me
Abbott
JNJ-1661010/Takeda
competitive
covalen t/reversible
N
Me
O
N
N
HN
N
O
N
N
N
N
Amgen
competitive
Renovis
competitive
OH
Figure 2. Structures of some known FAAH inhibitors and their mechanism.
the FAAH active site. OL-135 is thought to form a reversible tetra-
hedral hemiketal intermediate derived from the attack of Ser 241
onto the ketone.19 URB597 and the carbamates reported by Sanofi
are thought to undergo transesterification with the FAAH enzyme
with the concomitant loss of a phenolic or alcoholic fragment
respectively.20 The ureas also form a carbamate with the FAAH en-
zyme, but with the loss of an aniline or heteroaryl amine rather
than an alcohol. OL-135,14 URB597,21 and JNJ-166101022 have been
found to be efficacious in various animal models of pain without
the motor impairment associated with direct CB1 agonism.
Several competitive inhibitor classes have been reported as well.
Abbott disclosed piperidinyl sulfonamides,23 Amgen 2-aminopyr-
imidines24 and Renovis substituted 6-aza-tetrahydroisoquino-
lines.25 Several compounds have been profiled to some degree in
the clinic. Pfizer’s PF-0445784526 was evaluated in phase 2 as an
analgesic in subjects with osteoarthritis pain, but was apparently
ineffective despite evidence of peripheral target engagement.
Ongoing or completed studies with PF-04457845 include evaluat-
ing the potential for treating cannabinoid dependence27 and acute
and chronic pain,28 fear conditioning,29 Vernalis’ V158866 did a
FIH study,30 and Janssen’s JNJ-42165279 is currently in phase 1 clin-
ical studies.31
An HTS campaign conducted late in our FAAH program pro-
duced an interesting and potent hit compound without any obvi-
ously reactive functionality (Fig. 3). As the hit was racemic, we
prepared the two enantiomers and found that the bulk of the FAAH
activity comes from the R-isomer. Encouraged by these data, we
explored the SAR of substituted phenyl groups directly appended
to the pyrimidine ring, a sampling of which is shown in Table 1.
The compounds in Table 1 were generally constructed accord-
ing to Scheme 1. Displacing one of the chlorine atoms of 4,
6-dichloropyrimidine with (R)-1-phenylethanol-2-amine gave the
mono-chloro intermediate in high yield. Subsequent Suzuki cou-
pling with substituted aryl boronic acids or esters gave the final
products.
Alternatively, if the ethanolamine side chain was to be intro-
duced last, then the molecules were generally constructed according
to Scheme 2. Coupling of 3-chloro-4-trifluoromethylphenylboronic
acid with 4,6-dichloropyrimidine followed by substitution of the
remaining pyrimidyl chloride with the desired aryl ethanolamine
yielded the final product.
Many of the 1-arylethanol-2-amines had to be prepared. Some
were constructed by forming a silyl cyanohydrin and then reducing
the nitrile in situ to give the racemic product (Scheme 3). This ap-
proach worked best for those 1-arylethanol-2-amines bearing sub-
stituents stable to metal hydride reducing conditions.
The amino alcohols bearing nitriles were prepared according to
Scheme 4. The corresponding cyano bromoacetophenones were
treated with BH3ÁTHF at 0 °C for 1 h followed by aqueous ammonia
to give the desired intermediate.
We were surprised to find that an absence of substitution on the
phenyl ring directly appended to the pyrimidine yields an inactive
compound (1). Substituents in the 2-position hurt activity,32 while
3- and 4-substitution with lipophilic groups tended to improve po-
tency. The most potent analogs possessed 3,4-disubstitution with
non-polar functionality. Unfortunately, this region of the molecule
was very sensitive to oxidative metabolism. Many of the most po-
tent compounds (4, 11, 12, 24, 26, 28) exhibited low bioavailability
and high clearance in the rat. Fortunately, we found that when the
3-chloro-4-trifluoromethylphenyl substituent was introduced, a
metabolically robust and potent molecule was obtained (31; JNJ-
40413269).
With a suitable substitution pattern on the aryl ring appended
to the pyrimidine, we next explored the SAR of substituents on
the phenyl ring of the ethanolamine side-chain (Table 2). Most
changes made to this part of the molecule resulted in a modest
to large decrease in activity.
We obtained an X-ray crystal structure of humanized rat FAAH
bound to one of our FAAH inhibitors (Fig. 4).33 Rationalizing the
greater potency of the (R)-inhibitors is now possible as the alcohol
Ph R-isomer
hFAAH IC50 = 17 5 nM
rFAAH IC50 = 37 8 nM
N
N
N
H
Ph
OH
OH
N
H
F3CO
S-isomer
Ph
HTS hit
hFAAH IC50 = 30 13 nM
rFAAH IC50 = 159 73 nM
N
H
hFAAH IC50 = 10 μM
rFAAH IC50 = 10 μM
OH
Figure 3. HTS hit and individual enantiomers.

1282
J. M. Keith et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1280–1284
Table 1
SAR of substituted phenyl ring appended to the pyrimidine
N
N
Ph
OH
Ar
N
H
Compd
Ar
hFAAH IC50 (nM)
>10,000
rFAAH IC50 (nM)
>10,000
Compd
Ar
hFAAH IC50 (nM)
598 132
rFAAH IC50 (nM)
1850 650
1⁄
Ph
17⁄
Cl
Me
2
445 95
3500 500
302 30
18⁄
19
317 96
1267 216
>10000
F3C
Et
3⁄
32
5
2
1433 363
MeO
4
2
100 20
680 93
94 12
20
>10000
>10000
5⁄
6
72 16
21⁄
22
477 122
2075 460
461 97
MeO
F3C
23
3
49
15
9
3
MeO
F3CO
7⁄
291 75
54 10
2902 886
345 40
263 34
633 83
23
24
25
26
27
28
29
30
31
39
7
6
F
EtO
F3C
EtO
8⁄
3
1
3
1
F3C
EtO
O
9
18
5
1.5 0.5
3
Cl
MeS
EtS
F3CS
Cl
EtO
10⁄
11
12
13⁄
14
55 17
15
4
43
5
F
O
1.3 0.2
13
21
1
6
6.3 2.5
3.2 0.8
86 15
F3C
Ac
F
8
0.6
5.4 1.6
F
F
F3C
Cl
783 265
3433 1683
>10,000
12
4
34
8
F
1784 183
55 14
210 51
6.3 3.7
F3C
F3C
NC
15
505 145
750 350
>10,000
5.3 3.2
Cl
16⁄
3340 338
*
Denotes racemate; IC50s are standard error.
N
N
N
N
N
N
a
b
Ph
Ph
Cl
Cl
Cl
N
H
N
H
R
OH
OH
Scheme 1. Reagents and conditions: (a) 1:1 4,6-dichloropyrimidine and (R)-1-phenylethanolamine, 6 equiv NaHCO3, 1,4-dioxane, 100 °C, 17 h, 81%; (b) 2 equiv arylboronic
acid or ester (Ar defined in Table 1), 3–10 mol % Pd(PPh3)4, K3PO4, DME, 85 °C, 15–18 h, yields varied.
is well positioned to make a hydrogen bond with Th488 which is
not readily accessible to the corresponding (S)-configured ana-
logs. The arene attached to the pyrimidine ring projects toward
the catalytic machinery, but not so close as to interfere with
binding.
Owing to its excellent FAAH potency, we elected to perform fur-
ther profiling of JNJ-40413269 in vivo in the rat. The compound
was seen to exhibit good pharmacokinetic properties (Fig. 5) and
a good blood brain barrier (BBB) penetration profile (Fig. 6).
JNJ-40413269 was cleared at a moderate rate, exhibited good oral
bioavailability and generated concentrations in the brain that were
similar to those seen in the plasma (brain-to-plasma ratio ꢀ 1).
This compound appeared to be an excellent candidate, from a
pharmacokinetic perspective, for efficacy studies in pain models.
Therefore JNJ-40413269 was profiled in the rat spinal nerve liga-
tion (Chung) model of neuropathic pain (Fig. 7).

J. M. Keith et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1280–1284
1283
B(OH)2
N
N
N
N
a
b
+
Cl
Cl
Cl
R
F3C
Cl
F3C
H2N
Cl
OH
R
N
N
N
H
OH
F3C
Cl
Scheme 2. Reagents and conditions: (a) Pd(OAc)2, PPh3, ACN/water (3:1), K3PO4, rt,
2 h, 35%; (b) 6 equiv NaHCO3, 1,4-dioxane, 100 °C, 15–18 h, yields varied (R defined
in Table 2).
Figure 4. An aryl-pyrimidine bound in the active site of FAAH
OTMS
CN
OH
NH2
a
b
O
R
R
R
p.o. 10 mg/kg
i.v. 1 mg/kg
10
Scheme 3. Reagents and conditions: (a) TMSCN, 10 mol % ZnI2, neat, 0 °C, 2–
15 min; (b) 1.0 M LiAlH4, THF, 0–50 °C, yields varied.
1
0.1
0.01
O
OH
OH
a
b
Br
Br
NH2
NC
NC
NC
0.001
0
4
8
12
Time (h)
16
20
24
Scheme 4. Reagents and conditions: (a) 1.2 equiv. BH3ÁTHF, THF, 1 h, 0 °C; (b)
concentrated NH3 (aq), rt, 12 h, 34% for two steps.
Figure 5. Rat pharmacokinetic data for JNJ-40413269: Cl = 8 mL/min/kg, Vss = 1.7 L/
kg, T1/2 = 4.1 h, %F = 94%. (iv vehicle = 50% glycofurol/saline; p.o. vehicle = 5%
pharmasolve, 20% cremaphore, 75% dextrose solution (5%)).
Table 2
SAR of aryl substituents on ethanolamine side-chain
N
N
Ar
OH
N
H
10
1
F3C
Cl
Compd
Ar
hFAAH IC50 (nM)
73 23
rFAAH IC50 (nM)
32⁄
29
6
Plasma
0.1
F
Brain
33⁄
34⁄
35⁄
61
7
65 21
0.01
F
0
1
2
3
4
5
6
7
SMe
110 44
228 79
34
23
9
5
Time (h)
Figure 6. Blood brain barrier penetration data for JNJ-40413269 (3 mg/kg p.o.,
vehicle = 5% pharmasolve, 20% cremaphore, 75% dextrose solution (5%)). The brain
to plasma ratio was 1–1.5 across a full dose range.
CF
3
36⁄
37⁄
38⁄
271 83
21
3
OCF3
CN
JNJ-40413269 was seen to produce a robust dose-dependent
decrease in mechanical allodynia in the spinal nerve ligation model
of neuropathic pain. The highest level of reversal was seen 30 min
after compound dosing and was about 55% of the maximal possible
effect (MPE). A similar maximal degree of efficacy was seen with
the 20, 40, and 100 mg/kg doses, but it is noteworthy that substan-
tial efficacy was retained for at least 4 h with the higher doses
tested.
In an effort to determine the degree of target engagement in the
brain, concentrations of three fatty acid amide (FAA) substrates of
FAAH [AEA, PEA and OEA] were measured at several time-points
after oral dosing of JNJ-40413269. JNJ-40413269 strongly raises
the brain levels of all three substrates (Fig. 8) with peak concentra-
tions occurring between 2 and 4 h post-dose. Further detailed
57
5
18 0.4
50 19
26
7
9
1.5
2
CN
F
39
14
3
F
Cl
F
40⁄
41⁄
59 14
19
8
F
33
3
2
Cl
*
Denotes racemate; IC50s are standard error.

1284
J. M. Keith et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1280–1284
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Baseline
Time (h)
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27. From Clinicaltrials.gov as of 2013 12-26: http://www.clinicaltrials.gov/ct2/
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28. From Clinicaltrials.gov as of 2013 12-26: http://www.clinicaltrials.gov/ct2/
show/NCT00836082?term=FAAH&rank=3.
pharmacological profiling of JNJ-40413269 will be reported
elsewhere.
In conclusion, we have discovered a class of potent phenyl eth-
anolaminopyrimidines that act as potent competitive inhibitors of
the FAAH enzyme. JNJ-40413269 was found to possess good phar-
macokinetic properties and was efficacious in the spinal nerve liga-
tion model of neuropathic pain in the rat.
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30. From Clinicaltrials.gov as of 2013 12-26: http://www.clinicaltrials.gov/ct2/
show/NCT01634529?term=FAAH&rank=6.
4. (a) Lichtman, A. H.; Hawkins, E. G.; Griffin, G.; Cravatt, B. F. JPET 2002, 302, 73;
(b) Steffens, M.; Zentner, J.; Honegger, J.; Feuerstein, T. J. Biochem. Pharmacol.
2005, 69, 169; (c) Cravatt, B. F.; Giang, D. K.; Mayfield, S. P.; Boger, D. L. Nature
(London, U.K.) 1996, 384, 83.
31. From Clinicaltrials.gov as of 2013 12-26: a) http://www.clinicaltrials.gov/ct2/
show/NCT01964651?term=FAAH&rank=9; b) http://www.clinicaltrials.gov/
ct2/show/NCT01650597?term=fatty+acid+amide+hydrolase&rank=5.
32. Data not shown.
5. Cravatt, B. F.; Demarest, K.; Patricelli, M. P.; Bracey, M. H.; Giang, D. K.; Martin,
B. R.; Lichtman, A. H. Proc. Natl. Acad. Sci. U.S.A. 2001, 98, 9371.
6. Willoughby, K. A.; Moore, S. F.; Martin, B. R.; Ellis, E. F. J. Pharmacol. Exp. Ther.
1997, 282, 243.
7. The cannabinoid tetrad: catalepsy, hypomotility, hypothermia and analgesia.
Hyperphagia is another side-effect commonly observed.
8. The studies were carried out in FAAH(À/À) mice: Cravatt, B. F.; Demarest, K.;
Patricelli, M. P.; Bracey, M. H.; Giang, D. K.; Martin, B. R.; Lichtman, A. H. PNAS
2001, 98, 9371.
33. This compound was used for crystallography studies because it is more soluble
than most other analogs:
N
N
O
O
Ph
OH
N
H
hFAAH IC50 = 28
8
rFAAH IC50 = 270 93
.
9. (a) Patricelli, M. P.; Cravatt, B. F. Biochemistry 1999, 38, 14125; (b) Boger, D. L.;
Fecik, R. A.; Patterson, J. E.; Miyauchi, H.; Patricelli, M. P.; Cravatt, B. F. Bioorg.
Med. Chem. Lett. 2000, 10, 2613.