Synthesis and evaluation of diarylthiazole derivatives that inhibit activation of sterol regulatory element-binding proteins

Article abstract of DOI:10.1021/jm200304y

Fatostatin, a recently discovered small molecule that inhibits activation of sterol regulatory element-binding protein (SREBP), blocks biosynthesis and accumulation of fat in obese mice. We synthesized and evaluated a series of fatostatin derivatives. Our

Full text of DOI:10.1021/jm200304y

BRIEF ARTICLE
pubs.acs.org/jmc
Synthesis and Evaluation of Diarylthiazole Derivatives That Inhibit
Activation of Sterol Regulatory Element-Binding Proteins
Shinji Kamisuki,† Takashi Shirakawa,† Akira Kugimiya,† Lutfi Abu-Elheiga,‡ Hea-Young Park Choo,†,§
Kohei Yamada,† Hiroki Shimogawa,† Salih J. Wakil,*,‡ and Motonari Uesugi*,†,‡
†Institute for Chemical Research and Institute for Integrated Cell-Material Sciences, Kyoto University, Uji, Kyoto 611-0011, Japan
‡The Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030,
United States
S Supporting Information
b
ABSTRACT: Fatostatin, a recently discovered small molecule that inhibits activation of sterol regulatory element-binding protein
(SREBP), blocks biosynthesis and accumulation of fat in obese mice. We synthesized and evaluated a series of fatostatin derivatives.
Our structureꢀactivity relationships led to the identification of N-(4-(2-(2-propylpyridin-4-yl)thiazol-4-yl)phenyl)methane-
sulfonamide (24, FGH10019) as the most potent druglike molecule among the analogues tested. Compound 24 has high aqueous
solubility and membrane permeability and may serve as a seed molecule for further development.
’ INTRODUCTION
(INSIG) and binds to SCAP at a site distinct from that of
sterols.9 Thus, fatostatin is a unique small molecule that blocks
the activation of SREBPs independently of INSIG and sterols.
Fatostatin or its analogues may serve as research tools for
investigating the SREBP/SCAP pathway.
Long-chain fatty acids are major sources of energy and impor-
tant components of the lipids that compose cellular membranes.
De novo lipid synthesis is activated in some types of cancers, and
synthesized lipids are accumulated in the body in metabolic syn-
drome. Therefore, pharmacological intervention for de novo lipid
synthesis may prove to be effective against a number of human
diseases. The conversion of carbohydrates into lipids through de
novo fatty acid involves at least 12 enzymatic reactions, and conver-
sion through cholesterol synthesis involves at least 23. Expression
levels of the genes encoding these enzymes are controlled by trans-
cription factors, which are designated sterol regulatory element-
binding proteins (SREBPs).1,2 SREBPs are synthesized as ER
membrane-bound precursors and must be proteolytically released
by two proteases bound to the Golgi membrane (site-1 (S1P) and
site-2 (S2P) proteases) to generate forms that activate transcription
of target genes in the nucleus.1,3 Activation of SREBPs is tightly
regulated by negative feedback: sterols interact with SREBP clea-
vage-activating protein (SCAP), an ER membrane-bound escort
protein of SREBPs, thereby retaining the SCAP/SREBP complex in
the ER.4,5 Binding of the sterol to SCAP promotes the interaction of
SCAP with INSIG, a retention protein in the ER.6,7 Thus, SREBPs
are key lipogenic transcription factors that govern the homeostasis
of fat metabolism, and SCAP plays a pivotal role in the regulation of
SREBPs.
We previously described a synthetic diarylthiazole molecule
fatostatin (1, Figure 1) and identified its target. Fatostatin
(125B11) was originally discovered from a chemical library as
a synthetic small molecule that inhibited insulin-induced adipo-
genesis and serum-independent growth of cancer cells in cell
culture.8 The molecule was later shown to selectively reduce the
expression of SREBP target genes by blocking the activation of
SREBP transcription factors.9 The direct target of fatostatin
appears to be SCAP; however, fatostatin does not affect the
interaction of SCAP with SREBP-2 or insulin-induced gene
The structure of fatostatin also provides a model that may help
direct the design of molecules for pharmacological intervention
against cancer progression and metabolic diseases, including fatty
liver disease. In fact, fatostatin down-regulated the expression of
lipogenic enzymes and blocked increases in body weight, blood
glucose, and hepatic fat accumulation in obese ob/ob mice, even
under uncontrolled food intake.9 However, fatostatin showed
only moderate potency in mice, and its utility was limited by low
aqueous solubility. In this study, we synthesized a number of
fatostatin derivatives and compared their potency and physico-
chemical properties to identify an analogue with improved
characteristics for use in further in vivo evaluation in a variety
of disease models.
’ CHEMISTRY
Fatostatin is composed of three aromatic rings: pyridine,
thiazole, and toluene. Four routes were used to synthesize fatostatin
derivatives (Schemes 1, S1ꢀ3 in Supporting Information). In the
first route, a central thiazole ring was constructed by reacting
various thioamide derivatives with R-bromoketone derivatives
(Scheme 1). Thioamide 2 or 3 was coupled with an R-bromo-
ketone precursor in warm ethanol to yield 4-phenyl-2-(pyridin-4-
yl)thiazole derivatives (4ꢀ9). The products crystallized directly
from the mixtures were filtered to provide high yields of pure
thiazoles. Analogue 10 was synthesized by the reaction of 3 with
2-bromo-1-(thiophen-2-yl)ethanone. Diphenylthiazole 12 was
Received: March 17, 2011
Published: May 11, 2011
r
2011 American Chemical Society
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|

Journal of Medicinal Chemistry
BRIEF ARTICLE
Figure 1. Structure of fatostatin (1).
Scheme 1. Synthesis of Analogues 4ꢀ10, 12
Figure 2. Inhibitory activities of fatostatin (1) and analogues 10, 12,
and 15 against the activation of SREBP in the luciferase reporter assay.
Table 1. Effects of Pyridine Group Substitutions on the
Activation of SREBP
compd
R
IC50 (μM)a
1
n-Pr
Et
5.6 ( 2.9
6.8 ( 3.4
>30
4a
4b
H
a All values are the mean ( standard deviation, n g 3.
similarly synthesized from benzothioamide (11) and 2-bro-
mo-1-p-tolylethanone.
To prepare analogue 15, 4-bromo-2-propylpyridine (14) was first
synthesized from 4-bromopyridine (13), as previously described.10
Suzuki coupling of bromide 14 with 40-methyl-4-biphenylboronic
acid produced analogue 15 (Scheme S1).
Phenol derivatives (Scheme S2) were prepared by alkaline
hydrolysis of analogue 6, producing the p-phenol derivative 16,
or demethylation of methyl ether 8 and 9 by BBr3, producing the
m-phenol derivative 17 and o-phenol derivative 18.
Amine, amide, and sulfonamide derivatives were also synthe-
sized (Scheme S3). Isopropylamine 20, benzylamine 21, and
cyclopropylmethylamine 22 were prepared in high yields by a
direct reductive amination reaction of acetone, benzaldehyde, or
cyclopropanecarboxaldehyde with a previously prepared primary
amine 19.11 Amine 19 was also reacted with acetyl chloride,
methanesulfonyl chloride, thiophenesulfonyl chloride, or tosyl
chloride in the presence of pyridine to yield acetoamide 23,
methanesulfoneamide 24, thiophenesulfoneamide 25, or tolue-
nesulfoneamide 26, respectively.
upon lipid depletion.9 Fatostatin decreased activation of the
reporter gene with an IC50 of 5.6 μM (Figure 2), which is
consistent with results of previous studies.9
Replacement of any one of fatostatin’s three aromatic rings
with simpler aromatic structures affected activity. For example,
10, a thiophene substitution, had an IC50 of 14.7 μM in the
reporter assay (Figure 2). Replacement of the 2-propylpyridine
group with phenyl group (12) resulted in a 3.3-fold decrease in
potency. Analogue 15, which lacked the central thiazole of
fatostatin, showed a large loss of activity, suggesting that the
central thiazole moiety is important.
Changing the length of the alkyl chain at the 2-position of
pyridine moiety also influenced activity of the fatostatin deriva-
tives. Activity of the ethyl derivative (4a) was almost the same as
that of fatostatin (Table 1). However, removal of n-propyl group
(4b) resulted in reduced activity, suggesting that a lipophilic alkyl
group at this position is essential.
The methyl group of toluene is often oxidized in vivo by
cytochrome P450. Therefore, the effects of substitutions of the
toluene moiety of fatostatin were examined (5ꢀ9 and 16ꢀ18).
Removal of the methyl group in the toluene moiety (5a) led to a
4-fold decrease in potency (Table 2). Halogen substitutions
(5bꢀd), which are likely to be more metabolically stable than
fatostatin, showed moderate activity. Incorporation of a large
benzoyl group (6) resulted in potency similar to that of the
halogenated derivatives. Hydrophilic substitutions, such as hydro-
xy and methoxy groups (7 and 16) also failed to increase activity.
Effects of substitution at 2- and 3-positions of the benzene ring
were also examined. 3-Methoxy, 3-hydroxy, and 2-hydroxy deriv-
atives (8, 17, and 18) were less potent than fatostatin. However,
the 2-methoxy derivative (9) exhibited a slight increase in activity
’ RESULTS AND DISCUSSION
All of the synthesized fatostatin derivatives were assayed for
their ability to inhibit the expression of a luciferase reporter gene,
in which expression of luciferase was controlled by three repeats
of sterol regulatory elements (SREs). This SREBP-responsive
reporter construct was co-transfected into Chinese hamster
ovary K1 (CHO-K1) cells with a control β-gal reporter gene in
which the expression of β-gal was driven by a constitutively active
actin promoter. Luciferase expression from the SREBP-respon-
sive reporter gene, normalized to β-gal expression, was activated
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BRIEF ARTICLE
Table 2. Effects of Phenyl Group Substitutions on the Acti-
vation of SREBP
compd
R
IC50 (μM)a
5a
5b
5c
5d
6
H
23.0 ( 5.6
12.4 ( 3.1
10.7 ( 0.9
9.8 ( 0.6
7.7 ( 1.0
13.0 ( 3.3
10.2 ( 1.2
3.2 ( 0.4
9.6 ( 1.2
9.5 ( 0.4
14.4 ( 0.2
4-F
4-Cl
4-Br
4-OBz
4-OMe
3-OMe
2-OMe
4-OH
3-OH
2-OH
7
8
9
16
17
18
Figure 3. Effects of fatostatin (1) and 24 on the proteolytic activation of
SREBP-2 in cells. Top: Western blot analysis of SREBP-2. CHO-K1 cells
were treated with 1% (v/v) DMSO (vehicle), varied concentrations
(1, 5, and 20 μM) of fatostatin (1) or 24, or sterols (10 μg mLꢀ1
cholesterol or 1 μg mLꢀ1 25-hydroxycholesterol). The precursor and
mature forms of SREBP-2 were detected by an SREBP-2 antibody. The
positions of the precursor and mature forms of SREBP-2 are indicated.
Bottom: Quantification of the Western blot analysis. Percentages of the
mature form of SREBP-2 are shown. Values are the mean ( SD of three
independent experiments.
a All values are the mean ( standard deviation, n g 3.
Table 3. Effects of N-Substitution on the Activation of
SREBP
comparable to the potency of endogenous inhibitor 25-hydro-
xycholesterol, which had an IC50 of 0.3 μM.12
The inhibition of SREBP activation mediated by 24 was
confirmed by Western blot analysis of SREBP-2 (Figure 3).
Treatment of the CHO-K1 cells with 24 decreased the percentage
of the mature form of SREBP-2 (68 kDa) at lower concentrations
than treatment with fatostatin. Densitometric analysis of the gels
indicated that the IC50 of 24 was ∼1 μM, which is 5ꢀ10 times
lower than the IC50 of fatostatin (∼10 μM). The IC50 values were
consistent with the values obtained via the reporter gene assays.
Fatostatin selectively down-regulates endogenous SREBP-
responsive genes in cultured human prostate cancer cells.9
Real-time RT-PCR analysis of nine representative SREBP-re-
sponsive genes13 was carried out to determine the selectivity of
analogue 24. Transcription of all nine genes was down-regulated by
at least 25% (Figure 4). In contrast, treatment with 24 had no
significant effect on transcription of three control genes unre-
lated to SREBP. Thus, the mode of action of 24 appears to be
similar to that of fatostatin.
The in silico properties calculated for fatostatin and analogues 20
and 24 suggested that 24 has potential for further pharmaceutical
development (see Supporting Information, Table S1). Typically,
compounds that violate one or more of the “rule-of-five”
(molecular weight of >500 Da, log P > 5, more than 5 H-bond
donors, and more than 10 H-bond acceptors) are poorly
absorbed.14 Fatostatin and 20 violated one “rule-of-five”; their
clogP values were 5.72 and 5.82, respectively. Analogue 24 had a
clogP of 3.97 and a polar surface area of 108.57 Å2. As expected,
the in vitro aqueous solubility of 24 at pH 7 was more than
10 times higher than that of fatostatin or 20 (Table 4).
compd
R
IC50 (μM)a
19
20
21
22
23
24
25
26
27
H
8.6 ( 2.0
2.8 ( 0.4
3.0 ( 0.1
4.9 ( 3.1
7.1 ( 1.5
0.7 ( 0.2
0.9 ( 0.5
2.3 ( 0.0
1.9 ( 0.2
0.3 ( 0.0
isopropyl
benzyl
methylcyclopropyl
acetyl
methansulfonyl
thiophenesulfonyl
tosyl
tert-butoxycarbonyl
25-hydroxycholesterol
a All values are the mean ( standard deviation, n g 3.
(Table 2), suggesting that substitution of the toluene moiety of
fatostatin might further optimize potency and aqueous solubility.
Therefore, further efforts were focused on substitution at the
4-position of the toluene moiety.
A variety of basic amine groups were introduced in the
4-position of the toluene moiety. The potency of an aniline deriva-
tive (19) was similar to that of fatostatin, and secondary amine
derivatives (20ꢀ22) showed slight improvement in activity
(Table 3). Introduction of amide (23) or carbamate (27)9 did
not significantly improve potency; however, addition of sulfon-
amide (24ꢀ26) increased activity. Analogue 24, with methanesulfo-
namide, exhibited the most potent activity: an IC50 of 0.7 μM,
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BRIEF ARTICLE
Table 5. PAMPA Permeability Results for Fatostatin (1) and
Analogues 20 and 24
%
PAMPA Papp membrane
compd (10ꢀ6 cm/s) retention
ref
ref %
PAMPA Papp membrane
(10ꢀ6 cm/s) retention
ref
1
0.7555
1.059
14.98
94
warfarin
warfarin
warfarin
4.11
5.34
5.58
0
0
0
20
24
93.95
97.35
Table 6. Effect of Feeding ob/ob Mice Analogue 24a
control
treated
body weight (g/mouse)
glucose (mg/dL)
cholesterol (dL)
41.4 ( 1.1
243.7 ( 27.6
285 ( 8
37.9 ( 0.9*
214 ( 16#
220 ( 11*
164.5 ( 5.3
50.2 ( 4.4*
28 ( 1*
Figure 4. Effects of 24 on the expression of SREBP-responsive genes in
DU145 cells: MVK, mevalonate kinase; HMGCR, HMG-CoA reductase;
ACL, ATP citrate lyase; INSIG1, insulin induced gene 1; MVD, mevalonate
pyrophosphate decarboxylase; HMGCS, HMG-CoA synthase 1; IDI1,
isopentenyl diphosphate δ isomerase 1; SCD1, stearoyl-CoA desaturase;
LDLR, LDL receptor; RPL13A, ribosomal protein L13a; B2M, β-2
microglobulin; GAPDH, glyceraldehyde 3-phosphate dehydrogenase.
Values are the mean ( SD of two independent experiments.
HDL (mg/dL)
164.83 ( 4.5
79.38 ( 2.85
42 ( 2
LDL (mg/dL)
TG in liver (mg/g tissue)
a Male ob/ob mice were fed either normal chow (controls) or normal
chow with 24 for 8 weeks. Body weight and food intake were monitored
and recorded daily. At the end of the experiments, serum constituents
were determined and TG levels in liver were determined as we described
previously.9 HDL, high-density lipoprotein; LDL, low-density lipopro-
tein; TG, triglycerides. Values are the mean ( SE (n = 10): (/) P < 0.05;
(#) P = 0.09.
Table 4. In Vitro Aqueous Solubility at pH 3 and 7
compd
solubility, pH 3 (μM)
solubility, pH 7 (μM)
1
80.0
>225
2.0
3.0
controls (214 ( 16 vs 243.7 ( 27.6 mg/dL) (Table 6). The
serum level of total cholesterol was lower in the treated mice
compared to controls (220 ( 11 vs 285 ( 8 mg/dL). There was
a ∼37% decrease in the level of LDL in the serum of treated mice
compared to controls (50.2 ( 4.4 vs 79.38 ( 2.85 mg/dL);
however, no detectable change was observed in the HDL level in
the serum of treated mice compared to controls (164.5 ( 5.3 vs
164.83 ( 4.5 mg/dL) (Table 6). The triglyceride level in the liver
tissues was significantly lower in the treated mice compared to
controls, suggesting fatty liver conditions were ameliorated in the
treated group (28 ( 1.0 vs 42 ( 2.0 mg/g tissue). These results
indicate that 24 is orally available in mice.
Overall, 24, a methanesulfonamide derivative of fatostatin, exhib-
ited the highest activity in a cell-based assay and exhibited better in
vitro and in vivo physicochemical properties than fatostatin or the
other derivatives that were synthesized and evaluated. Analogue 24
(FGH10019) is the most appropriate molecule for further testing in
animal models, and this testing is currently underway.
20
24
>225
33.0
We examined other physicochemical properties of fatostatin and
analogues 20 and 24. The intrinsic clearance rates measured in mouse
hepatocytes were 606, 272, and 137 mL minꢀ1 kgꢀ1, respec-
tively, and the corresponding half-lives (t1/2) were 10.1, 22.4, and
44.4 min. Although fatostatin and 20 showed low metabolic
stability in mouse hepatocytes, 24 was moderately stable.
Results of parallel artificial membrane permeability assays
(PAMPA) indicated that passive permeability through an artifi-
cial membrane was low for fatostatin, moderate for 20, and high
for 24 (Table 5). Thus, 24 is likely to have greater permeability
in vivo than fatostatin or 20. Warfarin (10 μM) was used as a
control for the integrity of membrane. Retention of all com-
pounds within the membrane was greater than 90%, probably
because of the high lipophilicity of the compounds.
We previously demonstrated that intraperitoneal injection of
fatostatin blocked increases in body weight, blood glucose, and
hepatic fat accumulation in obese ob/ob mice, even under condi-
tions of uncontrolled food intake.9 However, fatostatin was not
suited for oral administration and further animal studies. To
demonstrate oral availability of 24, we provided ob/ob mice with
ad libitum access over an 8-week period to normal chow that
contained 24. The 24-treated chow was fed at a dose rate
calculated to provide about 0.7 mg of 24 per day, at about 23
mg/kg body weight, to 5-week-old male ob/ob mice weighing an
average of ∼30 g. After 8 weeks on the 24-treated chow, the mice
gained 8ꢀ9% less weight than control mice, which were fed the
same chow minus the compound (37.9 ( 0.9 vs 41.4 ( 1.1
g/mouse, respectively) (Table 6). Food intake was slightly lower in
the treated mice compared to controls (3.4 ( 0.54 vs 3.6 ( 0.54
g/mouse per day). Blood glucose was lower in the treated mice vs
’ EXPERIMENTAL SECTION
General. The general chemistry, experimental details, and syntheses
of all other compounds are described in the Supporting Information. All
tested compounds were >95% pure, as determined by LC (wavelength
235 nm) (Table S2) and/or combustion analysis (Table S3).
4-(2-Methoxyphenyl)-2-(2-propylpyridin-4-yl)thiazole (9).
A mixture of prothionamide (3) (700 mg, 3.88 mmol) and 2-bromo-
1-(2-methoxyphenyl)ethanone (890 mg, 3.89 mmol) in ethanol
(15 mL) was stirred for 0.5 h at 80 °C, then cooled to 0 °C. The yellow
precipitate was filtered off and washed with cold ethanol. The residue
was partitioned between EtOAc and saturated NaHCO3 solution. The
aqueous phase was extracted with EtOAc. The combined extracts were
dried over Na2SO4 and concentrated to produce 9 (742 mg, 62%) as a
yellow foam. 1H NMR (300 MHz, CDCl3): δ 8.60 (d, J = 5.2 Hz, 1H),
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BRIEF ARTICLE
8.38 (d, J = 7.7 Hz, 1H), 8.06 (s, 1H), 7.78 (s, 1H), 7.71 (d, J = 5.2 Hz,
1H), 7.33 (t, J = 7.7 Hz, 1H), 7.09 (t, J = 7.7 Hz, 1H), 7.01 (d, J = 7.7 Hz,
1H), 3.95 (s, 3H), 2.87 (t, J = 7.7 Hz, 2H), 1.83 (m, 2H), 1.00 (t, J = 7.4
Hz, 3H). m/z = 311 [M þ H]þ. Anal. (C18H18N2OS) C, H, N, S.
N-Isopropyl-4-(2-(2-propylpyridin-4-yl)thiazol-4-yl)ani-
line (20). Acetone (2.5 mL, 34.5 mmol) and acetic acid (2.0 mL,
34.5 mmol) were added to a stirred solution of 19 (1.02 g, 3.45 mmol)
in CH2Cl2 (20 mL). After the mixture was stirred for 1 h, Na-
(AcO)3BH (1.5 g, 6.9 mmol) was added. The mixture was stirred for
20 h. The mixture was poured into saturated NaHCO3 solution and
extracted with EtOAc. The combined extracts were dried over
Na2SO4 and concentrated. Chromatography of the crude product
(SiO2, 4:1 hexane/EtOAc) produced 20 (845 mg, 73%) as a white
foam. 1H NMR (300 MHz, CDCl3): δ 8.61 (d, J = 5.2 Hz, 1H), 7.81
(d, J = 8.5 Hz, 2H), 7.76 (d, J = 1.4 Hz, 1H), 7.68 (dd, J = 1.4, 5.2 Hz,
1H), 7.34 (s, 1H), 6.65 (d, J = 8.5 Hz, 2H), 3.70 (m, 1H), 2.86 (t, J =
7.6 Hz, 2H), 1.83 (m, 2H), 1.25 (d, J = 6.0 Hz, 6H), 1.02 (t, J = 7.4 Hz,
3H). m/z = 338 [M þ H]þ. Anal. (C20H23N3S) C, H, N, S.
’ ABBREVIATIONS USED
SREBP, sterol regulatory element-binding protein; S1P, site-1 pro-
tease; S2P, site-2 protease; SCAP, SREBP cleavage-activating pro-
tein; CHO-K1, Chinese hamster ovary K1; PAMPA, parallel artifi-
cial membrane permeability assay; MVK, mevalonate kinase;
HMGCR, HMG-CoA reductase; ACL, ATP citrate lyase; INSIG1,
insulin-induced gene 1; MVD, mevalonate pyrophosphate decar-
boxylase; HMGCS1, HMG-CoA synthase 1; IDI1, isopentenyl
diphosphate δ isomerase 1; SCD1, stearoyl-CoA desaturase; LDLR,
low-density lipoprotein receptor; RPL13A, ribosomal protein L13a;
B2M, β-2 microglobulin; GAPDH, glyceraldehyde 3-phosphate
dehydrogenase; HDL, high-density lipoprotein; TG, triglycerides
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’ ASSOCIATED CONTENT
S
Supporting Information. Schemes S1ꢀS3; synthesis
b
details of 4ꢀ8, 10, 12, 15ꢀ18, 21ꢀ23, 25, and 26; biological
assay methods; HPLC and combustion data. This material is
available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*For S.J.W.: phone, 713-798-4783; fax, 713-796-9438; e-mail,
swakil@bcm.edu. for M.U.: phone, þ81-774-38-3225; fax,
þ81-774-38-3226; e-mail, uesugi@scl.kyoto-u.ac.jp.
Present Addresses
§Ewha Woman’s University, Seoul 120-750, Korea.
Notes
L.A.-E., S.J.W., and M.U. have interests in FGH Biotech, Inc., a
Houston-based company that exclusively licensed the technol-
ogy described in this manuscript.
’ ACKNOWLEDGMENT
This work was supported in part by grants to M.U. from the
Hoh-ansha Foundation and MEXT (Grant-in-Aid 21310140)
and by grants to S.J.W. from the Hefni Technical Training
Foundation and the National Institutes of Health (Grant GM-
63115). We also thank J. Sakai for an SREBP-2 antibody and a
reporter gene construct, and T. Orihara, T. Morii, and T.
Hasegawa for experimental support. S.K. is a postdoctoral fellow
of JSPS. The Kyoto research group participates in the Global
COE program “Integrated Materials Science” (No. B-09).
(14) Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J.
Experimental and computational approaches to estimate solubility and
permeability in drug discovery and development settings. Adv. Drug
Delivery Rev. 1997, 23, 3–25.
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