Synthesis and Pharmacological Properties of Silicon-Containing GPR81 and GPR109A Agonists

Article abstract of DOI:10.1002/cmdc.201500343

The GPR81 and GPR109A receptors mediate antilipolytic effects and are potential drug targets for the treatment of metabolic disorders such as dyslipidemia and type2 diabetes. There is still a need to identify potent GPR81 agonists as pharmacological tools

Full text of DOI:10.1002/cmdc.201500343

DOI: 10.1002/cmdc.201500343
Full Papers
Synthesis and Pharmacological Properties of Silicon-
Containing GPR81 and GPR109A Agonists
Marcel Geyer,[a] Johannes A. Baus,[a] Ola Fjellstrçm,[b] Eric Wellner,[b] Linda Gustafsson,[b] and
Reinhold Tacke*[a]
The GPR81 and GPR109A receptors mediate antilipolytic effects
and are potential drug targets for the treatment of metabolic
disorders such as dyslipidemia and type 2 diabetes. There is
still a need to identify potent GPR81 agonists as pharmacologi-
cal tools. A high-throughput screen identified an acylurea-
based GPR81 agonist lead series, with activities at the
GPR109A receptor as well. To expand the chemical scope and
to explore the pharmacological and pharmacokinetic conse-
quences, a series of structurally related organosilicon com-
pounds with a 6-sila-4,5,6,7-tetrahydrobenzo[d]thiazole skele-
ton was synthesized and studied for their physicochemical
properties [octanol/water distribution coefficient (pH 7.4), solu-
bility in HBSS buffer (pH 7.4)], agonistic potency at rat GPR81
and GPR109A receptors, and intrinsic clearance in human liver
microsomes and rat hepatocytes. The straightforward synthesis
of these organosilicon compounds offered a valuable expan-
sion of the chemical scope in the above-mentioned GPR81 ag-
onist lead series, provided potency and efficacy SAR, and yield-
ed compounds with sub-micromolar GPR81 potency. This work
supports the value of including silicon chemistry into the tool-
box of medicinal chemistry.
Introduction
GPR81 (HCA1) is a G-protein-coupled receptor that belongs to
the family of hydroxycarboxylic acid receptors, and it displays
about 50% sequence identity to the nicotinic acid receptor
GPR109A.[1] Both GPR81 and GPR109A have been shown to
mediate antilipolytic effects and are potential drug targets for
the treatment of dyslipidemia and type 2 diabetes mellitus.[2–4]
In contrast to GPR109A, there are only a few reported agonists
for GPR81, and there is still a need to identify potent GPR81
Herein we report the synthesis, physicochemical characteri-
zation, and biological evaluation of the silicon compounds 1a–
1 f and 2a–2 f (Figure 1), which contain a quaternary silicon
atom. These compounds can be formally derived from the re-
spective reference compounds A and B (Figure 1) by replacing
a methylene group at the 6-position of their 4,5,6,7-tetrahydro-
benzo[d]thiazole skeleton with an SiR2 moiety [R=organyl (i.e.,
alkyl or aryl)]. Based on synthetic feasibility and knowledge of
achieving active GPR81 agonists with 6-substituted 4,5,6,7-tet-
rahydrobenzo[d]thiazole skeletons, the 6-position in the potent
GPR81 agonists A and B was targeted for silicon incorporation.
Importantly, the silicon chemistry chosen for this study offers
a synthetically more attractive SAR exploration than the corre-
sponding carbon chemistry. For principle reasons, compounds
with quaternary carbon atoms are often very difficult to syn-
thesize, whereas the synthesis of organosilicon compounds
with quaternary silicon atoms is mostly straightforward. For ex-
ample, tetraorganylsilanes can be easily prepared by stepwise
introduction of the respective organyl groups via Grignard or
organolithium reagents, starting from tetrachlorosilane or tet-
raalkoxysilanes. With the synthesis of 1a–1 f and 2a–2 f, we
made use of this particular benefit of silicon chemistry to
expand the chemical scope within the above-mentioned lead
series.
agonists as pharmacological tools.[5–8]
A high-throughput
screen identified an acylurea-based GPR81 agonist lead series,
with activities on the GPR109A receptor as well. A detailed
structure–activity relationship (SAR) analysis of this lead series
will be published separately. To explore GPR81 pharmacology
in vivo, selectivity is an important issue. However, dual GPR81
and GPR109A activity may be beneficial if the flushing side ef-
fects associated with GPR109A agonism can be avoided. The
objective of the current study was to increase the chemical
scope of the aforementioned lead series by introducing silicon-
containing skeletons and then to characterize these com-
pounds with respect to physicochemical, in vitro pharmacolog-
ical, and pharmacokinetic parameters to evaluate the value of
these organosilicon compounds.
[a] M. Geyer, J. A. Baus, Prof. Dr. R. Tacke
Universität Würzburg, Institut für Anorganische Chemie
Am Hubland, 97074 Würzburg (Germany)
E-mail: r.tacke@uni-wuerzburg.de
Following the first pioneering studies on biologically active
organosilicon compounds five decades ago, silicon chemistry
is nowadays accepted as a novel source of chemical diversity
in drug design.[9] The investigations reported herein were per-
formed as part of our systematic studies on silicon-based
drugs.[10]
[b] Dr. O. Fjellstrçm, Dr. E. Wellner, L. Gustafsson
AstraZeneca R&D Mçlndal, CVMD Innovative Medicines
Pepparedsleden 1, 43183 Mçlndal (Sweden)
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under http://dx.doi.org/10.1002/cmdc.201500343.
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yl)benzoyl)carbamate (7) in toluene finally afforded
the target compounds 1a–1 f and 2a–2 f, respective-
ly.
Compounds 1a–1 f and 2a–2 f were isolated as
colorless crystalline solids, whereas 5a–5 f were ob-
tained as yellow crystalline solids. The respective
yields are given in Scheme 1. The identities of 1a–1 f,
2a–2 f, and 5a–5 f were established by high-resolu-
tion mass spectrometry (ESI+) and NMR spectroscop-
ic studies (1H, 13C, 29Si). In addition, compound 2d
was structurally characterized by single-crystal X-ray
diffraction.
Crystal structure analysis
Compound 2d was structurally characterized by
single-crystal X-ray diffraction. The crystal data and
experimental parameters used for crystal structure
analysis are given in the Supporting Information
(Table S1). The molecular structure of 2d is depicted
in Figure 2. The bond lengths and angles of 2d are
in the expected ranges and do not require further
discussion.
Figure 1. Chemical structures of compounds A, B, 1a–1 f, and 2a–2 f.
Results and Discussion
Syntheses
The silicon compounds 1a–1 f
and 2a–2 f were prepared in
straightforward three-step syn-
theses, starting from the corre-
sponding
4-silacyclohexan-1-
ones 3a–3 f (Scheme 1), which
are available from the respective
silanes of the formula type
RSi(OMe)3 (R=nPr, Me, Ph; see
refs. [11] and [12] for details of
the syntheses of 3a–3 f). Thus,
treatment of 3a–3 f with 5,5-di-
bromobarbituric acid in diethyl
ether yielded the respective 2-
bromo-4,4-diorganyl-4-silacyclo-
hexan-1-ones 4a–4 f (isolated as
crude products and not charac-
terized; in this context, see
ref. [12]). Subsequent treatment
of 4a–4 f with thiourea in aceto-
nitrile, in the presence of sodium
carbonate, yielded the respective
2-amino-6,6-diorganyl-6-sila-
4,5,6,7-tetrahydrobenzo[d]thia-
zoles 5a–5 f, which upon reac-
tion with phenyl N-(2-chloro-4-
ethoxy-5-morpholinobenzoyl)car-
bamate (6) or phenyl N-(2-
chloro-4-ethoxy-5-(1H-pyrazol-1-
Scheme 1. Syntheses of compounds 1a–1 f and 2a–2 f.
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the rank order of the compounds with regard to potency is
similar for the two receptors, suggesting overlapping SARs. It
is noted that the moderate selectivities for GPR81 against
GPR109A of the reference compounds A and B are essentially
diminished for the silicon compounds 1a–1 f and 2a–2 f. The
silicon compounds with R1 =Me, that is, compounds 1b, 1e,
2b, and 2e, maintain GPR81 and GPR109A potency and effica-
cy and show GPR81 EC50 values only about tenfold lower than
those of the respective reference compounds A and B, where-
as the GPR109A EC50 values are very similar to those of the ref-
erence compounds. Compound 2c is a partial agonist on
GPR81 (EC50 =2.0 mm and top efficacy=43%), and even
though this compound displayed a top efficacy of 36% on
GPR109A, an EC50 value could not be calculated, as no plateau
was reached. In contrast to 2c, compounds 1a, 1d, 2a, and
2d show partial agonistic behavior on both receptors. Finally,
the SAR with regard to R1 suggests that R1 =Me, in contrast to
R1 =nPr or Ph, is well tolerated
Figure 2. Molecular structure of 2d in the crystal (occupation factor 55%;
the structure is slightly disordered).
Physicochemical properties
Compounds A, B, 1a–1 f, and 2a–2 f were studied for their oc-
tanol/water (pH 7.4) distribution coefficient (logD value) and
their solubility in HBSS buffer (pH 7.4). As can be seen from
Table 1, all compounds are hydrophobic, with logD values
>4.0, and they also display low solubility. Comparing the steri-
for potency and efficacy.
Table 1. Physicochemical properties of A, B, 1a–1 f, and 2a–2 f.
Regarding agonists on the
two receptors in the public
domain, the GPR109A agonist
nicotinic acid, which is an ap-
proved drug within cardiovascu-
lar diseases, displays an EC50
value of 43 nm at rat GPR109A
and an EC50 value >100 mm at
Compd
logD[a]
Solubility [mm][b]
Compd
logD[a]
Solubility [mm][b]
rat GPR81 in our assays. A 50 nm
GPR81 agonist was recently re-
ported by Sakurai et al;[8] how-
ever, this compound was not
active in the cAMP GPR81 assay
described herein.
A
4.2Æ0.2
4.8Æ0.1
4.8Æ0.0
4.5Æ0.3
0.6Æ0.2
<0.3
<0.3
<0.3
<0.3
B
>4.5
>4.8
4.4Æ0.2
4.8Æ0.3
>5.2
1.8Æ1.8
<0.3
<0.3
<0.3
<0.3
1a
1b
1c
1d
1e
1 f
2a
2b
2c
2d
2e
2 f
>4.8
4.6Æ0.2
<0.3
<0.3
>4.9
>4.8
<0.3
<0.3
>5.1
[a] Determined at pH 7.4; values represent the mean ÆSD (n=2–4). [b] Determined in HBSS buffer (pH 7.4);
values represent the mean ÆSD (n=2–3).
cally bulkier silicon-containing
Table 2. Agonistic potency of A, B, 1a–1 f, and 2a–2 f at rat GPR81 and GPR109A receptors.[a]
compounds 1a–1 f and 2a–2 f
with the reference compounds A
and B, logD values are not dra-
matically different and solubili-
ties are lower.
In vitro pharmacology
Compd
GPR81
Top effect GPR109A Top effect Compd
GPR81
Top effect GPR109A Top effect
EC50 [mm][b]
[%]
EC50 [mm][b]
[%]
EC50 [mm][b]
[%]
EC50 [mm][b]
[%]
Compounds A, B, 1a–1 f, and
2a–2 f were studied for their ag-
onistic potency at rat GPR81 and
GPR109A receptors. The data ob-
tained are compiled in Table 2.
Most compounds that are active
on GPR81 are also active on
GPR109A and can therefore be
regarded as dual GPR81/
GPR109A agonists. Furthermore,
A
0.24
4.4
1.0
101
31
90
NA[c]
24
2.1
4.8
1.2
106
35
89
NA[c]
35
B
0.018
1.3
0.21
2.0
0.84
102
63
0.25
1.8
107
57
1a
1b
1c
1d
1e
1 f
2a
2b
2c
2d
2e
2 f
96
43
0.47
101
NA[c]
41
108[d]
NA[c]
>100
3.6
1.2
>100
>100
3.3
1.3
>100
>100
0.68
0.48[d]
>100
39
82
NA[c]
96
NA[c]
0.36[d]
>100
94[d]
NA[c]
[a] Rat GPR81 and GPR109A pIC50 SEM<0.32 for all compounds. [b] Values represent the geometric mean (nꢀ
3). [c] Not applicable; the respective compound was not active at the concentration tested. [d] n=1.
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Intrinsic clearance in human liver microsomes and rat hepa-
tocytes
and 2a–2 f increased the chemical scope of the GPR81 and
GPR109A lead series, revealed clear potency SAR, and dis-
played similar or slightly improved metabolic stability com-
pared with the reference compounds A and B. The current
work again emphasizes the value of including silicon chemistry
into the toolbox of medicinal chemistry.
Compounds A, B, 1a–1 f, and 2a–2 f were studied for their in-
trinsic clearance (CLint) in human liver microsomes and rat hep-
atocytes. The data obtained are summarized in Table 3. The
compounds display moderate to high intrinsic clearance, and
SAR analysis suggests that in general the structural alterations
covered by A, B, 1a–1 f, and 2a–2 f have only limited effects
on metabolic stability. Compounds 2a–2 f, however, all display
lower intrinsic clearance in rat hepatocytes than the reference
compound B.
Experimental Section
Syntheses
General procedures: All syntheses involving chemicals sensitive to
water and/or oxygen were carried out under a dry argon atmos-
phere. The organic solvents used were dried and purified accord-
1
ing to standard procedures and stored under dry nitrogen. H, 13C,
Conclusions
and 29Si NMR spectra were recorded at 238C on a Bruker Avance III
NMR spectrometer (1H: 500.0 MHz, 13C: 125.7 MHz, 29Si: 99.3 MHz)
using CD2Cl2 or CDCl3 as the solvent. Chemical shifts (d, ppm) were
determined relative to internal CHDCl2 (1H: d=5.32 ppm, CD2Cl2),
internal CD2Cl2 (13C: d=53.8 ppm, CD2Cl2), internal CHCl3 (1H: d=
7.24 ppm, CDCl3), internal CDCl3 (13C: d=77.0 ppm, CDCl3), and ex-
ternal TMS (29Si: d=0.0 ppm, CD2Cl2, CDCl3). Analysis and assign-
As part of a systematic SAR analysis within a new GPR81 ago-
nist lead series (with activities on the GPR109A receptor as
well), the silicon compounds 1a–1 f and 2a–2 f were synthe-
sized in three-step syntheses, starting from the corresponding
4-silacyclohexan-1-ones 3a–3 f. Compounds 1a–1 f and 2a–2 f,
all of which contain a quaternary silicon atom in their 6-sila-
4,5,6,7-tetrahydrobenzo[d]thiazole skeletons, were studied for
their physicochemical properties [octanol/water distribution
coefficient (pH 7.4), solubility in HBSS buffer (pH 7.4)], agonistic
potency at rat GPR81 and GPR109A receptors, and intrinsic
clearance in human liver microsomes and rat hepatocytes. The
data obtained were compared with those of the respective ref-
erence compounds A and B. All compounds studied are hydro-
phobic (logD>4.0) and display low solubility (<0.3 mm). They
display moderate-to-high intrinsic clearance, and the structural
alterations studied have only limited effects on their metabolic
stability. All compounds that display full agonism at the GPR81
and GPR109A receptors are also roughly equipotent at both re-
ceptors. Compounds 1b, 1e, 2b, and 2e (R1 =Me) show the
highest GPR81/GPR109A potency and efficacy in the series of
silicon compounds studied, with EC50 values in the micromolar
range. In conclusion, the silicon-containing compounds 1a–1 f
1
1
ment of the H NMR spectroscopic data were supported by H,1H
gradient-selected COSY, 13C,1H gradient-selected HMQC, and 13C,1H
gradient-selected HMBC experiments. Assignment of the 13C NMR
spectroscopic data was supported by DEPT-135 and the aforemen-
tioned 13C,1H correlation experiments. Coupling constants are
given as their absolute values. High-resolution mass spectra
(HRMS, ESI+) were recorded on a Waters LCTP mass spectrometer
using solutions in MeOH.
2-Chloro-4-ethoxy-5-morpholino-N-((4,5,6,7-tetrahydrobenzo[d]-
thiazol-2-yl)carbamoyl)benzamide (A): The synthesis of com-
pound A is described in the Supporting Information.
2-Chloro-4-ethoxy-5-(1H-pyrazol-1-yl)-N-((4,5,6,7-tetrahydroben-
zo[d]thiazol-2-yl)carbamoyl)benzamide (B): The synthesis of com-
pound B is described in the Supporting Information.
2-Chloro-4-ethoxy-N-((6-(4-methoxyphenyl)-6-propyl-6-sila-
4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)carbamoyl)-5-morpholino-
benzamide (1a): A solution of 5a (157 mg, 493 mmol) and 6
Table 3. Intrinsic clearance of A, B, 1a–1 f, and 2a–2 f in human liver microsomes and rat hepatocytes.
human liver microsomes
rat hepatocytes
[a]
[a]
[a]
[a]
Compd
CLint [mLminÀ1 mgÀ1
]
Compd
CLint [mLminÀ1 mgÀ1
]
Compd
CLint [mLminÀ1 (106 cells)À1
]
Compd
CLint [mLminÀ1 (106 cells)À1
]
A
18.2Æ2.9
11.8Æ2.9
36.2Æ0.7
25.9Æ3.5
22.3Æ3.3
23.0Æ2.6
21.5Æ5.5
B
32.7Æ3.8
7.49Æ1.92
48.4Æ10.7
14.7Æ4.3
21.7Æ4.9
35.2Æ5.2
16.8Æ7.3
A
48.8Æ2.6
16.2Æ3.0
36.2Æ9.4
19.8Æ10.4
17.3Æ5.4
37.3Æ9.8
12.7Æ0.6
B
123Æ9
1a
1b
1c
1d
1e
1 f
2a
2b
2c
2d
2e
2 f
1a
1b
1c
1d
1e
1 f
2a
2b
2c
2d
2e
2 f
15.4Æ4.6
24.9Æ4.8
13.6Æ2.3
15.7Æ10.8
24.2Æ8.0
8.3Æ2.9
[a] Values represent the mean ÆSD (n=3–4).
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(200 mg, 494 mmol) in toluene (10 mL) was stirred at 1008C for
30 min. The solvent was removed under reduced pressure, and the
residue was purified by automated flash column chromatography
on silica gel (Biotage SNAP cartridge, KP-Sil, 25 g; eluent, n-hep-
tane/EtOAc (1:1 v/v) to furnish 1a in 90% yield as a colorless crys-
2-Chloro-N-((6-(2,6-dimethoxyphenyl)-6-methyl-6-sila-4,5,6,7-tet-
rahydrobenzo[d]thiazol-2-yl)carbamoyl)-4-ethoxy-5-morpholino-
benzamide (1e): Compound 1e was synthesized and purified by
using the same procedure as that described for the preparation of
1a, starting from 5e (158 mg, 493 mmol), to furnish 1e in 95%
yield as a colorless crystalline solid (295 mg, 467 mmol). 1H NMR
(CD2Cl2): d=0.32 (s, 3H), 1.20–1.29 (m, 1H), 1.31–1.39 (m, 1H),
1.42–1.48 (m, 3H), 2.11–2.18 (m, 1H), 2.33–2.40 (m, 1H), 2.81–2.89
(m, 1H), 2.94–3.02 (m, 1H), 3.04–3.11 (m, 4H), 3.76 (s, 6H), 3.78–
1
talline solid (278 mg, 442 mmol). H NMR (CDCl3): d=0.84–0.90 (m,
2H), 0.91–0.98 (m, 3H), 1.10–1.21 (m, 2H), 1.35–1.44 (m, 2H), 1.42–
1.49 (m, 3H), 2.07–2.19 (m, 2H), 2.81–2.91 (m, 1H), 2.93–3.02 (m,
1H), 3.02–3.10 (m, 4H), 3.78 (s, 3H), 3.79–3.86 (m, 4H), 4.05–4.12
(m, 2H), 6.83 (s, 1H), 6.88–6.90 (m, 2H), 7.29 (s, 1H), 7.40–7.42 (m,
2H), 9.17 (s, 1H), 11.48 ppm (brs, 1H); 13C NMR (CDCl3): d=7.7, 7.9,
14.5, 15.6, 17.3, 18.2, 24.7, 50.7, 55.0, 64.7, 66.8, 113.8, 114.0, 120.2,
122.5, 123.3, 125.3, 126.6, 135.2, 140.5, 146.2, 150.1, 153.5, 154.9,
160.7, 166.4 ppm; 29Si NMR (CDCl3): d=À7.8 ppm; HRMS (ESI):
C30H37ClN4O5SSi [M]+, calcd: 629.2021, found: 629.2052.
3
3.84 (m, 4H), 4.07–4.14 (m, 2H), 6.52 (d, JHH =8.2 Hz, 2H), 6.90 (s,
3
1H), 7.25 (s, 1H), 7.31 (t, JHH =8.2 Hz, 1H), 9.16 (s, 1H), 11.38 ppm
(brs, 1H); 13C NMR (CD2Cl2): d=À2.7, 11.47, 11.53, 14.7, 25.5, 51.1,
55.6, 65.1, 67.2, 103.8, 111.5, 114.5, 120.0, 124.0, 124.2, 125.4, 132.4,
141.1, 146.5, 150.4, 153.1, 155.3, 165.9, 167.3 ppm; 29Si NMR
(CD2Cl2): d=À9.9 ppm; HRMS (ESI): C29H35ClN4O6SSi [M]+, calcd:
631.1813, found: 631.1838.
2-Chloro-4-ethoxy-N-((6-(4-methoxyphenyl)-6-methyl-6-sila-
4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)carbamoyl)-5-morpholino-
benzamide (1b): Compound 1b was synthesized and purified by
using the same procedure as that described for the preparation of
1a, starting from 5b (143 mg, 492 mmol), to furnish 1b in 79%
yield as a colorless crystalline solid (233 mg, 388 mmol). 1H NMR
(CDCl3): d=0.37 (s, 3H), 1.05–1.23 (m, 2H), 1.43–1.49 (m, 3H), 2.02–
2.09 (m, 1H), 2.15–2.22 (m, 1H), 2.92–2.98 (m, 2H), 3.04–3.10 (m,
4H), 3.79 (s, 3H), 3.80–3.86 (m, 4H), 4.06–4.12 (m, 2H), 6.84 (s, 1H),
6.89–6.90 (m, 2H), 7.31 (s, 1H), 7.42–7.44 (m, 2H), 9.10 (s, 1H),
11.50 ppm (brs, 1H); 13C NMR (CDCl3): d=4.3, 9.3, 9.4, 14.5, 24.7,
50.7, 55.0, 64.7, 66.8, 113.8, 114.0, 120.2, 122.6, 123.2, 125.3, 127.4,
135.1, 140.5, 146.1, 150.1, 153.7, 154.9, 160.8, 166.4 ppm; 29Si NMR
(CDCl3): d=À8.4 ppm; HRMS (ESI): C28H33ClN4O5SSi [M]+, calcd:
601.1708, found: 601.1750.
2-Chloro-N-((6-(2,6-dimethoxyphenyl)-6-phenyl-6-sila-4,5,6,7-tet-
rahydrobenzo[d]thiazol-2-yl)carbamoyl)-4-ethoxy-5-morpholino-
benzamide (1 f): Compound 1 f was synthesized and purified by
using the same procedure as that described for the preparation of
1a, starting from 5 f (104 mg, 272 mmol), to furnish 1 f in 80%
yield as a colorless crystalline solid (151 mg, 218 mmol). 1H NMR
(CD2Cl2): d=1.42–1.47 (m, 3H), 1.52–1.60 (m, 1H), 1.62–1.69 (m,
1H), 2.58–2.62 (m, 2H), 2.77–2.86 (m, 1H), 3.00–3.06 (m, 1H), 3.04–
3.10 (m, 4H), 3.74 (s, 6H), 3.79–3.82 (m, 4H), 4.07–4.13 (m, 2H),
3
6.54 (d, JHH =8.2 Hz, 2H), 6.90 (s, 1H), 7.26–7.33 (m, 4H), 7.35 (t,
3JHH =8.2 Hz, 1H), 7.51–7.55 (m, 2H), 8.95 (s, 1H), 11.41 ppm (brs,
1H); 13C NMR (CD2Cl2): d=10.5, 10.9, 14.7, 25.4, 51.1, 55.6, 65.1,
67.2, 104.0, 109.8, 114.5, 120.2, 123.7, 123.9, 125.5, 128.0, 129.3,
132.9, 134.3, 137.7, 141.1, 146.5, 150.3, 153.5, 155.4, 166.1,
167.1 ppm; 29Si NMR (CD2Cl2): d=À15.3 ppm; HRMS (ESI):
C34H37ClN4O6SSi [M]+, calcd: 693.1970, found: 693.2002.
2-Chloro-4-ethoxy-N-((6-(4-methoxyphenyl)-6-phenyl-6-sila-
4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)carbamoyl)-5-morpholino-
benzamide (1c): Compound 1c was synthesized and purified by
using the same procedure as that described for the preparation of
1a, starting from 5c (80 mg, 227 mmol), to furnish 1c in 76% yield
2-Chloro-4-ethoxy-N-((6-(4-methoxyphenyl)-6-propyl-6-sila-
4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)carbamoyl)-5-(1H-pyrazol-
1-yl)benzamide (2a): A solution of 5a (165 mg, 518 mmol) and 7
(200 mg, 518 mmol) in toluene (10 mL) was stirred at 1008C for
30 min. The solvent was removed under reduced pressure, and the
residue was purified by automated flash column chromatography
on silica gel (Biotage SNAP cartridge, KP-Sil, 25 g; eluent, n-hep-
tane/EtOAc (3:2 v/v) to furnish 2a in 87% yield as a colorless crys-
1
as a colorless crystalline solid (114 mg, 172 mmol). H NMR (CD2Cl2):
d=1.42–1.46 (m, 3H), 1.46–1.50 (m, 2H), 2.42–2.49 (m, 2H), 2.94–
2.99 (m, 2H), 3.05–3.09 (m, 4H), 3.78–3.82 (m, 4H), 3.79 (s, 3H),
4.07–4.13 (m, 2H), 6.90 (s, 1H), 6.91–6.94 (m, 2H), 7.27 (s, 1H),
7.35–7.39 (m, 2H), 7.38–7.42 (m, 1H), 7.45–7.49 (m, 2H), 7.52–7.56
(m, 2H), 9.03 (s, 1H), 11.42 ppm (brs, 1H); 13C NMR (CD2Cl2): d=
8.4, 8.6, 14.7, 25.2, 51.1, 55.4, 65.1, 67.2, 114.2, 114.5, 120.1, 122.5,
123.7, 125.5, 125.6, 128.4, 130.0, 134.8, 135.6, 136.4, 141.1, 147.0,
150.4, 153.8, 155.4, 161.5, 167.1 ppm; 29Si NMR (CD2Cl2): d=
À13.3 ppm; HRMS (ESI): C33H35ClN4O5SSi [M]+, calcd: 663.1864,
found: 663.1887.
1
talline solid (275 mg, 451 mmol). H NMR (CD2Cl2): d=0.87–0.92 (m,
2H), 0.95–0.99 (m, 3H), 1.12–1.23 (m, 2H), 1.37–1.45 (m, 2H), 1.45–
1.50 (m, 3H), 2.05–2.19 (m, 2H), 2.78–2.87 (m, 1H), 2.92–3.02 (m,
1H), 3.79 (s, 3H), 4.17–4.23 (m, 2H), 6.42–6.44 (m, 1H), 6.89–6.93
(m, 2H), 7.12 (s, 1H), 7.43–7.47 (m, 2H), 7.66–7.69 (m, 1H), 8.19–
8.21 (m, 1H), 8.24 (brs, 1H), 9.38 (brs, 1H), 11.34 ppm (brs, 1H);
13C NMR (CD2Cl2): d=8.0, 8.2, 14.6, 16.0, 17.7, 18.4, 25.2, 55.3, 66.2,
107.3, 114.1, 115.6, 122.9, 124.9, 126.4, 127.0, 129.1, 130.4 131.7,
135.7, 140.9, 146.9, 150.5, 152.9, 153.5, 161.2, 166.6 ppm; 29Si NMR
(CD2Cl2): d=À7.8 ppm; HRMS (ESI): C29H32ClN5O4SSi [M]+, calcd:
610.1711, found: 610.1737.
2-Chloro-N-((6-(2,6-dimethoxyphenyl)-6-propyl-6-sila-4,5,6,7-tet-
rahydrobenzo[d]thiazol-2-yl)carbamoyl)-4-ethoxy-5-morpholino-
benzamide (1d): Compound 1d was synthesized and purified by
using the same procedure as that described for the preparation of
1a, starting from 5d (69 mg, 198 mmol), to furnish 1d in 80% yield
1
as a colorless crystalline solid (105 mg, 159 mmol). H NMR (CDCl3):
2-Chloro-4-ethoxy-N-((6-(4-methoxyphenyl)-6-methyl-6-sila-
4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)carbamoyl)-5-(1H-pyrazol-
1-yl)benzamide (2b): Compound 2b was synthesized and purified
by using the same procedure as that described for the preparation
of 2a, starting from 5b (151 mg, 520 mmol), to furnish 2b in 96%
yield as a colorless crystalline solid (291 mg, 500 mmol). 1H NMR
(CD2Cl2): d=0.39 (s, 3H), 1.06–1.24 (m, 2H), 1.44–1.49 (m, 3H),
1.99–2.06 (m, 1H), 2.12–2.19 (m, 1H), 2.87–2.99 (m, 2H), 3.80 (s,
3H), 4.15–4.23 (m, 2H), 6.41–6.45 (m, 1H), 6.91–6.93 (m, 2H), 7.11
(s, 1H), 7.45–7.47 (m, 2H), 7.67–7.68 (m, 1H), 8.19–8.21 (m, 1H),
8.24 (brs, 1H), 9.53 (brs, 1H), 11.36 ppm (brs, 1H); 13C NMR
d=0.81–0.86 (m, 2H), 0.86–0.90 (m, 3H), 1.29–1.37 (m, 4H), 1.44–
1.49 (m, 3H), 2.14–2.19 (m, 1H), 2.31–2.36 (m, 1H), 2.85–2.93 (m,
1H), 2.94–3.02 (m, 1H), 3.05–3.10 (m, 4H), 3.74 (s, 6H), 3.82–3.87
3
(m, 4H), 4.07–4.13 (m, 2H), 6.47 (d, JHH =8.3 Hz, 2H), 6.83 (s, 1H),
3
7.27 (t, JHH =8.3 Hz, 1H), 7.32 (s, 1H), 8.86 (s, 1H), 11.42 ppm (brs,
1H); 13C NMR (CDCl3): d=9.9, 10.0, 14.5, 16.5, 17.6, 18.1, 25.2, 50.7,
55.2, 64.7, 66.9, 103.3, 110.7, 114.0, 120.4, 123.2, 124.2, 125.3, 131.9,
140.6, 145.9, 149.8, 152.9, 155.0, 165.6, 166.1 ppm; 29Si NMR
(CDCl3): d=À8.5 ppm; HRMS (ESI): C30H39ClN4O6SSi [M]+, calcd:
659.2126, found: 659.2141.
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Full Papers
3
(CD2Cl2): d=4.1, 9.6, 9.7, 14.6, 25.2, 55.4, 66.1, 107.3, 114.1, 115.6,
122.9, 125.0, 126.3, 127.8, 129.0, 130.5, 131.7, 135.5, 140.9, 146.8,
150.6, 152.8, 153.6, 161.3, 166.7 ppm; 29Si NMR (CD2Cl2): d=
À8.4 ppm; HRMS (ESI): C27H28ClN5O4SSi [M]+, calcd: 582.1398,
found: 582.1412.
(m, 2H), 6.37–6.42 (m, 1H), 6.50 (d, JHH =8.3 Hz, 2H), 7.03 (s, 1H),
7.23–7.28 (m, 3H), 7.31 (t, 3JHH =8.3 Hz, 1H), 7.46–7.51 (m, 2H),
7.66–7.69 (m, 1H), 8.06–8.12 (m, 1H), 8.24 (brs, 1H), 9.21 (brs, 1H),
11.38 ppm (brs, 1H); 13C NMR (CDCl3): d=10.3, 10.6, 14.4, 25.0,
55.3, 65.6, 103.6, 107.0, 109.5, 115.1, 123.8, 124.5, 126.5, 127.6,
128.7, 128.9, 130.2, 131.3, 132.5, 133.9, 137.3, 140.7, 146.2, 150.0,
152.6, 153.0, 153.1, 165.7 ppm; 29Si NMR (CDCl3): d=À15.2 ppm;
HRMS (ESI): C33H32ClN5O5SSi [M]+, calcd: 674.1660, found: 674.1696.
2-Chloro-4-ethoxy-N-((6-(4-methoxyphenyl)-6-phenyl-6-sila-
4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)carbamoyl)-5-(1H-pyrazol-
1-yl)benzamide (2c): Compound 2c was synthesized and purified
by using the same procedure as that described for the preparation
of 2a, starting from 5c (80 mg, 227 mmol), to furnish 2c in 83%
yield as a colorless crystalline solid (121 mg, 188 mmol). 1H NMR
(CD2Cl2): d=1.44–1.48 (m, 3H), 1.46–1.50 (m, 2H), 2.39–2.45 (m,
2H), 2.93–3.00 (m, 2H), 3.80 (s, 3H), 4.16–4.22 (m, 2H), 6.41–6.44
(m, 1H), 6.90–6.55 (m, 2H), 7.12 (s, 1H), 7.34–7.43 (m, 3H), 7.45–
7.47 (m, 2H), 7.52–7.56 (m, 2H), 7.67–7.68 (m, 1H), 8.18–8.21 (m,
1H), 8.25 (brs, 1H), 9.30 (s, 1H), 11.36 ppm (brs, 1H); 13C NMR
(CD2Cl2): d=8.4, 8.6, 14.6, 25.2, 55.4, 66.2, 107.3, 114.2, 115.6, 122.5,
124.8, 125.6, 126.4, 128.4, 129.1, 130.0, 130.5, 131.8, 134.8, 135.6,
136.3, 140.9, 146.9, 150.4, 153.0, 153.8, 161.5, 166.5 ppm; 29Si NMR
(CD2Cl2): d=À13.3 ppm; HRMS (ESI): C32H30ClN5O4SSi [M]+, calcd:
644.1555, found: 644.1597.
2-Amino-6-(4-methoxyphenyl)-6-propyl-6-sila-4,5,6,7-tetrahydro-
benzo[d]thiazole (5a): 5,5-dibromobarbituric acid (272 mg,
951 mmol) was added at 208C in a single portion to a stirred solu-
tion of 3a (500 mg, 1.91 mmol) in Et2O (30 mL), and the reaction
mixture was then stirred at 208C for 24 h. The liquid phase of the
reaction mixture was separated from the precipitate (barbituric
acid) by means of a syringe, and the solvent was removed under
reduced pressure. The crude product (2-bromo-4-(4-methoxyphen-
yl)-4-propyl-4-silacyclohexan-1-one; see ref. [5]) was dissolved in
CH3CN (30 mL), followed by addition of Na2CO3 (808 mg,
7.62 mmol) and thiourea (290 mg, 3.81 mmol) in single portions at
208C, and the reaction mixture was then stirred at 408C for 3 h.
After the mixture was cooled to 208C, CH2Cl2 (30 mL) and a saturat-
ed aqueous NaHCO3 solution (30 mL) were added sequentially, the
organic layer was separated, and the aqueous layer was extracted
with CH2Cl2 (3”20 mL) and discarded. The combined organic ex-
tracts were dried over anhydrous Na2SO4, the solvent was removed
under reduced pressure, and the residue was purified by automat-
ed flash column chromatography on silica gel (Biotage SNAP car-
tridge, KP-Sil, 25 g; eluent, EtOAc) to furnish 5a in 54% yield as
2-Chloro-N-((6-(2,6-dimethoxyphenyl)-6-propyl-6-sila-4,5,6,7-tet-
rahydrobenzo[d]thiazol-2-yl)carbamoyl)-4-ethoxy-5-(1H-pyrazol-
1-yl)benzamide (2d): Compound 2d was synthesized and purified
by using the same procedure as that described for the preparation
of 2a, starting from 5d (99 mg, 284 mmol), to furnish 2d in 92%
yield as a colorless crystalline solid (168 mg, 262 mmol). 1H NMR
(CDCl3): d=0.80–0.86 (m, 2H), 0.86–0.91 (m, 3H), 1.28–1.37 (m,
4H), 1.43–1.49 (m, 3H), 2.09–2.16 (m, 1H), 2.27–2.34 (m, 1H), 2.81–
2.92 (m, 1H), 2.93–3.03 (m, 1H), 3.73 (s, 6H), 4.13–4.21 (m, 2H),
1
a yellow crystalline solid (331 mg, 1.04 mmol). H NMR (CDCl3): d=
0.81–0.89 (m, 2H, SiCH2CH2CH3), 0.90–0.99 (m, 3H, SiCH2CH2CH3),
1.05–1.16 (m, 2H, SiCH2CH2C), 1.34–1.43 (m, 2H, SiCH2CH2CH3),
1.96–2.07 (m, 2H, SiCH2C=C), 2.67–2.92 (m, 2H, SiCH2CH2C), 3.79 (s,
3H, C6H4OCH3), 4.81 (brs, 2H, NH2), 6.87–6.90 (m, 2H, H-2/H-6,
C6H4OCH3), 7.39–7.41 ppm (m, 2H, H-3/H-5, C6H4OCH3); 13C NMR
(CDCl3): d=7.8 (SiCH2CH2C), 8.2 (SiCH2CH2CH3), 10.6 (SiCH2C=C),
17.3 (SiCH2CH2CH3), 18.2 (SiCH2CH2CH3), 24.7 (SiCH2CH2C), 55.0
(C6H4OCH3), 113.8 (C-3/C-5, C6H4OCH3), 117.5 (SiCH2C=C), 126.8 (C-1,
C6H4OCH3), 135.3 (C-2/C-6, C6H4OCH3), 146.8 (SiCH2C=C), 160.7 (C-4,
C6H4OCH3), 164.2 ppm (SCN); 29Si NMR (CDCl3): d=À7.9 ppm;
HRMS (ESI): C16H22N2OSSi [M+H]+, calcd: 319.1300, found:
319.1305.
3
6.37–6.42 (m, 1H), 6.47 (d, JHH =8.3 Hz, 2H), 7.04 (s, 1H), 7.27 (t,
3JHH =8.3 Hz, 1H), 7.67–7.68 (m, 1H), 8.08–8.12 (m, 1H), 8.23 (brs,
1H), 9.21 (brs, 1H), 11.36 ppm (brs, 1H); 13C NMR (CDCl3): d=9.92,
9.94, 14.4, 16.5, 17.5, 18.2, 25.2, 55.2, 65.6, 103.3, 107.0, 110.7, 115.1,
124.2, 124.5, 126.6, 128.7, 130.2, 131.3, 131.9, 140.7, 145.9, 150.0,
152.6, 152.8, 165.5, 165.7 ppm; 29Si NMR (CDCl3): d=À8.6 ppm;
HRMS (ESI): C30H34ClN5O5SSi [M]+, calcd: 640.1816, found: 640.1862.
2-Chloro-N-((6-(2,6-dimethoxyphenyl)-6-methyl-6-sila-4,5,6,7-tet-
rahydrobenzo[d]thiazol-2-yl)carbamoyl)-4-ethoxy-5-(1H-pyrazol-
1-yl)benzamide (2e): Compound 2e was synthesized and purified
by using the same procedure as that described for the preparation
of 2a, starting from 5e (166 mg, 518 mmol), to furnish 2e in 94%
yield as a colorless crystalline solid (298 mg, 487 mmol). 1H NMR
(CD2Cl2): d=0.32 (s, 3H), 1.21–1.28 (m, 1H), 1.32–1.39 (m, 1H),
1.45–1.50 (m, 3H), 2.04–2.15 (m, 1H), 2.28–2.39 (m, 1H), 2.81–2.91
(m, 1H), 2.93–3.03 (m, 1H), 3.76 (s, 6H), 4.17–4.23 (m, 2H), 6.42–
2-Amino-6-(4-methoxyphenyl)-6-methyl-6-sila-4,5,6,7-tetrahy-
drobenzo[d]thiazole (5b): Compound 5b was synthesized and pu-
rified by using the same procedure as that described for the prepa-
ration of 5a, starting from 3b (1.26 g, 5.38 mmol; Biotage SNAP
cartridge, KP-Sil, 100 g), to furnish 5b in 67% yield as a yellow crys-
talline solid (1.05 g, 3.61 mmol). 1H NMR (CDCl3): d=0.35 (s, 3H,
SiCH3), 0.99–1.17 (m, 2H, SiCH2CH2C), 1.90–2.10 (m, 2H, SiCH2C=C),
2.80–2.86 (m, 2H, SiCH2CH2C), 3.79 (s, 3H, C6H4OCH3), 4.85 (brs, 2H,
NH2), 6.87–6.90 (m, 2H, H-2/H-6, C6H4OCH3), 7.41–7.45 ppm (m, 2H,
H-3/H-5, C6H4OCH3); 13C NMR (CDCl3): d=À4.3 (SiCH3), 9.3
(SiCH2CH2C), 9.9 (SiCH2C=C), 24.8 (SiCH2CH2C), 55.0 (C6H4OCH3),
113.8 (C-3/C-5, C6H4OCH3), 117.5 (SiCH2C=C), 127.6 (C-1, C6H4OCH3),
135.1 (C-2/C-6, C6H4OCH3), 146.5 (SiCH2C=C), 160.7 (C-4, C6H4OCH3),
164.3 ppm (SCN); 29Si NMR (CDCl3): d=À8.5 ppm; HRMS (ESI):
C14H18N2OSSi [M+H]+, calcd: 291.0987, found: 291.0970.
3
3
6.44 (m, 1H), 6.52 (d, JHH =8.3 Hz, 2H), 7.11 (s, 1H), 7.31 (t, JHH
=
8.3 Hz, 1H), 7.67–7.68 (m, 1H), 8.19–8.20 (m, 1H), 8.22 (brs, 1H),
9.49 (brs, 1H), 11.33 ppm (brs, 1H); 13C NMR (CD2Cl2): d=À2.7,
11.4, 11.5, 14.6, 25.4, 55.6, 66.1, 103.8, 107.2, 111.5, 115.6, 124.2,
125.0, 126.3, 129.0, 130.4, 131.7, 132.4, 140.9, 146.5, 150.5, 152.8,
153.0, 165.9, 166.7 ppm; 29Si NMR (CD2Cl2): d=À9.9 ppm; HRMS
(ESI): C28H30ClN5O5SSi [M]+, calcd: 612.1503, found: 612.1547.
2-Chloro-N-((6-(2,6-dimethoxyphenyl)-6-phenyl-6-sila-4,5,6,7-tet-
rahydrobenzo[d]thiazol-2-yl)carbamoyl)-4-ethoxy-5-(1H-pyrazol-
1-yl)benzamide (2 f): Compound 2 f was synthesized and purified
by using the same procedure as that described for the preparation
of 2a, starting from 5 f (100 mg, 261 mmol), to furnish 2 f in 82%
yield as a colorless crystalline solid (144 mg, 214 mmol). 1H NMR
(CDCl3): d=1.41–1.46 (m, 3H), 1.50–1.65 (m, 2H), 2.44–2.58 (m,
2H), 2.80–2.90 (m, 1H), 3.00–3.10 (m, 1H), 3.70 (s, 6H), 4.11–4.18
2-Amino-6-(4-methoxyphenyl)-6-phenyl-6-sila-4,5,6,7-tetrahydro-
benzo[d]thiazole (5c): Compound 5c was synthesized and purified
by using the same procedure as that described for the preparation
of 5a, starting from 3c (485 mg, 1.64 mmol), to furnish 5c in 43%
yield as a yellow crystalline solid (247 mg, 701 mmol). 1H NMR
(CD2Cl2): d=1.38–1.44 (m, 2H, SiCH2CH2C), 2.31–2.36 (m, 2H,
ChemMedChem 2015, 10, 2063 – 2070
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Full Papers
SiCH2C=C), 2.79–2.85 (m, 2H, SiCH2CH2C), 3.80 (s, 3H, C6H4OCH3),
4.94 (brs, 2H, NH2), 6.90–6.93 (m, 2H, H-2/H-6, C6H4OCH3), 7.34–
7.39 (m, 2H, H-3/H-5, C6H5), 7.38–7.41 (m, 1H, H-4, C6H5), 7.43–7.47
(m, 2H, H-3/H-5, C6H4OCH3), 7.51–7.55 ppm (m, 2H, H-2/H-6, C6H5);
13C NMR (CD2Cl2): d=8.3 (SiCH2CH2C), 9.0 (SiCH2C=C), 25.1
(SiCH2CH2C), 55.4 (C6H4OCH3), 114.2 (C-3/C-5, C6H4OCH3), 117.1
(SiCH2C=C), 125.8 (C-4, C6H5), 128.4 (C-1, C6H4OCH3), 129.7 (C-3/C-5,
C6H5), 134.7 (C-2/C-6, C6H4OCH3), 135.8 (C-1, C6H5), 136.3 (C-2/C-6,
C6H5), 147.2 (SiCH2C=C), 161.4 (C-4, C6H4OCH3), 164.7 ppm (SCN);
29Si NMR (CD2Cl2): d=À13.3 ppm; HRMS (ESI): C19H20N2OSSi [M+
H]+, calcd: 353.1144, found: 353.1148.
HRMS (ESI): C20H22N2O2SSi [M+H]+, calcd: 383.1249, found:
383.1245.
Phenyl
N-(2-chloro-4-ethoxy-5-morpholinobenzoyl)carbamate
(6): The synthesis of compound 6 is described in the Supporting
Information.
Phenyl
N-(2-chloro-4-ethoxy-5-(1H-pyrazol-1-yl)benzoyl)carba-
mate (7): The synthesis of compound 7 is described in the Sup-
porting Information.
Crystal structure analysis
2-Amino-6-(2,6-dimethoxyphenyl)-6-propyl-6-sila-4,5,6,7-tetra-
hydrobenzo[d]thiazole (5d): Compound 5d was synthesized and
purified by using the same procedure as that described for the
preparation of 5a, starting from 3d (550 mg, 1.88 mmol), to furnish
5d in 52% yield as a yellow crystalline solid (340 mg, 975 mmol).
1H NMR (CDCl3): d=0.80–0.85 (m, 2H, SiCH2CH2CH3), 0.85–0.90 (m,
3H, SiCH2CH2CH3), 1.25–1.32 (m, 2H, SiCH2CH2C), 1.28–1.37 (m, 2H,
SiCH2CH2CH3), 2.01–2.24 (m, 2H, SiCH2C=C), 2.71–2.80 and 2.82–
2.92 (m, 2H, SiCH2CH2C), 3.73 (s, 6H, C6H3(OCH3)2), 4.70 (brs, 2H,
A suitable single crystal of 2d was obtained directly from the re-
spective synthesis. The crystal was mounted in inert oil (perfluoro-
polyalkyl ether) on a glass fiber and then transferred to the cold ni-
trogen gas stream of the diffractometer (Montel mirror, MoKa radia-
tion, l=0.71073 Š). The structure was solved by direct methods
(SHELXS-2013) and refined by full-matrix least-squares methods on
F2 for all unique reflections (SHELXL-2013).[13] SHELXLE was used as
refinement GUI.[14] A riding model was employed in the refinement
of the CH hydrogen atoms. CCDC 1407089 contains the supple-
mentary crystallographic data for this paper. These data are provid-
ed free of charge by The Cambridge Crystallographic Data Centre.
3
NH2), 6.46 (d, 2H, JHH =8.2 Hz, H-3/H-5, C6H3(OCH3)2), 7.27 ppm (t,
3JHH =8.2 Hz, 1H, H-4, C6H3(OCH3)2); 13C NMR (CDCl3): d=9.8
(SiCH2CH2C), 10.4 (SiCH2CH2CH3), 16.3 (SiCH2C=C), 17.5
(SiCH2CH2CH3), 18.1 (SiCH2CH2CH3), 25.2 (SiCH2CH2C), 55.2
(C6H3(OCH3)2), 103.3 (C-3/C-5, C6H3(OCH3)2), 111.0 (C-1, C6H3(OCH3)2),
119.2 (SiCH2C=C), 131.8 (C-4, C6H3(OCH3)2), 146.2 (SiCH2C=C), 163.7
(SCN), 165.6 ppm (C-2/C-6, C6H3(OCH3)2); 29Si NMR (CDCl3): d=
À8.5 ppm; HRMS (ESI): C17H24N2O2SSi [M+H]+, calcd: 349.1406,
found: 349.1403.
Determination of physicochemical properties
logD values (pH 7.4): The logD values were determined by using
the same method as described in ref. [10h].
Solubility in HBSS buffer (pH 7.4): The solubilities in HBSS buffer
were determined by using the same method as described in
ref. [10h].
2-Amino-6-(2,6-dimethoxyphenyl)-6-methyl-6-sila-4,5,6,7-tetra-
hydrobenzo[d]thiazole (5e): Compound 5e was synthesized and
purified by using the same procedure as that described for the
preparation of 5a, starting from 3e (960 mg, 3.63 mmol; Biotage
SNAP cartridge, KP-Sil, 100 g), to furnish 5e in 58% yield as
Determination of GPR81 and GPR109A agonism in cAMP
assays
1
a yellow crystalline solid (680 mg, 2.12 mmol). H NMR (CD2Cl2): d=
0.30 (s, 3H, SiCH3), 1.17–1.34 (m, 2H, SiCH2CH2C), 1.99–2.27 (m, 2H,
SiCH2C=C), 2.67–2.76 and 2.82–2.91 (m, 2H, SiCH2CH2C), 3.75 (s, 6H,
T-REx-CHO cells (Life Technologies) were transfected with rat
GPR81 or GPR109A receptors, and stable clones were cryopre-
served until use in the assay. On the day of the experiments, the
cells were thawed in a water bath (378C), centrifuged (180 g), and
suspended in in HBSS/HEPES buffer (pH 7.4) containing 0.1% BSA.
Assays were performed at 208C according to the protocol de-
scribed in the cAMP assay kit (PerkinElmer LANCE cAMP Detection
Kit) with minor modifications. Cell suspensions (2 mL each, 500 cells
per well) were added to 1536-well microplates pre-dispensed with
40 nL of the screening compounds dissolved in DMSO (half-log di-
lution series to constitute 10-point concentration–response curves
in quadruplicate) and incubated for 30 min, followed by the addi-
tion of 2 mL of a forskolin solution (containing anti-cAMP antibody
labeled with Alexa Fluor 647) to stimulate cAMP production. After
20 min at 208C, the incubation was terminated by addition of 2 mL
of the detection mix (containing europium-labeled cAMP), and the
fluorescence transfer was measured at lex 340 nm and lem 620 and
665 nm using a PHERAstar microplate reader (BMG Labtech). TR-
FRET values were converted into nanomolar cAMP using a cAMP
standard curve. The maximal effect (efficacy) was defined by using
a selective AstraZeneca R&D in-house-developed agonist for the
GPR81 assay (compound with the same efficacy as lactate) or nico-
tinic acid for the GPR109A assay. The Z’-factor was typically be-
tween 0.5 and 0.6 EC50, and the efficacy values were calculated by
fitting concentration–response curves to a four-parameter logistic
nonlinear regression model using Genedata Screener software (ver-
sion 12).
3
C6H3(OCH3)2), 4.95 (brs, 2H, NH2), 6.51 (d, 2H, JHH =8.3 Hz, H-3/H-5,
C6H3(OCH3)2), 7.30 ppm (t, 3JHH =8.3 Hz, 1H, H-4, C6H3(OCH3)2);
13C NMR (CD2Cl2): d=À2.9 (SiCH3), 11.4 (SiCH2CH2C), 11.9 (SiCH2C=
C), 25.5 (SiCH2CH2C), 55.5 (C6H3(OCH3)2), 103.8 (C-3/C-5,
C6H3(OCH3)2), 111.8 (C-1, C6H3(OCH3)2), 118.8 (SiCH2C=C), 132.3 (C-4,
C6H3(OCH3)2), 146.8 (SiCH2C=C), 164.2 (SCN), 165.9 ppm (C-2/C-6,
C6H3(OCH3)2); 29Si NMR (CD2Cl2): d=À9.9 ppm; HRMS (ESI):
C15H20N2O2SSi [M+H]+, calcd: 321.1093, found: 321.1108.
2-Amino-6-(2,6-dimethoxyphenyl)-6-phenyl-6-sila-4,5,6,7-tetra-
hydrobenzo[d]thiazole (5 f): Compound 5 f was synthesized and
purified by using the same procedure as that described for the
preparation of 5a, starting from 3 f (655 mg, 2.01 mmol; Biotage
SNAP cartridge, KP-Sil, 100 g), to furnish 5 f in 45% yield as
1
a yellow crystalline solid (346 mg, 904 mmol). H NMR (CDCl3): d=
1.44–1.63 (m, 2H, SiCH2CH2C), 2.41–2.46 (m, 2H, SiCH2C=C), 2.67–
2.77 and 2.89–2.99 (m, 2H, SiCH2CH2C), 3.70 (s, 6H, (C6H3(OCH3)2),
3
4.73 (brs, 2H, NH2), 6.49 (d, 2H, JHH =8.2 Hz, H-3/H-5, C6H3(OCH3)2),
7.23–7.28 (m, 2H, H-3/H-5, C6H5), 7.28 (t, 3JHH =8.3 Hz, 1H, H-4,
C6H3(OCH3)2), 7.29–7.34 (m, 1H, H-4, C6H5), 7.48–7.52 ppm (m, 2H,
H-2/H-6, C6H5); 13C NMR (CDCl3): d=10.5 (SiCH2CH2C), 10.6 (SiCH2C=
C), 24.9 (SiCH2CH2C), 55.3 (C6H3(OCH3)2), 103.6 (C-3/C-5,
C6H3(OCH3)2), 109.8 (C-1, C6H3(OCH3)2), 118.7 (SiCH2C=C), 127.6 (C-4,
C6H5), 128.8 (C-3/C-5, C6H5), 132.4 (C-4, C6H3(OCH3)2), 133.9 (C-1,
C6H5), 137.4 (C-2/C-6, C6H5), 146.4 (SiCH2C=C), 164.0 (SCN),
165.7 ppm (C-2/C-6, C6H3(OCH3)2); 29Si NMR (CDCl3): d=À15.1 ppm;
ChemMedChem 2015, 10, 2063 – 2070
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2069
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Papers
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Determination of intrinsic clearance in human liver micro-
somes and rat hepatocytes
The intrinsic clearance in human liver microsomes and rat hepato-
cytes was studied by using the same method as described in
ref. [10h].
Acknowledgements
The following people at AstraZeneca R&D are gratefully acknowl-
edged for their work on chemistry, biological studies, and DMPK
assays: Petra Johannesson, Öjvind Davidsson, Jonas Brånalt,
Frank Jansen, Ulrik Jurva, Anna NovØn, and Johan Wernevik.
[10] Recent original publications dealing with silicon-based drugs: a) R.
Tacke, F. Popp, B. Müller, B. Theis, C. Burschka, A. Hamacher, M. U. Kas-
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Keywords: GPR81 receptor · GPR109A receptor · silicon ·
silicon-based drugs · structure–activity relationships
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Received: August 3, 2015
Revised: September 28, 2015
Published online on October 13, 2015
ChemMedChem 2015, 10, 2063 – 2070
www.chemmedchem.org
2070
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim