Synthesis of deuterated benzopyran derivatives as selective COX-2 inhibitors with improved pharmacokinetic properties

Article abstract of DOI:10.1021/ml500299q

We designed a series of specifically deuterated benzopyran analogues as new COX-2 inhibitors with the aim of improving their pharmacokinetic properties. As expected, the deuterated compounds retained potency and selectivity for COX-2. The new molecules possess improved pharmacokinetic profiles in rats compared to their nondeuterated congeners. Most importantly, the new compounds showed pharmacodynamic efficacy in several murine models of inflammation and pain. The benzopyran derivatives were separated into their enantiomers, and the activity was found to reside with the S-isomers. To streamline the synthesis of the desired S-isomers, an organocatalytic asymmetric domino oxa-Michael/aldol condensation reaction was developed for their preparation.

Full text of DOI:10.1021/ml500299q

Letter
pubs.acs.org/acsmedchemlett
Synthesis of Deuterated Benzopyran Derivatives as Selective COX‑2
Inhibitors with Improved Pharmacokinetic Properties
Yanmei Zhang,*,† Micky D. Tortorella,† Yican Wang,† Jianqi Liu,† Zhengchao Tu,† Xiaorong Liu,†
Yang Bai,† Dingsheng Wen,† Xin Lu,† Yongzhi Lu,† and John J. Talley*,‡,§
†Drug Discovery Pipeline, Guangzhou Institutes of Biomedicine and Health, Science City, Guangzhou 510530, P. R. China
‡Department of Chemistry, St. Louis University, St. Louis, Missouri 63108, United States
§Euclises Pharmaceuticals, St. Louis, Missouri 63108, United States
S
* Supporting Information
ABSTRACT: We designed a series of specifically deuterated benzopyran analogues as new COX-2 inhibitors with the aim of
improving their pharmacokinetic properties. As expected, the deuterated compounds retained potency and selectivity for COX-2.
The new molecules possess improved pharmacokinetic profiles in rats compared to their nondeuterated congeners. Most importantly,
the new compounds showed pharmacodynamic efficacy in several murine models of inflammation and pain. The benzopyran derivatives
were separated into their enantiomers, and the activity was found to reside with the S-isomers. To streamline the synthesis of the desired
S-isomers, an organocatalytic asymmetric domino oxa-Michael/aldol condensation reaction was developed for their preparation.
KEYWORDS: COX-2, coxib, deuterium, benzopyran, NSAID
onsteroidal anti-inflammatory drugs (NSAIDs) inhibit
both COX-1 and COX-2 enzymes and have been a
address unmet medical conditions.9−12 Such clinical conditions
include treating pain and inflammation without further compro-
mising renal function and in treating or preventing certain types
of cancer associated with inflammation mediated by COX-2.
Benzopyran compounds as selective COX-2 inhibitors were
investigated.13−15 It was reported that 2-trifluoromethyl, 3-carboxy,
and 4-H substituents were key elements of the benzopyran phar-
macophore. Chiral chromatographic separation of 2-trifluoromethyl
enantiomers and evaluation of the individual isomers showed that
S-isomers were far more effective in blocking COX-2 activity than
N
mainstay in clinical medicine for the treatment of inflammation
and pain for many years. COX-2-selective inhibitors (coxibs)1,2
developed in the mid 2000s supplanted traditional NSAIDs
by virtue of their comparable efficacy with improved gastro-
intestinal safety.3 Coxibs were initially thought to be able to
avoid renal and cardiovascular side effects; however, this proved
not to be entirely accurate.4 In the kidney, COX-2 is expressed
constitutively in certain regions (i.e., macula densa) and is
highly regulated in response to changes in blood volume. COX-
2-mediated metabolites (e.g., PGE2 and PGI2) play a mecha-
nistic role in renin release, sodium excretion, and the main-
tenance of renal blood flow and glomerular filtration rate.5
Coxibs fell into disfavor as clinical medicine because initial data
linked them to cardiovascular risks of stroke and myocardial
infarction compared with traditional NSAIDs.6 However, data
analysis from two recent clinical trials7,8 clearly demonstrated
that chronic and even short-term use of NSAIDs increased
renal and cardiovascular side-effect risk no lesser than coxibs,
and that the risks appeared to be drug-dependent rather than
class-dependent. These data among other studies have inspired
renewed interest in selective COX-2 inhibitors, particularly with
coxibs that have a unique pharmacological profile, which could
Figure 1. Benzopyran template and SC-75416.
Received: July 24, 2014
Accepted: July 27, 2014
Published: July 27, 2014
© 2014 American Chemical Society
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Letter
a
Scheme 1. Synthesis of Trideuteromethyl Derivatives
a
R represents substituents on C5, C6, C7, or C8 position; RD represents deuterated substituents. Reagents and conditions: (a) potassium t-butoxide,
DMSO-d6, 110 °C 6 h; (b) BBr3, DCM, 0 °C, 2 h; (c) HTMA, TFA, rt, 1 h; (d) ethyl 4,4,4-trifluorocrotonate, K2CO3, DMF, 80−100 °C, 2−4 h; (e)
NaOH, THF/CH3OH/H2O.
a
Scheme 2. Synthesis of Pentadeuterated Analogue 6i
a
Reagents and conditions: (a) CuI, Pd(PPh3)4, ethynyltrimethylsilane, TEA, MeCN, rt, 24 h; (b) K2CO3, anhydrous ethanol, D2O, rt, 30 min; (c)
D2, EtOAc, Pd/C, rt, 1 h; (d) NaOH, THF/CH3OH/H2O.
the corresponding R-isomers. Substitutions at the 5, 6, 7, and 8
positions were optimized for potency, efficacy, and pharmacoki-
netic profiles. Several clinical candidates were identified including
SC-75416 and advanced into clinical trials (Figure 1).
may also be conducted prior to O-demethylation if needed.
Substituted salicylaldehydes 4 were synthesized by the Duff
reaction.20−22 Key intermediate 4 was then condensed with
commercially available ethyl trifluorocrotonate to produce the
specifically deuterium substituted benzopyran nucleus 5, in a
one-step procedure by heating in K2CO3 and DMF. The
resulting esters 5 were hydrolyzed with sodium hydroxide yield-
ing the acids 6a−h; see Scheme 1 (see synthesis and charac-
terization of compounds, Supporting Information).
Deuteration of compounds is a strategy for creating new
chemical entities that has recently been used in drug discovery
to make improved drugs. Carbon−deuterium bonds are stronger
than the more common carbon−hydrogen bonds, and the re-
placement of hydrogen atoms with deuterium at metabolically
labile positions can significantly improve the PK and thus efficacy
of physiologically active compounds by slowing metabolism due
to the kinetic isotope effect. Deuterium substituted compounds
retain both biochemical potency and selectivity for their target,
suggesting that deuterium atom substitution does not appreciably
alter ligand−receptor binding. More importantly, replacing hy-
drogen with deuterium can enable substantial benefits to the
overall pharmacological profile of the compounds.16−18 In an
effort to develop improved selective COX-2 inhibitors, we de-
signed and synthesized a series of specifically deuterated
analogues of benzopyran coxibs. The initial synthetic efforts
focused on deuteration of the methyl group, which is outlined
in Scheme 1. Commercially available anisoles 1 were deuterium
labeled on the methyl group under strongly basic conditions in
DMSO-d6 to give compound 2, which converted methyl or
dimethyl into CD3 or di-CD3 derivatives.19 Deuterium sub-
stituted phenols 3 were prepared by O-demethylation, followed
by chlorination or bromination to provide the desired chlo-
rinated or brominated products. Chlorination or bromination
Compound 6i was prepared according to the procedure
outlined in Scheme 2. The benzopyran 7 was prepared by a
published procedure23 and then coupled with ethynyltrime-
thylsilane in the presence of a base and a catalytic amount of
cuprous iodide and tetrakis(triphenylphosphine)palladium(0)
to afford 8. Removal of the trimethylsilyl group was key to yield
the terminal deuterated compound 9 (K2CO3 in D2O), and
reduction of 9 (D2, Pd/C in ethyl acetate) and finally saponi-
fication of the ester with aqueous sodium hydroxide gave deu-
terated benzopyran 6i (see Scheme 2 and synthesis and char-
acterization of compounds in Supporting Information). The
corresponding nondeuterated benzopyran derivatives 6an−in
were synthesized by known methods.23
The analogues 6a−i and 6an−in were tested for their inhi-
bitory activity against recombinant human COX-1 and COX-2
enzymes, the results are shown in Table 1 (see in vitro COX
enzyme assay in Supporting Information). There were no
significant differences in the inhibitory profile against COX-1
or COX-2 between deuterated versus the corresponding
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ACS Medicinal Chemistry Letters
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Table 1. Evaluation of Substituted Benzopyrans against
COX-1 and COX-2 Enzymes
Table 4. In Vivo Murine Models of Inflammation and Pain
air pouch
EC50
edema EC50
(mg/kg)
hyperalgesia
EC50 (mg/kg)
arthritis ED50
(mg/kg)
compd
(mg/kg)
celecoxib
6a
0.69 0.10
0.47 0.05
0.57 0.10
0.45 0.03
0.27 0.02
0.77 0.10
0.61 0.09
0.47 0.06
2.81 0.43
5.18 1.01
2.26 0.36
6.48 1.25
3.00 0.31
5.0 0.64
2.77 0.25
3.82 0.75
3.33 0.49
2.19 0.32
1.57 0.21
0.42 0.08
6b
6g
6h
rh IC50 (μM)
6an
6gn
compd
R1
R2
R3
Cl
R4
COX-1
COX-2
6hn
3.47 0.62
3.52 0.77
6a
H
H
Br
H
Cl
CD3
CD3
CD3
H
CD3
CD3
CD3
H
0.054 0.013
0.043 0.018
0.084 0.020
>10
6b
6c
Br
Br
>100
>100
6d
6e
CD3
CD3
CD3
Cl
H
H
0.063 0.015
0.15 0.035
0.059 0.009
0.039 0.005
0.061 0.009
0.069 0.025
0.19 0.042
0.069 0.008
>10
6f
CD3
CD3
CD3
CD2CD3
H
H
H
6g
H
H
6h
6i
H
Br
H
H
OCF3
Cl
H
6an
6bn
6cn
6dn
6en
6fn
6gn
6hn
6in
CH3
CH3
CH3
H
CH3
CH3
CH3
H
>100
>100
>100
H
Br
Figure 2. Dose-dependent inhibition of arthritis by compound 6h.
Indomethacin (2 mg/kg) was used a positive control and PBS was
used as the vehicle (Veh).
Br
Br
H
CH3
CH3
CH3
Cl
Cl
H
H
>100
0.078 0.022
0.100 0.024
0.051 0.022
0.028 0.001
0.049 0.007
CH3
CH3
CH3
CH2CH3
H
H
bearing a 6-chloro or 6-bromo substituent were the most
potent and selective inhibitors of COX-2.
H
H
H
Br
H
>100
>100
The pharmacokinetic properties of analogues 6a−i and 6an−in
were studied in male SD rats following i.v. and oral adminis-
tration, the results are described in Tables 2 and 3 (see rat po PK
results of deuterated and nondeuterated analogues (Table 2) and
rat iv PK results of deuterated and nondeuterated analogues
(Table 3) in Supporting Information). There were significant
H
OCF3
H
nondeuterated analogues. Most analogues had potency for
COX-2 with an IC50 < 100 nM and were relatively inactive
against COX-1. Within this series of compounds, the analogues
Table 2. Rat PK of Deuterated Analogues (PO)
dose (mg/kg)
BA%
Tmax (h)
Cmax (μg/L)
Vd (L/kg)
t1/2 (h)
AUC(0−∞) (μg/L·h)
CLz/F (L/h/kg)
6a
10
10
2.5
10
30
10
2.5
2.5
5
92.8
1.167
0.5
20900
21300
8945
0.26
2.1
118331.438
84789.673
38881.983
142686.966
402662.508
12846.927
12529.512
4627.624
0.086
0.125
0.066
0.072
0.075
0.195
0.211
0.547
0.298
0.049
0.242
6b
111.8
110.7
107.4
60.2
0.57
3.35
3.37
5.2
6g
0.5
0.316
0.53
6h
0.417
1.25
35300
33475
6592
6i
0.491
1.25
4.542
3.09
3.53
1.75
1.51
9.542
6.68
6an
6bn
6gn
6hn
6in
78.5
0.438
0.375
0.25
56.7
5338
1.13
128.5
46.3
2720
1.37
0.438
1.625
0.75
11523
29525
8152.5
0.65
17190.28
25
10
78.6
0.678
2.314
511440.855
42223.264
SC-75416
67.5
Table 3. Rat PK of Deuterated Analogues (IV)
dose (mg/kg)
Cmax (μg/L)
Vd (L/kg)
t1/2 (h)
AUC(0−∞) (μg/L·h)
CLz/F (L/h/kg)
6a
5
38750
26175
9068.75
38975
51625
5035
0.287
0.529
0.404
0.461
0.39
2.525
2.733
3.909
4.186
5.946
1.5
63759.714
37914.156
14043.753
66436.832
222923.421
4898.988
0.079
0.135
0.072
0.077
0.047
0.207
0.119
0.706
0.172
0.038
0.16
6b
5
6g
1
6h
5
6i
10
1
6an
6bn
6gn
6hn
6in
0.45
1
16681
4131
0.38
2.30
8843.992
1
0.59
0.59
1440.446
2.5
5
38581
37250
37187
0.15
0.58
14843.535
130985.986
31271.923
0.301
1.353
5.446
5.78
SC-75416
5
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a
Scheme 3. Enantioselective Synthesis of (S)-2-(Trifluoromethyl)-2H-chromene-3-carboxylic Acids
a
R represents substituents on C5, C6, C7, or C8 position. Reagents and conditions: (a) 2-nitrobenzoic acid, CH2Cl2, rt, 24 h; (b) OXONE, DMF,
rt, 24 h.
compound 6h, tested in the rat adjuvant arthritis model is
shown in Figure 2.
Normally, separation of the enantiomers can be accom-
plished by classical diastereomeric salt formation (selective
crystallization using chiral amines, such as α-methylbenzyl-
amine) or by chiral chromatography. We discovered that the
protected α,α-diphenyl-2-pyrrolidinemethanol24−26 (com-
pound 12 of Scheme 3) was able to catalyze the formation of
S-stereoisomer with more than 80% ee, which is a much more
efficient method for making the compound especially for large
scale synthesis. Iminium activation of α,β-unsaturated alde-
hydes 1127 by 12 leads to enantioselective oxa-Michael addition
with 4 and generates enamine intermediates that undergo
subsequent intramolecular 6-exo-trig aldol condensations to
give the corresponding S-6a−i24 (see Scheme 3 and page 9 of
Supporting Information). X-ray analysis of S-6h established that
the absolute configuration at C2 was S; see Figure 3 (see crystal
structure of S-6h, Supporting Information). As expected,
S-stereoisomers were found to be 2−5 times more potent for
COX-2 than their corresponding racemic mixtures; see Table 5.
In conclusion, we synthesized a series of specifically deu-
terium substituted benzopyran analogues as potent and selec-
tive COX-2 inhibitors. Analogues 6a, 6b, 6g, and 6h showed
Figure 3. Ortep picture of S-6h.
not only excellent selective COX-2 inhibition but also a signifi-
cantly improved PK profile. These compounds were efficacious
in the gold standard rodent models of inflammation and pain.
We also developed a new enantioselective synthetic protocol
for preparation of S-stereoisomers for this series of molecules.
Collectively, these compounds deserve further evaluation as
clinical candidates for the treatment of inflammatory mediated
diseases.
Table 5. COX-2 Inhibition of S-Stereoisomers
ASSOCIATED CONTENT
ee value (%)
rh IC50 (μM) COX-2
rh IC50 (μM) COX-1
■
S-6a
S-6b
S-6g
S-6h
86.5
80.7
89.7
90.2
0.016
0.009
0.02
>100
>100
>100
>100
S
* Supporting Information
Complete experimental details along with the characterizations
of the synthesized compound. This material is available free of
charge via the Internet at http://pubs.acs.org.
0.014
AUTHOR INFORMATION
changes in the overall pharmacokinetic profile between deu-
terated versus the corresponding nondeuterated analogues. Overall
the deuterated analogues demonstrated a better PK profile. Ana-
logue 6h bearing a 6-bromo substituent was shown to have the
longest half-life.
Moreover, compounds 6a, 6b, 6g, and 6h were efficacious in
several key animal models used to assess the potency of
NSAIDs including the air pouch model of PGE2 release and
inflammation, paw edema, hyperalgesia in rats and the adjuvant
induced arthritis model in mice; see Table 4. All compounds
displayed potent efficacy and dose-dependent suppression in
each of these disease models.
■
Corresponding Author
*(Y.Z.) Phone: 0086-20-32015277. E-mail: zhang_yanmei@
gibh.ac.cn.
*(J.J.T.) Phone: 001-314-601-3096. E-mail: jjtalley@euclises.
com.
Funding
Y.Z. is grateful to the Guangzhou Government and Guangzhou
Institute of Biomedicine and Health (GIBH), Chinese
Academy of Sciences (CAS) for the joint sponsorship of this
work under the Drug Discovery Pipeline (DDP) grant.
Notes
As an example of the dose-dependent efficacy that we ob-
served for these compounds, a full dose response curve for
The authors declare no competing financial interest.
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