Novel selective PPARδ agonists: Optimization of activity by modification of alkynylallylic moiety

Article abstract of DOI:10.1016/j.bmcl.2007.05.051

Y-shaped molecules bearing alkynylallylic moieties were found to be potent and selective PPARδ activators. The alkynylallylic moiety was synthesized from alkyn-1-ols by hydroalumination followed by a cross-coupling reaction. Series of active compounds 6 w

Full text of DOI:10.1016/j.bmcl.2007.05.051

Bioorganic & Medicinal Chemistry Letters 17 (2007) 4144–4149
Novel selective PPARd agonists: Optimization of activity
by modification of alkynylallylic moiety
Miroslav Havranek,a,* Per Sauerberg,b John P. Mogensen,b Pavel Kratina,a
Claus B. Jeppesen,b Ingrid Petterssonb and Pavel Piheraa
a
´
RE&D VUFB, s.r.o., Podeˇbradska´ 56/186, 180 66 Praha 9, Czech Republic
b
˚
Novo Nordisk A/S, Novo Nordisk Park, DK-2670 Maløv, Denmark
Received 29 March 2007; revised 17 May 2007; accepted 17 May 2007
Available online 21 May 2007
Abstract—Y-shaped molecules bearing alkynylallylic moieties were found to be potent and selective PPARd activators. The alky-
nylallylic moiety was synthesized from alkyn-1-ols by hydroalumination followed by a cross-coupling reaction. Series of active com-
pounds 6 were obtained by stepwise changing the structure of the known PPARpan agonist 5 into Y-shaped compounds. The most
active and selective compound, 6f, had a PPARd potency of 0.13 lM, which is 50-fold more potent than compound 5.
ꢀ 2007 Elsevier Ltd. All rights reserved.
The peroxisome proliferator-activated receptors
(PPARs) are ligand-activated transcription factors
belonging to the nuclear receptor gene superfamily.1,2
They play a central role in regulating the storage and
catabolism of dietary fat. There are three PPAR sub-
types: PPARa, PPARc, and PPARd.3 Synthetic ligands
for PPARa and PPARc have been known for decades
and the function of the receptors is well studied.4–6
The human PPARd receptor was cloned in the early
1990s7 and many research groups have been trying to
prepare selective ligands to study the biological function
and possible application in human therapy.
ment with Epple’s recent finding, where Y-shaped
1,3,5-trisubstituted aryls (e.g., 4) were found to be po-
tent and selective d agonists (Fig. 1).12
We investigated the possibility to obtain selective
PPARd agonists by stepwise changing the structure of
the known PPARpan agonist 5,13 with first the head
group of 1 and then with a Y-shaped tail group consist-
ing of the conformationally restricted phenylalkynylallyl
getting compounds of the general structure 6 (Fig. 2).
PPAR agonist can be regarded to consist of three parts:
a head group, a linker, and a lipophilic tail group. The
head group may consist of a phenyl ring bearing a car-
boxylate functionality.9 Examination of the ligand-bind-
ing domain in the PPARd receptor revealed a Y-shaped
pocket. One of the first selective and potent PPARd ago-
nists was GW501516 (1).8 Recently, agonist 2 was found
by optimization of hits from a high-throughput screen-
ing.9,10 The structure of compound 3 fitted the cavity
of the receptor well, according to docking experiment
into a co-crystal structure of the PPARd ligand-binding
domain and GW2433.11,14 This finding is in an agree-
Keywords: Nuclear receptor; Peroxisome proliferator-activated recep-
tor d; PPAR agonists; Hydroalumination; Substituted allyl alcohols.
*
Corresponding author. Tel.: +420 266 107 827; fax: +420 266 107
852; e-mail: havranek@readvufb.cz
Figure 1. Reported selective PPARd agonists.8,10–12
0960-894X/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.05.051

M. Havranek et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4144–4149
4145
Scheme 2. Ar and R groups are listed in Table 1. Reagents and
conditions: (a) di-2-pyridyl azadicarboxylate, THF, rt, 48 h, 50%; (b)
CBr4, PPh3, CH2Cl2, 0 ꢁC to rt, overnight; (c) THF/CH2Cl2 5:6,
DIPEA, rt, overnight, 65%; (d) LiOH, THF/MeOH/H2O 3:1:1, rt, 1–
2 h; (e) diisopropyl azadicarboxylate, THF, rt, overnight; (f) reaction
with 13: THF/CH2Cl2 5:6, DIPEA, rt, overnight; reaction with 15:
Cs2CO3, MeCN, rt, overnight; (g) Pd(PPh3)2Cl2, CuI, diisopropyl
amine, THF, 65 ꢁC.
Figure 2. Graphic evolution of the program.
The alkynylallylic tail group was synthesized using a
method leading to substituted allylic alcohols with de-
fined stereochemistry. The preparation of the allyliodide
intermediate (8) was accomplished using hydroalumina-
tion15 followed by a cross-coupling reaction (Scheme 1).
The stereochemistry was set-up by formation of the cyc-
lic hydroalumination product. After quench of this
product with iodine the (Z)-3-iodoallylic alcohol was
obtained (8). The configuration was retained during
the subsequent Sonogashira cross-coupling reactions
giving alkynylallylic alcohols (9).
the one-step Mitsunobu reaction. First the alcohol was
converted to the allyllic bromide and then the bromine
was substituted with thiophenolate (salt of 13) or with
phenolate (salt of 15). Pd(PPh3)2Cl2 was used as a cata-
lyst for Sonogashira reaction. This catalyst was selective
for the reaction with vinylic iodine of 16 over the aro-
matic bromide (14d–m). This selectivity was not ob-
tained using the Fu catalytic conditions (t-Bu3P,
Pd(PhCN)2Cl2).17
Coupling with the phenol head group, 10, was accom-
plished under Mitsunobu reaction condition to give
the ester 11, which was hydrolyzed to the desired car-
boxylic acid 12 (Scheme 2). Thioether 6a was prepared
by conversion of allylic alcohol 9 into bromide and sub-
sequent reaction with thiol 13. Hydrolysis of the ester
afforded the acid 6a. An alternative method was devel-
oped in the preparation of some acids 6. 3-Iodoallylic
alcohol 8 was coupled first with the head group 13 or
15 followed by Sonogashira cross-coupling reaction to
give 14.16 This methodology allowed the preparation
of a wide number of different compounds in the late
stage of the synthesis.
The aromatic bromine in 14d was used for the synthesis
of 6n. For this reaction the modified Fu conditions18,19
using thiophen stannane20 were used. Preparations of
thioether analogs using 13 were only accomplished with
a few substituents. The stability of thioethers depended
for unknown reason on the substituents. E.g. com-
pounds 6a and b were successively prepared, whereas
the preparation of the compounds 6r–t (Fig. 3) failed,
due to decomposition of final compounds.
A few heteroaromatic derivatives were also synthesized.
The starting propargylic alcohols (7) were prepared
It was also found that the coupling with head groups 13
or 15 gave a better yield using a two-step approach, than
Scheme 1. Reagents and conditions: (a) i—LiAlH4, THF, 0 ꢁC, 3 h;
ii—(MeO)2CO, 0.5 h; (b) I2, THF, 0 ꢁC, overnight; (c) Pd(PPh3)2Cl2,
CuI, diisopropyl amine, THF, 65 ꢁC, overnight.
Figure 3. Examples of unstable thioethers.

4146
M. Havranek et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4144–4149
Table 1. Activity of compounds of the general structure 6 in the hPPAR transactivation assay
Ar
COOH
O
X
R
Compound
Ar
R
X
hPPARa
hPPARc
EC50 (lM)
hPPARd
EC50 (lM)
EC50 (lM)
% max
% max
>10
% max
172
6a
6b
S
S
>10
>10
>24
>10
>10
0.16
Br
>58
>33
0.011
176
MeO
6c
6d
6e
6f
O
O
O
O
O
—
<10
<10
>22
>19
>12
—
—
—
—
—
<10
<10
<10
<10
<10
>10
0.77
0.24
0.13
0.32
>121
174
199
185
184
—
Br
Br
Br
Br
N
>10
>10
>10
F3C
Cl
6g
F
6h
6i
O
O
>10
>10
>11
>15
—
—
<10
<10
2.0
177
184
Br
Br
Me
0.22
S
Me
HO
6j
O
>10
>12
>10
>13
0.49
214
Br
O
6k
6l
O
O
>10
—
>34
<10
>10
—
>28
<10
3.0
23
Br
Br
N
>10
>131
N
N
O
S
O
6m
O
—
<10
—
<10
1.2
159
Br
Me
6n
6o
6p
6q
O
O
O
O
>10
5.8
>60
<10
>41
33
>10
>10
>10
6.6
>12
23
3.9
214
230
188
172
S
Me
Me
0.15
0.29
0.29
S
Me
F
O
>10
4.1
>11
28
Me
O
N
NNC 61-4655 (5)
Rosiglitazone
GW501516
0.01
>10
3.9
100
>24
68
2.6
0.3
96
6.4
—
152
<10
272
100
>22
>10
0.008
Compounds were tested in at least three separate experiments in at least five concentrations ranging from 0.001 to 30 lM. EC50 is the concentration
giving 50% of the maximal activity observed for a given compound. For each compound the efficacy (% max) is given as a relative compared to the
maximal activity of NNC 61-4655 (5) for PPARa, Rosiglitazone for PPARc and Carbacyclin for PPARd. The results are expressed as means and
SEM was less than 15%. If a plateau was not reached at the highest concentration of compound tested (30 lM), the effect at this concentration was
calculated, and the maximal effect is indicted to be grater than this value. In such cases the EC50 was assigned as >10 lM. If the maximal effect of a
compound was less than 10% no EC50 could be calculated.
from the haloaromatics21 by Sonogashira reaction.22
Hydroalumination reaction gave again isomerically pure
intermediates 8. The yields of the reactions were how-
ever lower than in the previous cases. Next steps were
performed by standard procedures, except for the syn-
thesis of the quinoline derivative, where iodoalcohol 8

M. Havranek et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4144–4149
4147
group, exhibited a similar activity profile as 6d. Replace-
ment of the bromophenyl group (Ar group, Table 1)
with a heteroaryl group did not change the activity sig-
nificantly (6n vs. 6d; 6o vs. 6i). The quinoline derivative
gained PPARd activity but lost the selectivity (6q vs. 6d).
The benzofuran derivatives 6o and p exhibited good
activity and selectivity.
Compound 6f, which exhibited good PPARd potency
and good selectivity, was docked into the crystal struc-
ture of the ligand binding domain of the PPARd recep-
tor crystallized with GW2433 (1GWX).14,26 The
Y-shaped molecule 6f adopted similar conformation as
the PPAR pan-agonist GW2433 (Fig. 4). The reduced
conformational flexibility of 6f in comparison to
GW2433 resulted in higher PPARd selectivity. Lipo-
philic Br and CF3 groups attached on the phenyl rings
helped better filling up the hydrophobic cavity. Elec-
tronic effects of both the substituents also played the
role in the charge distribution in the tail group and thus
in interactions between ligand and the cavity of the
receptor.
Figure 4. 6f (yellow) docked into the crystal structure of the ligand
binding domain of the PPARd receptor crystallized with GW2433
(magenta). H323, H449, and Y473 are shown as ball-and-stick.
was converted into allylic chloride by reaction with thio-
nyl chloride in CH2Cl2.
In conclusion, Y-shaped compounds of the general
structure 6 were found to be selective and potent PPARd
activators. Good activity and selectivity was obtained by
proper combination of both substituents on the allylic
tail group. Compound 6f exhibited good PPARd po-
tency combined with good selectivity.
The structural starting point was the known compound
5, which is a PPARpan agonist with high PPARa po-
tency.13 Replacement of the head group (the moiety
bearing the carboxyl) with the one being used in
GW501516 (1) decreased a and c activity25 giving the
dual PPARa, d agonist, 17 (Fig. 2). Modification of
the tail group of compound 5 with the Y-shaped alky-
nylallylic group gave compound 12 which had decreased
the PPARa, c, and d potency. The combination of both
‘‘new’’ head and tail group, gave a selective PPARd ago-
nist (6c) with low potency. Bromine substitution on the
tail group (6d) increased the PPARd potency. The thio-
ether analog 6a exhibited even higher PPARd potency.
Acknowledgments
The technical assistance of D. D. Andersen, P. Kovar-
ova, M. Jelinkova, J. Novak, and V. Balsanek is greatly
appreciated.
Supplementary data
The synthesis of a series of thioether analogs of com-
pound 6a was attempted, but many of the thioethers
were unstable and decomposed during the work-up.
Compound 6b was one of few stable compounds which
exhibited very good PPARd potency (Table 1).
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.bmcl.
2007.05.051.
Because of the instability of thioethers attention was
turned back to ether bridged compounds. A large set
of alkynylallylic ethers with diverse substituents were
synthesized and screened (Table 1). Introduction of a
hydrophobic bromine group in the Ar group in 6c gave
compound 6d with improved PPARd activity. This re-
flected that the hydrophobic pocket was better filled
up by the bromophenyl group compared with the
unsubstituted phenyl ring. In the series of compounds
6d–m, only the acetylenic substituent (R) was altered.
Many compounds exhibited higher potency and efficacy
on PPARd activity compared to 6d, while good selectiv-
ity was retained. Generally, aromatic and non-polar
substituents exhibited good activity (6d–g, i), while
bulky substituents and polar groups decreased the activ-
ity (6k–m). Compound 6h had a different substitution
pattern in the phenyl ring and this resulted in a de-
creased PPARd potency. Compound 6j, having an OH
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M. Havranek et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4144–4149
9. Epple, R.; Russo, R.; Azimioara, M.; Cow, C.; Xie, Y.;
Method B. Allylic alcohol (8 or 9) (2.8 mmol), carbon
tetrabromide (0.913 g, 3 mmol), and triphenylphosphine
(0.786 g, 3 mmol) were mixed in anhydrous dichlorometh-
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bromophenyl)-3-iodoallyloxy]-2-methylphenoxy] acetate
(13d) was prepared in 71% yield. 1H NMR (CDCl3,
300 MHz): 7.46–7.42 (m, 2H); 7.37–7.32 (m, 2H); 6.78 (s,
1H), 6.68 (d, J = 1.5 Hz, 2H); 6.35 (t, J = 5.0 Hz, 1H); 4.68
(d, J = 5.0 Hz, 2H); 4.61 (s, 2H); 3.80 (s, 3H); 2.29 (s, 3H).
The alkylation of thiophenol 1324 was performed in
CH2Cl2/THF mixture (5:6) under exclusion of oxygen with
DIPEA as a base.
Method C. (Z)-3-Iodo-3-(quinoline-3-yl)prop-2-en-1-ol
(8q, 1.061 g, 3.41 mmol) was dissolved in anhydrous
dichloromethane (15 mL) and thionyl chloride (0.45 mL,
6 mmol) was added. The mixture was stirred for 5 h at
ambient temperature. The solvent and excess of thionyl
chloride were removed in vacuo and sufficiently pure crude
hydrochloride of (Z)-3-iodo-3-(quinoline-3-yl)allyl chlo-
ride was obtained. This product (0.704 g, 1.9 mmol), phenol
15 (0.392 g, 2.0 mmol), and cesium carbonate (1.304 g,
4 mmol) were mixed in acetonitrile (15 mL) and the
resulting mixture was stirred for 3 days. The work-up
procedure was as described in Method B.
Sonogashira cross-coupling reaction, the preparation of
compounds 9 and 14a, d–m, o–q: Iododerivative 8 or 16a,
d–m, o–q (0.77 mmol), terminal alkyne (R-CCH)
(1.54 mmol), and diisopropylamine (0.51 mL, 3.6 mmol)
were dissolved in THF (15 mL). The solution was degassed;
CuI (15 mg, 0.075 mmol) and PdCl2(PPh3)2 (30 mg,
0.042 mmol) were added; the reaction mixture was degassed
again and then stirred under inert atmosphere at 65 ꢁC. The
reaction was monitored by TLC. When the conversion was
completed the reaction mixture was diluted with ethyl
acetate (20 mL) and filtered through a pad of silica gel. The
pad was washed with ethyl acetate and the combined
filtrates were concentrated in vacuo. The residue was
purified by column chromatography giving desired product
in high yield. E.g. Methyl (Z)-[4-[3-(4-bromophenyl)-5-(4-
trifluoromethylphenyl)pent-2-en-4-ynyloxy]-2-methylphen-
oxy] acetate (14f) was obtained in 96% yield. 1H NMR
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16. General procedure for the preparation of compounds
6.Hydroalumination (the preparation of iodide 8): NaOMe
(0.027 g, 0.5 mmol) was added to a 1 M solution of LiAlH4
in THF (6 mL, 6 mmol). The mixture was cooled to 0 ꢁC
22,23
and a solution of the appropriate alk-2-yn-1-ol (7)
(5 mmol) in THF (10 mL) was slowly added. The reaction
mixture was stirred for 3 h under nitrogen atmosphere at
0 ꢁC and dimethyl carbonate (0.7 mL, 8 mmol) or ethyl
acetate (1 mL, 10 mmol) was added. The mixture was
stirred for 0.5 h without cooling, then cooled to 0 ꢁC and a
solution of iodine (1.52 g, 6 mmol) in THF (10 mL) was
added. The mixture was left in a refrigerator (4 ꢁC)
overnight. Then MeOH (2 mL) was added, the mixture
was stirred for 0.5 h at rt and poured into water, acidified
with HCl, and extracted with ethyl acetate (3 · 50 mL).
Combined organic layers were washed with aqueous solu-
tion of sodium thiosulfate (5%, 100 mL) to remove excess of
iodine, dried with sodium sulfate, and concentrated. The
residue was purified by column chromatography (silica gel)
giving substituted 3-iodoprop-2-en-1-ol. E.g. (Z)-3-(4-
bromophenyl)-3-iodo-prop-2-en-1-ol was obtained in 84%
yield. 1H NMR (CDCl3, 300 MHz): 7.47–7.42 (m, 2H);
7.36–7.31 (m, 2H); 6.25 (t, J = 6.0 Hz, 1H); 4.37 (t,
J = 6.0 Hz, 2H); 1.86 (t, J = 6.0 Hz, 1H).
Alkylation of phenol 15 or thiophenol 13: Method A. Methyl
(4-hydroxy-2-methylphenoxy) acetate (15)8 (1.17 g,
5.96 mmol), triphenylphosphine (1.70 g, 6.48 mmol), and
allylic alcohol (8 or 9) were dissolved in the mixture of
anhydrous toluene (90 mL) and THF (30 mL). Diisopropyl
azodicarboxylate (1.2 mL, 6.05 mmol) in THF (10 mL) was
added dropwise under nitrogen atmosphere at 0 ꢁC over
20 min. The reaction mixture was stirred overnight at room
temperature. The solvents were evaporated in vacuo and the
residue was submitted to flash column chromatography
(silica gel) giving the desired ether. E.g. Methyl (Z)-[4-[3-
iodo-3-(2-methylbenzo[b]furan-5-yl)allyloxy]-2-methylphen-
oxy] acetate (16o) was obtained in 59% yield. Mp: 74–77 ꢁC;
1H NMR (CDCl3, 300 MHz): 7.59 (bd, J = 1.5 Hz, 1H);
7.35 (dd, J = 8.6 and 1.8 Hz, 1H); 7.32 (d, J = 8.6 Hz, 1H);
6.80 (bd, J = 2.1 Hz, 1H); 6.72-6.66 (m, 2H); 6.36 (s,
1H); 6.28 (t, J = 5.1 Hz, 1H); 4.71 (d, J = 5.1 Hz, 2H);
4.61 (s, 2H); 3.80 (s, 3H); 2.45 (s, 3H); 2.29 (s, 3H).
(CDCl3,
300 MHz):
7.53–7.48
(m,
4H);
7.45
(dm,J = 8.6 Hz, 2H); 7.35 (dm, J = 8.4 Hz, 2H); 6.82 (d,
J = 2.8 Hz, 1H); 6.72 (dd, J = 8.8 and 2.9 Hz, 1H); 6.68–
6.60 (m, 2H); 4.97 (d, J = 6.3 Hz, 2H); 4.60 (s, 2H); 3.80 (s,
3H); 2.28 (s, 3H).
Hydrolysis of esters: ester (ꢀ0.3 mmol) was dissolved in a
mixture of THF (3 mL) and MeOH (1 mL), and aqueous
solution of lithium hydroxide monohydrate (22 mg,
0.5 mmol, 1 mL) was added. The mixture was stirred for
2 h and then diluted with saturated aqueous solution of
ammonium chloride (20 mL). The resulting mixture was
extracted with ethyl acetate (3 · 15 mL); the organic layers
were combined and dried with sodium sulfate. The com-
pound was either crystallized or chromatographed on silica
gel. E.g. (Z)-[4-[3-(4-bromophenyl)-5-(4-trifluoromethyl-
phenyl) pent-2-en-4-ynyloxy]-2-methylphenoxy] acetic acid
(6f) was obtained in 75% yield. 1H NMR (CDCl3,

M. Havranek et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4144–4149
4149
300 MHz): 7.82 (m, 4H); 7.73 (d, J = 8.3 Hz, 2H); 7.72 (d,
J = 8.3 Hz, 2H); 6.94 (t, J = 5.9 Hz, 1H); 6.86 (m, 1H); 6.79–
6.74 (m, 2H); 4.97 (d, J = 6.0 Hz, 2H); 4.54 (s, 2H); 2.15 (s,
3H).
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18. Littke, A. F.; Fu, G. C. Angew. Chem. Int. Ed. 1999, 38,
2411.
22. Tretyakov, E.; Tkachev, A. V.; Rybalova, T. V.; Gatilov,
Y. V.; Knight, D. V.; Vasilevsky, S. F. Tetrahedron 2000,
56, 10075.
19. The preparation of compound 14n. Compound 14d
(216 mg, 0.440 mmol) and tributyl-(5-methylthiophen-2-
yl)tin [20] (223 mg, 0.576 mmol) were dissolved in DMF
(10 mL), the solution was degassed and put under nitro-
gen. Pd2dba3ÆCHCl3 (15.4 mg, 0.015 mmol) and t-Bu3P in
cyclohexane (0.15 M, 0.40 mL, 0.060 mmol) were added.
The reaction mixture was stirred at 50 ꢁC for 90 min,
cooled down, and 10% aqueous solution of potassium
fluoride was added. The mixture was stirred for 10 min,
filtered through a pad of silica gel and the silica gel was
washed with ethyl acetate (50 mL). The filtrate was
washed with brine (3 · 15 mL), 10% aqueous solution of
potassium fluoride (2 · 10 mL), water (2 · 10 mL), and
brine (3 · 15 mL). The organic solution was dried with
sodium sulfate, concentrated and purified by flash column
chromatography (silica gel, hexanes/ethyl acetate 10:1).
The crude product was triturated with hexanes/ethyl
acetate mixture (15:1, 16 mL) yielding methyl (Z)-[2-
methyl-4-[3-[4-(5-methylthiophen-2-yl)phenyl]-5-phenylpent-
2- en-4-ynyloxy]phenoxy] acetate (14n) as a yellowish
amorphous mass in 47% yield.
23. Denis, J.-N.; Greene, A. E.; Serre, A. A.; Luche, M.-J.
J. Org. Chem. 1986, 51, 46.
24. Martin, M. T.; Thomas, A. M.; York, D. G. Tetrahedron
Lett. 2002, 43, 2145.
25. PPAR in-vitro transactivation assay was performed as
described in Ref. 11.
26. Glide docking. The structure manipulations were per-
formed in Maestro version 7.5 (Maestro 7.0, Schro¨dinger,
LLC, New York, NY, 1999–2005). Glide calculations were
performed with Impact version 4.0.27,28 6f was built in
Maestro version 7.5, a formal charge of À1 was assigned,
and the molecule was minimized with the OPLS_2005
force field. 6f was docked with Glide version 4.0 using the
SP mode and the van der Waals radii of the ligand atoms
were scaled by 0.8.
27. Friesner, R. A.; Banks, J. L.; Murphy, R. B.; Halgren, T.
A.; Klicic, J. J.; Mainz, D. T.; Repasky, M. P.; Knoll, E.
H.; Shaw, D. E.; Shelley, M.; Perry, J. K.; Francis, P.;
Shenkin, P. S. J. Med. Chem. 2004, 47, 1739.
28. Halgren, T. A.; Murphy, R. B.; Friesner, R. A.; Beard, H.
S.; Frye, L. L.; Pollard, W. T.; Banks, J. L. J. Med. Chem.
2004, 47, 1750.
20. Morimoto, H.; Shimadzu, H.; Kushiyama, E.; Kawanishi,
H.; Hosaka, T.; Kawase, Y.; Yasuda, K.; Kikkawa, K.;