Discovery, optimisation and in vivo evaluation of novel GPR119 agonists

Article abstract of DOI:10.1016/j.bmcl.2011.10.033

GPR119 is increasingly seen as an attractive target for the treatment of type II diabetes and other elements of the metabolic syndrome. During a programme aimed at developing agonists of the GPR119 receptor, we identified compounds that were potent with reduced hERG liabilities, that had good pharmacokinetic properties and that displayed excellent glucose-lowering effects in vivo. However, further profiling in a GPR119 knock-out (KO) mouse model revealed that the biological effects were not exclusively due to GPR119 agonism, highlighting the value of transgenic animals in drug discovery programs.

Full text of DOI:10.1016/j.bmcl.2011.10.033

Bioorganic & Medicinal Chemistry Letters 21 (2011) 7310–7316
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery, optimisation and in vivo evaluation of novel GPR119 agonists
Katy J. Brocklehurst a, Anders Broo b, Roger J. Butlin a, Hayley S. Brown a, David S. Clarke a,
Öjvind Davidsson b, Kristin Goldberg a, Sam D. Groombridge a, Elizabeth E. Kelly a, Andrew Leach a,
Darren McKerrecher a, Charles O’Donnell a, Simon Poucher a, Paul Schofield a, James S. Scott a,
Joanne Teague a, Leanne Westgate a, Matt J.M. Wood a
,
⇑
a Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK
b Pepparedsleden 1, 431 83 Mölndal, Sweden
a r t i c l e i n f o
a b s t r a c t
Article history:
GPR119 is increasingly seen as an attractive target for the treatment of type II diabetes and other ele-
ments of the metabolic syndrome. During a programme aimed at developing agonists of the GPR119
receptor, we identified compounds that were potent with reduced hERG liabilities, that had good phar-
macokinetic properties and that displayed excellent glucose-lowering effects in vivo. However, further
profiling in a GPR119 knock-out (KO) mouse model revealed that the biological effects were not exclu-
sively due to GPR119 agonism, highlighting the value of transgenic animals in drug discovery programs.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 7 September 2011
Revised 7 October 2011
Accepted 9 October 2011
Available online 18 October 2011
Keywords:
GPR119 agonist
hERG
Knock-out mice
Transgenic animals
GPR119 is a class A G-protein coupled receptor that is predom-
inantly expressed in pancreatic islets and sections of the GI tract.1
Recent work has led to the de-orphanisation of this receptor with
the identification of oleoylethanolamide (OEA) and related com-
pounds being proposed as natural agonists.2 Studies have shown
that agonism of GPR119 results in incretin release in the gut
F3C
N
N
O
S
O O
1
(e.g., glucagon-like peptide-1 release from L-cells) in addition to
Figure 1. Structure of the initial high-throughput screening hit.
the stimulation of insulin release from b-cells in the pancreas.3 This
dual mechanism of action has generated considerable interest in
the potential of GPR119 agonists as a therapeutic intervention in
the treatment of diabetes.4
efficiency,14,15 LLE (pEC50 À logD = 3.4), and the compound had
moderate metabolic stability in human microsomes (Clint = 8 lL/
Following an initial demonstration that a synthetic GPR119
agonist was capable of controlling glucose excursions in preclinical
animal models,5 a number of groups have described their efforts in
this area.6–10 Herein we report the synthesis and structure–activity
relationships of a series of novel GPR119 agonists together with
their in vivo effects in both wild-type and GPR119 knock-out
mouse studies.
min/mg). A key issue with this compound was the measured affinity
against the hERG ion channel16 (IC50 = 2.5
lM) leading to a selectiv-
ity based on the ratio of primary potency/hERG of less than fivefold.
Improvement of the selectivity against hERG was therefore the
initial focus of the optimisation campaign.
The compounds described in this paper were prepared using a
modular approach that allowed diversification of R1 or R2 at the
Our initial hit 1 was identified from screening of the AstraZeneca
compound collection (Fig. 1). This compound had moderate potency
against the GPR119 receptor (EC50 = 538 nM in an in vitro cAMP as-
say)11 and displayed modest efficacy (42% top effect).12 The logD
was measured13 at 2.9 resulting in a reasonable ligand lipophilicity
final step (Scheme 1). Route
A involved amide coupling of
tert-butyl 4-(methylamino)piperidine-1-carboxylate with phenyl
acetic acids (step a) using 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-
methylmorpholinium chloride (DMTMM) followed by Boc depro-
tection to give the piperidine (step b). Subsequent alkylation (step
c) provided compounds 2 & 8. Route B involved alkylation of iso-
meric N-tert-butyl N-methyl-N-(4-piperidyl)carbamate followed
by Boc deprotection to give the piperidine intermediate that was
acylated to provide compounds 7 & 9–13. Compound 14 was
⇑
Corresponding author. Tel.: +44 (0) 1625 232567; fax: +44 (0) 1625 516667.
E-mail address: jamie.scott@astrazeneca.com (J.S. Scott).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.10.033

K. J. Brocklehurst et al. / Bioorg. Med. Chem. Lett. 21 (2011) 7310–7316
7311
Route A
N
N
N
NH
R1
R1
c)
a)
R2
O
N
N
O
O
N
BocN
R
R=Boc
R=H
2, 8
b)
Route B
NBoc
N
R1
c)
a)
R
R2
R2
HN
N
R=Boc
R=H
7, 9-13
b)
d) used for 14
Scheme 1. General synthetic procedure. Reagents and conditions: (a) R1CH2COOH, DMTMM, THF, rt, 60–73%; (b) trifluoroacetic acid (TFA), CH2Cl2, rt, 77–100%; (c) R2CH2X
(X = Br, Cl or OMs), N(iPr)2Et, CH3CN, rt, 15–94%; (d) NaBH(OAc)3, N(iPr)2Et, MgSO4, THF, 44%.
X=COOMe
F3C
N
N
d)
e)
X=COOH
N
N
O
O
NBoc
X
X
F3C
N
X=CONHMe (5)
X=NO2
a)
c)
R
N
N
g)
h)
X=NH2
F
R=Boc
R=H
X=NHCOMe (6)
F3C
b)
X=Br
i)
X=SO2Me (3,4)
Scheme 2. Functional group conversion for diversification of R1. Reagents and conditions: (a) p-CF3PhCH2Br, N(iPr)2Et, CH2Cl2, 94%; (b) TFA, CH2Cl2, 100%; (c) N(iPr)2Et,
CH2Cl2, R1CH2COCl, 71–86%; (d) LiOH, H2O/THF, 88%; (e) HATU, N(iPr)2Et, DMF, MeNH2, 44%; (g) H2, Pd/C, 60%; (h) MeCOCl, Pyridine, CH2Cl2, 65%; (i) MeSO2Na, Cu(I)OTf.
toluene, Me2NCH2CH2NMe2, DMSO, 12–23%.
synthesised using route B with a reductive amination of the
corresponding aldehyde (step d) as the final step.
a) and the carboxybenzyl (Cbz) protecting group removed under
hydrogenating conditions (step b). Coupling with the required phe-
nyl acetic acid using HATU (2-(7-Aza-1H-benzotriazole-1-yl)-
1,1,3,3-tetramethyluronium hexafluorophosphate) (step c) and
deprotection of the Boc group (step d) afforded an intermediate
that could be alkylated (step e) to afford the final compounds 15
& 19–24. Compound 16 was synthesised from the enantiomeric
(3R,4S) intermediate using the same synthetic sequence. For the
methoxy analogues, the known (3S,4R)-3-methoxy-piperazine
intermediate18 was carboxybenzyl protected (step f) and then
methylated (step g). Removal of the carboxybenzyl protecting
group (step h) was followed by coupling with the required phenyl
Other examples (3–6) were synthesised by elaboration of func-
tional groups (Scheme 2). Amide 5 was synthesised from an ester
intermediate through hydrolysis and coupling with methylamine
(steps d, e) whereas the reversed amide 6 was synthesised through
reduction of a nitro group followed by coupling with an acid chlo-
ride (steps g, h). Fluoro substituted aromatic examples 3 & 4 were
synthesised via formation of the bromo intermediates followed by
conversion to sulphone (step i) using copper catalysis.
For the fluorinated piperidine examples (Scheme 3), the known
(3S,4R)-3-fluoro-piperazine intermediate17 was methylated (step
N
NHCbz
F
R1
NCbz
F
N
F
a)
R1
c)
e)
R2
N
O
BocN
BocN
RN
O
F
15, 19-24
(16 as enantiomer)
R=Boc
R=H
R=Bz
R=H
d)
b)
H
N
R
N
N
g)
i)
R1
k)
N
R1
R
R2
EtO
N
N
O
EtO
N
h)
RN
O
OMe
OMe
OMe
OMe
O
O
17
(18 as enantiomer)
R=Cbz
R=H
R=COOEt
R=H
R=H
j)
f)
R=Cbz
Scheme 3. General synthetic procedure for substituted piperazines. Reagents and conditions: (a) NaH, MeI, DMF, 91%; (b) H2, Pd/C, EtOH, 90%; (c) R1CH2COOH, HATU,
N(iPr)2Et, DMF, 44–100%; (d) TFA, CH2Cl2, 100%; (e) R2CH2X (X = Br,Cl or OMs), N(iPr)2Et, CH3CN, r, 36–86%; (f) BnOCOCl, N(iPr)2Et, CH2Cl2, 99%; (g) NaH, MeI, DMF, 79%; (h) H2,
Pd/C, EtOH; (i) 2-[4-(tetrazol-1-yl)phenyl]acetic acid, DMTMM, THF; 85% (over two steps); (j) TMSI, CH2Cl2, 54%; (k) p-CF3PhCH2Br, N(iPr)2Et, CH3CN, 85%.

7312
K. J. Brocklehurst et al. / Bioorg. Med. Chem. Lett. 21 (2011) 7310–7316
acetic acid (step i) using DMTMM. Deprotection of the ethyl carba-
mate was carried out using trimethylsilyl iodide (step j) and the
product was then alkylated (step k) to afford the final compound
17. Compound 18 was synthesised from the enantiomeric (3R,4S)
intermediate using the same synthetic sequence.
Exploration of the R2 substituent is shown in Table 2 with the R2
substituent fixed as the N-tetrazole as in compound
7
(EC50 = 74 nM; LLE = 4.1). Incorporation of a pyridyl N (9 & 10) re-
duced potency in line with the reduction in lipophilicity (LLE
scores of 4.1, 4.0 & 3.9 for compounds 7, 9 & 10, respectively)
but with efficacy remaining high. Consequently, although reduc-
tions in hERG were observed this did not result in increased mar-
gins. Fluorination of the aryl ring (11) resulted in a modest
potency increase and decrease in hERG affinity leading to increased
selectivity (53-fold) however, increased susceptibility to metabo-
Truncation of the N-ethyl to an N-methyl amide 2 improved the
in vitro metabolic profile (Clint = 3
lL/min/mg) whilst maintaining
potency (EC50 = 456 nM), LLE (3.8) and hERG (IC50 = 3
lM; now
eightfold relative to primary target). We were keen to improve po-
tency but not at the cost of additional lipophilicity and therefore
had LLE as a key optimization parameter. Exploration of the R1 sub-
stituent is shown in Table 1. Fluorination of the aryl ring (3 & 4) re-
sulted in an increase in LLE score (LLE = 4.2 & 3.9, respectively) and
efficacies (88% & 73%, respectively) relative to the unsubstituted
analogue 2. Although the hERG affinities had remained unaltered,
the increase in primary potency resulted in an improved selectivity
ratio (>20-fold in both cases). C and N linked amides were tolerated
(5 & 6) although neither offered significant advantages over the
sulphone 2. The N-linked tetrazole 7 was the most potent com-
pound identified (EC50 = 74 nM) and had the highest efficacy
(132%) with an LLE of 4.1. Although this compound showed in-
lism was observed (Clint = 14 lL/min/mg). The CF3 unit could be re-
placed by polar heterocycles such as the oxadiazole 12 with
potency loss broadly in line with lipophilicity reduction
(LLE = 4.3) but with efficacy maintained and selectivity against
hERG remaining at similar levels (15-fold) to compound 7. Benzo-
thiazole 13 was identified as an interesting group that had a simi-
lar profile to the trifluoroaryl 7 with high LLE (4.3) and similar
selectivity against hERG (17-fold). Attempts to saturate the aryl
ring (14) had the desired effect of reducing the absolute affinity
for hERG (IC50 = 7.6
crease in turnover in human microsomes (Clint = 169
l
M), but led to a reduction in LLE and an in-
L/min/mg).
l
creased hERG affinity (1.2
l
M), the increased potency resulted in
Our last area of exploration was the piperidine core as shown in
Table 3. We rationalised that the basicity of the nitrogen (mea-
sured pKa = 7.0) may be responsible for the affinity for the hERG
receptor19 and we therefore sought to moderate this by incorpora-
tion of electronegative groups at the 3-position. To this end, the
an increased hERG selectivity (16Â). Substitution of the aryl ring
was crucial to activity as exemplified by compound 8 which was
inactive in the in vitro cAMP assay, despite being considerably
more lipophilic than the other compounds investigated.
Table 1
Human GPR119 potencies, physical and DMPK properties for R1 variation
F3C
N
R1
N
O
Compd
R1
h GPR119 EC50
0.456
(lM)
h GPR119 activity (%)
logD
LLE (pEC50ÀlogD)
hERG IC50
(
lM)
h Mics Clint (lL/min/mg)
2
54
88
73
2.5
3.8
3
3
S
O O
F
3
4
0.122
0.131
2.7
3.0
4.2
3.9
2.6
2.9
18
15
S
O O
F
S
O O
H
5
6
0.489
0.535
75
65
2.8
2.9
3.5
3.4
2.1
4.5
<6
29
N
O
O
N
H
7
8
0.074
>30
132
24
3
4.1
—
1.2
1.6
7
N
N
N
N
>4.0
20

K. J. Brocklehurst et al. / Bioorg. Med. Chem. Lett. 21 (2011) 7310–7316
7313
Table 2
Human GPR119 potencies, physical and DMPK properties for R2 variation
N
R2
N
O
N
N
N
N
Compd
R2
h GPR119 EC50
1.345
(lM)
h GPR119 activity (%)
98
logD
LLE (pEC50ÀlogD)
hERG IC50
4.2
(
lM)
h Mics Clint
<5
(lL/min/mg)
F3C
9
1.9
4.0
N
F3C
10
11
1.89
79
83
1.8
—
3.9
—
13
<2
14
N
F3C
F
0.053
2.8
O N
12
13
14
0.441
0.076
0.396
98
85
68
2.1
2.9
2.5
4.3
4.3
3.9
6.5
1.3
7.6
<2
N
F
S
21
N
S
169
N
Table 3
Human GPR119, physical and DMPK properties for R3 variation
F3C
N
N
O
R3
N
N
N
N
Compd
R3 (stereo)
h GPR119 EC50
(lM)
h GPR119 activity (%)
logD
LLE (pEC50ÀlogD)
hERG IC50
(lM)
h Mics Clint (lL/min/mg)
15
16
17
18
F (3R,4S)
F (3S,4R)
OMe (3R,4S)
OMe (3S,4R)
0.029
0.007
0.029
0.172
104
123
84
3.3
3.3
3.1
3
4.2
4.9
4.4
3.8
3.6
2.0
2.0
1.2
5
6
71
65
30
enantiomeric pairs of the cis-F (15 & 16; predicted pKa = 5.5)20 and
cis-OMe (17 & 18 predicted pKa = 6.4) were synthesized and com-
pared to the unsubstituted analogue 7. For the fluoro substitution,
we observed modest reduction in the absolute affinities for hERG
despite an increase in lipophilicity. In the case of the (3S,4R) isomer
16, we achieved a dramatic improvement in GPR119 potency
(EC50 = 7 nM) with high efficacy (123%) leading to improved LLE
(4.9) and hERG selectivity (>250-fold). The methoxy analogues
had significant increases in metabolic instability (Clint = 71 &
the CF3 aryl ring delivered compounds 19 & 20 which were potent
against GPR119 with hERG affinities >10 M and that were stable
in rat and human microsomes (Clint = 4 & 3 L/min/mg, respec-
tively). The benzothiazole 21 was found to have excellent potency
(EC50 = 12 nM) with improved selectivity against hERG (>390-fold).
Switching to a sulphone R1 substituent, gave 22 which was the
most potent compound to date (EC50 = 4 nM) and with high LLE
l
l
(5.7) and robust efficacy (85%). The affinity for hERG was 4.2
leading to a selectivity in excess of 1000-fold, and the compound
was metabolically stable (Clint = 6 L/min/mg). The benzothiazole
lM
65
l
L/min/mg for compounds 17 and 18, respectively). It was of
l
interest to note that for the F and OMe, different enantiomers of
the pairs were preferred in each case and that the potency and effi-
cacy of the (3S,4R) OMe compound 18 was significantly reduced.
With this knowledge of the structure–activity relationships
within this series, we elected to fix the core as the (3S,4R)-F isomer
and synthesise examples of what we felt to be optimal combina-
tions as shown in Table 4. Incorporation of a pyridyl group into
combinations 23 & 24 were potent and compound 23 was notable
for having good potency (EC50 = 24 nM) in combination with low
affinity for the hERG channel (IC50 = 16 lM).
In parallel with this optimisation work, further profiling of
compound 7 had revealed that this compound had many attractive
features. The compound displayed no inhibition towards five major
isoforms of cytochrome P450 enzymes (CYP1A2, CYP2C9, CYP2C19,

7314
K. J. Brocklehurst et al. / Bioorg. Med. Chem. Lett. 21 (2011) 7310–7316
Table 4
Human GPR119, physical and DMPK properties for selected combinations
N
F
R2
N
O
R1
Compd R1
R2
h GPR119 EC50
(
lM) h GPR119 activity (%) logD LLE
hERG IC50
(
lM) h Mics Clint
(lL/min/
(pEC50ÀlogD)
mg)
F3C
N
N
N
N
N
19
20
0.140
0.485
139
78
2.1
1.8
4.8
10
15
4
3
N
N
N
N
F3C
N
N
4.5
5.3
5.7
5.5
N
N
N
F
S
21
22
23
0.012
0.004
0.024
86
85
44
2.6
2.7
2.1
4.7
4.2
16
<7
6
N
F3C
S
O O
S
O O
S
9
N
S
O O
F
S
24
0.018
39
2.2
5.6
7
13
N
CYP2D6 and CYP3A4) in a high throughput fluorescence assay,
with IC50 values >25 M. Plasma protein binding showed reason-
able free drug levels consistently across species (mouse = 9.9% free;
rat = 8.1% free; dog = 6.8% free; human = 7.6% free). The solubility
as measured on crystalline material was modest at 18 lM but
excursion in a mouse (C57BL6/JAX) oral glucose tolerance test
(OGTT). In order to establish that this glucose control was medi-
ated by GPR119, compound 7 was tested in an OGTT with both
wild-type and GPR119 knock-out mice at a dose of 20 mg/Kg. A sig-
nificant glucose lowering effect was observed in the wild-type
mice however, to our surprise, an effect of similar magnitude
was also observed in the knock-out mice group indicating that
the effects observed were not exclusively mediated through
GPR119 (Fig. 2). Reducing the dose of compound 7 led to lower glu-
cose lowering effects (data not shown) but crucially no separation
of wild-type and knock-out activities.
l
when coupled with good cellular permeability as measured in an
in vitro CACO-2 assay (apical to basolateral Papp = 57 Â 10À6 cm/s,
efflux ratio = 0.4 at a compound concentration of 10 lM) or MDCK
assay (apical to basolateral Papp = 17 Â 10À6 cm/s, efflux ratio = 0.8
at a compound concentration of 10 lM) it was predicted that this
would lead to good absorption in vivo.
The pharmacokinetic profiles of 7 were determined in vivo in
three pre-clinical species; mouse, rat and dog (Table 5). The com-
pound showed good pharmacokinetic properties across species,
with low clearance (rat and dog) and good bioavailability (mouse,
rat). A bile duct cannulation study in rat indicated no biliary or re-
nal elimination. This was consistent with the excellent correlation
of in vitro/in vivo scaling of clearance from hepatocytes.
Compound 7 was tested against the murine form of GPR119 and
was found to retain potency (EC50 = 147 nM in an in vitro cAMP
assay) with an efficacy of 74% relative to that of OEA. Based on
the favourable mouse pharmacokinetics with this compound, it
was investigated in vivo for its potential to control the glucose
In order to investigate whether this off-target activity was re-
lated to a particular structural feature of this compound or was
characteristic of the series, compounds 5, 13 and 17 were selected
as being matched pairs with compound 7 but with structural var-
iation in terms of the R1, R2 and R3 groups, respectively. Based on
the DMPK profiles of these compounds in mouse, we selected
doses that would give coverage of the murine EC50 for the entire
duration of the experiment. Upon testing these compounds
in vivo, and confirming that the targeted exposures had been
achieved, we again observed glucose lowering in both wild-type
and knock-out animals in all three cases. This led us to conclude
that the pharmacophore displayed by this chemical series was
Table 5
Pharmacokinetic parameters for selected compound 7a
Species
Clp (mL/min/kg)
Vdss (L/kg)
PO half-life (h)
IV half-life (h)
PO Cmax
(lM)
Bioavailability (%)
Mouse
Rat
Dog
12
6.8
1.3
2.0
1.4
2.3
2.4
2.8
18
2.2
2.8
20
2.2
2.4
6.4
64
66
35
a
Compounds were dosed at 2 mg/kg (IV) and 5 mg/kg (PO—mouse and rat), 13 mg/kg (PO—dog) in 5% DMSO:95% hydroxylpropyl beta cyclodextrin, and a 0.1% pluronic
F127suspension, respectively at volumes of 5 mL/kg (mouse and rat) and 2 mL/kg (dog).21

K. J. Brocklehurst et al. / Bioorg. Med. Chem. Lett. 21 (2011) 7310–7316
7315
Figure 2. In vivo glucose lowering effects of compound 7 (a) OGTT blood glucose profile in C57BL6/J mice (b) OGTT blood glucose AUC GPR119 knock-out (KO) mice and wild-
type (WT) controls. Compound was administered po in 0.1% pluronic F127 vehicle (n = 6–7/group) 30 min prior to a glucose load of 2 g/kg. Glucose levels were monitored for
90 min post glucose load. ⁄⁄⁄p 6 0.001 versus vehicle control ANCOVA analysis.
Figure 3. In vivo glucose lowering effects of (a) compound 5 (b) compound 13 (c) compound 17 in GPR119 knock-out (KO) mice and wild-type (WT) controls. Compound was
administered po in 0.1% pluronic F127 vehicle (n = 11–12 vehicle, n = 8 compound treated) 30 min prior to a glucose load of 2 g/kg. Glucose levels were monitored for 90 min
post glucose load and used to calculate reductions in blood glucose AUC. ⁄p 6 0.05, ⁄⁄p 6 0.01, ⁄⁄⁄p 6 0.001 versus vehicle control ANCOVA analysis.
giving glucose lowering effects through mechanisms other than
GPR119 (Fig. 3).
In efforts to identify what target may be responsible for these
effects, compound 7 was screened against a panel of 100 targets.
Only three targets were identified (5HT2A, D4.2 & CCR5) that gave
excellent pharmacokinetic properties and displayed excellent glu-
cose lowering in vivo. However the glucose lowering effects were
also observed in a GPR119 knock-out mouse model leading us to
conclude that the biological effects were not exclusively due to
GPR119 agonism. Further studies on alternative chemical series
that do not exhibit activity in the GPR119 knock-out mouse model
will be reported in due course
>75% activity at a concentration of 30
13 was inactive against both D4.2 & CCR5 (<10% activity at
30 M) yet still showed off-target activity. Compounds from other
lM. In contrast, compound
l
series being profiled in the project which showed glucose lowering
in the wild type but not the knock-out mouse, had similar levels of
activity against 5HT2A (data not shown) suggesting that this was
not the target responsible. Further attempts to ascertain the cause
of the ‘off-target’ effects have not provided a clear outcome at
present.
Acknowledgement
Members of the AstraZeneca Animal Science & Welfare group
are thanked both for their work on breeding the mice and their
technical support in running the experiments.
In summary, optimisation of a novel series of GPR119 agonists
allowed us to identify compounds that were potent against the
receptor with reduced hERG liabilities relative to the initial lead
as exemplified by compound 23. A representative example 7 had
References and notes
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K. J. Brocklehurst et al. / Bioorg. Med. Chem. Lett. 21 (2011) 7310–7316
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21. DMSO is used as a solvent to dissolve polar and non polar compounds, while
the cyclodextrins are used as solubilising agents to increase the water
solubility of lipophilic compounds. This vehicle is commonly used in drug
discovery, with the volume of DMSO being within the acceptable limits. The
vehicle is well tolerated in all three pre-clinical species. The concentration of
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