Modulation of PPAR receptor subtype selectivity of the ligands: Aliphatic chain vs aromatic ring as a spacer between pharmacophore and the lipophilic moiety

Article abstract of DOI:10.1016/j.bmcl.2008.10.062

Oxazole containing glycine and oximinobutyric acid derivatives were synthesized as PPARα agonists by incorporating polymethylene spacer as a replacement of commonly used phenylene group that connects the acidic head with lipophilic tail. Compound 13a was

Full text of DOI:10.1016/j.bmcl.2008.10.062

Bioorganic & Medicinal Chemistry Letters 18 (2008) 6471–6475
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Modulation of PPAR receptor subtype selectivity of the ligands: Aliphatic
chain vs aromatic ring as a spacer between pharmacophore and the
lipophilic moiety q
a
b
a
a
a
Harikishore Pingali a,b, , Mukul Jain , Shailesh Shah , Pravin Patil , Pankaj Makadia , Pandurang Zaware ,
*
Kalapatapu V. V. M. Sairam a, Jeevankumar Jamili a, Ashish Goel a, Megha Patel a, Pankaj Patel a
a Zydus Research Centre, Sarkhej-Bavla N.H. No. 8A, Moraiya, Ahmedabad, Gujarat 382210, India
b Department of Chemistry, Faculty of Science, M. S. University of Baroda, Vadodara 390002, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Oxazole containing glycine and oximinobutyric acid derivatives were synthesized as PPARa agonists by
Received 27 June 2008
Revised 11 September 2008
Accepted 14 October 2008
Available online 17 October 2008
incorporating polymethylene spacer as a replacement of commonly used phenylene group that connects
the acidic head with lipophilic tail. Compound 13a was found to be a selective and potent PPAR agonist.
Further 1,3-dioxane-2-carboxylic acid derivative 20 was synthesized by replacing the tetramethylene
spacer of NS-220, a selective PPAR agonist with phenylene group and found to exhibit PPAR dual
agonism. These results suggest that compounds possessing polymethylene spacer between pharmaco-
a
a
a/c
Keywords:
PPARa agonist
Oxazole
Imiglitazar
Muraglitazar
phore and lipophilic tail exhibit predominantly PPAR
a
agonism whereas those with an aromatic pheny-
lene spacer shows PPAR dual agonism.
a/c
Ó 2008 Elsevier Ltd. All rights reserved.
The peroxisome proliferator-activated receptors (PPARs) are li-
gand-activated transcription factors in the nuclear hormone recep-
efficacy. The hypothesis that PPARa/c dual agonism provides an
additive, and possibly synergistic, pharmacology has resulted in
an intensive effort within the pharmaceutical industry to develop
and evaluate these agents.5 The first dual agonist Farglitazar6
tor superfamily.1 Three distinct PPAR subtypes (PPAR
a, PPARc, and
PPARd) have been identified in most mammalian species. The mul-
tiple roles of the PPARs in physiological regulation of glucose
homeostasis, fatty acid metabolism, inflammation, and cellular dif-
ferentiation have been reviewed extensively in recent years.2
which is a potent PPAR
was dropped in an advanced stage due to the emergence of edema.
Two more dual agonists with substantial PPAR dual activity
c agonist with a moderate PPARa activation
a/c
PPAR
and has been implicated as the primary receptor modulating the
antidiabetic activity through insulin sensitization.3 PPAR
agonists,
c
is well known at a cellular level for its role in adipogenesis
Ragaglitazar7 and Tesaglitazar8 were also dropped from late clini-
cal development due to carcinogenicity in rodent toxicity models
and elevated serum creatinine and associated decrease in glomular
filtration rate, respectively. The only dual agonist that has been ad-
vanced to NDA filing, Muraglitazar9 was dropped very recently due
to the incidence of edema, heart failure, and cardiovascular compli-
c
such as TZDs, have proven to be efficacious as insulin-sensitizing
agents in the treatment of type 2 diabetes. Two of these TZDs
namely Rosiglitazone and Pioglitazone are currently available in
the market. Unfortunately, they are also known to cause undesir-
able side effects including weight gain, edema, and anemia in both
cations. Activation of PPAR
vate HDL, and exert insulin-sensitizing effects.10 These findings
suggest that even chronic administration of selective PPAR ago-
a is known to lower triglycerides, ele-
animal models and humans. PPAR
a
is known to play a pivotal role
a
in the uptake and oxidation of fatty acids and also in lipoprotein
metabolism.4 Fibrate compounds such as Fenofibrate and Bezafi-
brate used to treat hyperlipidemia are effective in reducing triglyc-
erides, increasing HDL cholesterol and lowering LDL cholesterol are
nist will serve as a better remedy for the treatment of metabolic
disorder and led us to develop useful chemical tools to aid discov-
ery of novel PPARa agonists. A typical structural design of a PPAR
agonist as shown in Figure 1 comprises of a lipophilic heterocyclic
tail and an acidic pharmacophore with a spacer in-between. As a
part of our research in the field of PPARs to develop novel thera-
peutic agents to treat metabolic disorders11 we have recently re-
ported a series of 1,3-dioxane-2-carboxylic acid derivatives as
poor activators of PPARa and need high doses to show significant
q
ZRC communication # 229.
* Corresponding author. Tel.: +91 2717 250801; fax: +91 2717 250606.
E-mail addresses: pingalihk@rediffmail.com (H. Pingali), shailesh-chem@msu-
baroda.ac.in (S. Shah).
PPAR
a
/
c
dual agonist12 and the lead compound of this series 20
recently reported PPAR agonist
differs structurally from
a
a
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.10.062

6472
H. Pingali et al. / Bioorg. Med. Chem. Lett. 18 (2008) 6471–6475
O
N
O
OH
N
O
O
ACIDIC PHARMACOPHORE
SPACER
LIPOPHILIC GROUP
ACIDIC PHARMACOFORE
SPACER
LIPOPHILIC GROUP
Imiglitazar
Figure 1. Structural design of PPAR ligand.
NS-22013 in spacer region as compound 20 and other dual agonists
like Imiglitazar14 and Muraglitazar possess aromatic phenylene
spacer whereas NS-220 possesses an alkyl chain as a spacer be-
tween acidic head and lipophilic tail (Fig. 2). Based on these obser-
vations we envisioned that PPAR subtype selectivity of ligands may
be sensitive to chemical variations in the spacer region of the
structure and intended to study the effect of changing the pheny-
lene spacer of Imiglitazar and Muraglitazar to a polymethylene
the methylene chain to yield compounds 6a–b. Compounds 9a–c
were synthesized according to Scheme 2. The hydroxy compounds
4b and 6a–b were oxidized to corresponding aldehydes 7a–c with
pyridiniumchlorochromate in dichloromethane which were re-
acted with glycine ethyl ester under reductive amination condi-
tions followed by acylation of the intermediate with 4-
methoxyphenylchloroformate to yield the ester 8a–c. Hydrolysis
of 8a–c in aqueous basic medium resulted to yield acid compounds
9a–c. Synthesis of compounds 13a–c were described in Scheme 3.
The hydroxy compounds 4b and 6a–b were converted to their
mesylate derivatives 4d and 10a–b, respectively, and coupled with
compound 11 in presence of base and the corresponding esters
12a–c obtained were hydrolyzed with aqueous base to afford acids
13a–c. Compound 2012 was synthesized as illustrated in Scheme 4
by coupling the intermediate 18 with 1 and hydrolyzing the ester
19 in presence of aqueous base. Intermediate 18 was prepared by
reducing the diester 15 to diol 16 which was then cyclized to
1,3-dioxane by treating with methylpyruvate in the presence of le-
wis acid to afford compound 17 and debenzylated under hydrogen
transfer reaction conditions. Imiglitazar,14 Muraglitazar,9 NS-
22013, Intermediates 1, 2,15 and 1114 were synthesized following
the methods reported in the literature.
spacer in order to develop selective PPAR
we herein report few oxazole containing glycine and oximinobu-
tyric acid derivatives as PPAR agonists designed by incorporating
a agonist. In this context
a
polymethylene spacer as a replacement of phenylene group of
Imiglitazar and Muraglitazar. We also report a previously discov-
ered dual agonist 20 synthesized by replacing the polymethylene
spacer of NS-220, a selective PPARa agonist with phenylene group
in order to show that the replacement of phenylene spacer of dual
agonist with a polymethylene spacer makes the compounds PPAR
a
selective agonists.
Synthesis of intermediate hydroxy compound 4a–b and 6a–b
was illustrated in Scheme 1. Carboxylic acids 3a–b were synthe-
sized by reacting 1 or 2 with diethylmalonate in presence of so-
dium hydride followed by hydrolysis of the diester followed by
decarboxylation under thermal condition. Esterification of mono-
acids 3a–b followed by reduction of the resulted esters 3c–d with
lithium aluminum hydride yielded the hydroxy compounds 4a–b.
The mesylate derivatives 4c–d were subjected to a similar series
of reactions described for the synthesis of 4 in order to elongate
Newly synthesized compounds16 9a–c, 13a–c, and 20 along
with Imiglitazar, Muraglitazar, and NS-220 were screened for
hPPARa, c, and d agonistic activity on full length PPAR receptor
transfected in HepG2 cells following the procedure described in
our earlier publication.12 WY-14643, Rosiglitazone, and GW-
O
N
OH
O
OH
O
N
N
O
O
N
O
O
O
O
O
Muraglitazar
Imiglitazar
O
O
N
O
N
OH
13a
O
O
N
N
O
O
O
COOR'
O
O
OH
O
20
NS-220
Figure 2. Chemical structures of PPAR ligands. Imiglitazar, Muraglitazar and 20 possess aromatic phenylene spacer between acidic head and lipophilic tail and are PPAR a/g
dual agonists whereas NS-220 and 13a contain polymethylene spacer and are PPARa selective agonists.

H. Pingali et al. / Bioorg. Med. Chem. Lett. 18 (2008) 6471–6475
6473
O
O
N
a,b,c
O
e
L
N
X
COOR
R'
N
X
X
1, X=CH2, L=Cl
2, X=(CH2)2, L=OSO2CH3
4a, X=CH2, R' = OH
4b, X=(CH2)2, R' =OH
3a, X=CH2, R = H
3b, X=(CH2)2, R = H
d
f
3c, X=CH2, R = Et
3d, X=(CH2)2, R = Et
4c, X=CH2, R' = OMs
4d, X=(CH2)2, R' = OMs
O
O
a,b,c
e
OH
N
X
COOR"
N
X
5a, X=CH2, R = H
5b, X=(CH2)2, R = H
6a, X=CH2
6b, X=(CH2)2
d
5c, X=CH2, R = Et
5d, X=(CH2)2, R = Et
Scheme 1. Reagents and conditions: (a) diethyl malonate, NaH, DMF, 25 °C, 18 h; (b) aq NaOH, MeOH, 25 °C, 0.25 h; (c) xylene, reflux, 5 h; (d) EtOH, H2SO4, reflux, 24 h; (e)
LiAlH4, THF, 25 °C, 0.5 h; (f) CH3SO2Cl, Et3N, CH2Cl2, 10 °C, 0.25 h.
O
O
O
b,c
a
O
X
O
OH
CHO
O
O
N
X
N
X
N
N
O
4b, X=(CH2)4
6a, X=(CH2)5
6b, X=(CH2)6
7a, X=(CH2)3
7b, X=(CH2)4
7c, X=(CH2)5
8a, X=(CH2)4
8b X=(CH2)5
8c, X=(CH2)6
O
O
d
O
O
O
N
N
X
OH
9a, X=(CH2)4
9b, X=(CH2)5
9c, X=(CH2)6
Scheme 2. Reagents and condition: (a) PCC, celite, CH2Cl2, 25 °C, 2 h; (b) glycine ethyl ester hydrochloride, MeOH, NaBH(OAc)3, 25 °C, 1.5 h; (c) 4-methoxyphenylchlo-
roformate, CH2Cl2, 25 °C, 2 h; (d) LiOHÁH2O, THF, H2O, MeOH, 25 °C, 3 h.
O
O
b
a
OH
OMs
N
X
N
X
O
N
OMe
4b, X=(CH2)4
6a, X=(CH2)5
6b, X=(CH2)6
4d, X=(CH2)4
10a, X=(CH2)5
10b, X=(CH2)6
HO
11
O
O
c
O
OMe
O
OH
N
X
N
N
X
N
O
O
12a, X=(CH2)4
12b, X=(CH2)5
12c, X=(CH2)6
13a, X=(CH2)4
13b, X=(CH2)5
13c, X=(CH2)6
Scheme 3. Reagents and conditions: (a) CH3SO2Cl, Et3N, CH2Cl2, 10 °C, 0.25 h; (b) NaH (50%), DMF, 60 °C, 24 h; (c) LiOHÁH2O, THF, H2O, MeOH, 25 °C, 5 h.

6474
H. Pingali et al. / Bioorg. Med. Chem. Lett. 18 (2008) 6471–6475
O
OH
OH
a
OEt
OEt
b
Cl
BnO
BnO
O
BnO
14
15
16
O
RO
d
OMe
e
c
O
N
O
O
COOR'
O
O
O
17, R = Bn
18, R = H
19, R' = Me
20, R' = H
f
Scheme 4. Reagents and conditions: (a) diethyl malonate, NaH (50%), THF, 20 °C, 14 h; (b) LiAlH4, THF, 20 °C, 6 h; (c) methyl pyruvate, BF3 etherate, CH3CN, 25 °C, 4 h; (d)
HCOONH4, Pd/C (10%), MeOH, reflux, 2 h; (e) 1, K2CO3, DMF, 60 °C, 20 h; (f) NaOH, MeOH, H2O, 25 °C, 18 h.
lue was smaller than 0.001 kcal/mol Å. The complexed X-ray crys-
tal structure of the ligand binding domain (LBD) of PPAR with
GW40954417 (1k7l.pdb) and PPAR
with Rosiglitazone (2PRG.pdb)
were obtained from RCSB Protein Data Bank. When docked into
PPAR binding pocket the most stable docking models both 13a
Table 1
hPPAR transactivation data.
a
hPPAR transactivationa,b EC50
(
l
M)
c
Compound
a
c
Ratio
c
/
a
d
a
9a
9b
9c
13a
13b
13c
20
Imiglitazar
Muraglitazar
NS-220
IA
IA
—
IA
IA
IA
IA
IA
IA
IA
IA
IA
IA
and Imiglitazar adopted a confirmation that allows the carboxylic
group to form hydrogen bonds with Tyr 314, Tyr 464, and Ser280
0.044
0.034
0.0000038
0.002
0.0001
0.072
0.008
0.15
0.56
0.45
0.43
0.031
0.1
0.015
0.004
0.09
6.85
12
13
113157
15
1000
0.2
0.5
(Fig. 3) which are reported to be essential interaction for a PPAR
a
agonist. However, in the docking model of 13a an additional H-
bond between the nitrogen atom of oxazole ring and Cys276 was
observed. This additional H-bond may actually be responsible for
improved activity of this compound over Imiglitazar. Compound
0.6
131
0.052
13a when docked into PPARc binding pocket none of the confor-
mations showed H-bond interactions with any of the amino acids
though the molecular orientation was similar to that of Imiglitazar
which correlates with moderate PPARc activity of this compound
a
IA denotes inactive where compounds did not show any fold induction above
M concentration.
EC50 is the concentration of the test compound that affords half-maximum
the basal level (shown by vehicle) up to 1
l
b
transactivation activity.
501516 were used as controls for PPARa, c, and d, respectively, and
the results were summarized in Table 1. As described earlier we in-
tended to replace the central phenylene spacer of Muraglitazar
with an alkyl chain and synthesized compounds 9a–c and evalu-
ated their PPAR transactivation potentials. Among these three
compounds, 9a with tetramethylene spacer was found inactive to-
wards both PPAR
a
and
c
whereas 9b and 9c were found less potent
increasing the ratio of EC50
towards PPAR compared to PPAR
c
a
c/a
to 12 and 13, respectively, against 0.6 as in case of Muraglitazar.
Having felt encouraged with these results and in urge of potent
and highly selective PPARa agonist we then synthesized the com-
pounds 13a–c taking this time Imiglitazar as initial lead. The trans-
activation results of the compounds 13a–c were found very
interesting and were in line with our hypothesis. Compounds
13a and 13c found very potent and selective PPAR
picomolar and nanomolar range EC50, respectively, and multi-fold
selectivity towards PPAR over PPAR whereas Compounds 13b
showed inferior results in terms of selectivity towards PPAR
a agonists with
a
c
a
transactivation. To support our hypothesis further and cross vali-
date the same we synthesized the compound 20 by replacing the
tetramethylene group of the compound NS-220 with phenylene
group. This compound 20 turned out to be a dual PPAR
with equipotent activation towards both PPAR and whereas its
parent compound NS-220 is a selective PPAR agonist.
a/c agonist
a
c
a
To better understand the activity of 13a at molecular level,
docking simulations were carried out for this compound and Imi-
glitrazar using Discovery Studio software version 1.6. The geome-
try of compounds docked was subsequently optimized using the
CHARMM force field. The energy minimization was carried out
using smart minimizer option in the software until the gradient va-
Figure 3. Molecular docking of 13a (B) and Imiglitazar (A) into PPARa binding site.
H-bond interactions with amino acids are shown in dashed lines.

H. Pingali et al. / Bioorg. Med. Chem. Lett. 18 (2008) 6471–6475
6475
C.; Feige, J. N.; Pingali, H.; Lohray, V. B.; Wahli, W.; Desvergne, B.; Engelborghs,
Y.; Gelman, L. J. Biol. Chem. 2007, 282, 4417.
12. Pingali, H.; Jain, M.; Shah, S.; Makadia, P.; Zaware, P.; Goel, A.; Patel, M.; Giri, S.;
Patel, H.; Patel, P. Bioorg. Med. Chem. 2008, 16, 7117.
whereas Imiglitazar showed H-bond interactions with Cys295
while Ser289 and Tyr473 are lying in close proximity of the ligand.
In summary we discovered novel oxazole containing glycine
13. Asaki, T.; Aoki, T.; Hamamoto, T.; Sugiyama, Y.; Ohmachi, S.; Kuwabara, K.;
Murakami, K.; Todo, M. Bioorg. Med. Chem. 2008, 16, 981.
14. Imoto, H.; Sugiyama, Y.; Kimura, H.; Momose, Y. Chem. Pharm. Bull. 2003, 51,
138.
15. Brooks, D. A.; Etgen, G. J.; Rito, C. J.; Shuker, A. J.; Dominianni, S. J.;
Warshawsky, A. M.; Ardecky, R.; Paterniti, J. R.; Tyhonas, J.; Karanewsky,
D. S.; Kauffman, R. F.; Broderick, C. L.; Oldham, B. A.; Montrose-Rafizadeh,
C.; Winneroski, L. L.; Faul, M. M.; McCarthy, J. R. J. Med. Chem. 2001, 44,
2061.
and oximinobutyric acid derivatives as PPARa agonists by incorpo-
rating polymethylene spacer as a replacement of commonly used
phenylene group that connects the acidic head with lipophilic tail
as exemplified by 13a. On the other hand we also designed com-
pound 20 as PPARa/c dual agonist by replacing tetramethylene
spacer of a known compound NS-220 with phenylene group. The
above results clearly established that the spacer of polymethylene
chain of varying length between the pharmacophore and the lipo-
philic heterocycle improves selectivity of the compound towards
16. Spectroscopic analysis of the compounds 9a–c, 13a–c, and 20: 9a: {(4-methoxy-
phenoxycarbonyl)-[4-(5-methyl-2-(4-methylphenyl)oxazol-4-yl)-butyl]-
amino}acetic acid: thick liquid; yield: 96%; purity by HPLC: 99%; IR (Nujol):
3018, 2939, 1716, 1458, 1180, 761 cmÀ1
;
1H NMR (CDCl3): d 1.69–1.72 (m, 4H),
PPARa receptor compared to the compounds having phenylene
2.29 (s, 3H), 2.36 (s, 3H), 2.52–2.57 (m, 2H), 3.52–3.56 (m, 2H), 3.77 (s, 3H),
4.17 (d, J = 8.0 Hz, 2H), 6.83 (d, J = 9.0 Hz, 2H), 7.01–7.05 (m, 2H), 7.21 (d,
J = 6.4 Hz, 2H), 7.82 (d, J = 7.8 Hz, 2H); 13C NMR (100 MHz, DMSO-d6): d 9.70,
20.94, 23.68, 24.24, 24.65, 25.80, 26.66, 28.23, 47.80, 53.40, 55.31, 62.96,
113.96, 122.5, 124.69, 125.39, 129.53, 135.52, 139.61, 143.17, 145.14, 155.07,
156.16, 157.76, 158.37. ESI-S m/z: 453.1 [M+H]+; 9b: {(4-methoxy-
phenoxycarbonyl)-[5-(5-methyl-2-(4-methylphenyl)oxazol-4-yl)-pentyl]-
amino}acetic acid: white solid; mp: 140–141 °C; yield: 32%; purity by HPLC:
group as a spacer. Further work in the development of SAR of this
lead series based on 13a will be described in a subsequent
publication.
Acknowledgments
96%; IR (KBr): 2925, 1720, 1450, 1182, 827 cmÀ1 1H NMR (CDCl3): d 1.40–1.44
;
Authors are thankful to management of Zydus Cadila for the
encouragement and to analytical department for the support.
(m, 2H), 1.68–1.72 (m, 4H), 2.22 (s, 3H), 2.31 (s, 3H), 2.52 (t, J = 7.4 Hz, 2H),
3.39–3.47 (m, 2H), 3.81 (s, 3H), 4.12 (d, J = 8.0 Hz, 2H), 6.81 (d, J = 8.8 Hz, 2H),
6.97–7.04 (m, 2H), 7.21 (d, J = 8.1 Hz, 2H), 7.82 (d, J = 8.2 Hz, 2H); 13C NMR:
(100 MHz, DMSO-d6): d 9.71, 20.97, 24.90, 25.64, 27.15, 28.23, 48.48, 59.78,
114.16, 122.56, 124.71, 125.39, 129.56, 135.63, 139.64, 143.13, 144.62, 154.57,
156.48, 158.37.; ESI-S m/z: 467.3 [M+H]+; 9c: {(4-Methoxy-phenoxycarbonyl)-
[6-(5-methyl-2-(4-methylphenyl)oxazol-4-yl)-hexyl]amino}acetic acid: thick
liquid; yield: 82%; purity by HPLC: 98%; IR (Nujol): 3016, 2935, 1720, 1508,
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1199, 1180, 756 cmÀ1 1H NMR (CDCl3): d 1.41–1.45 (m, 2H), 1.59–1.63 (m,
;
6H), 2.32 (s, 3H), 2.36 (s, 3H), 2.52 (t, J = 7.3 Hz, 2H), 3.48–3.52 (m, 2H), 3.72 (s,
3H), 4.12 (d, J = 12.5 Hz, 2H), 6.81 (d, J = 8.1 Hz, 2H), 7.01–7.06 (m, 2H), 7.22 (d,
J = 7.9 Hz, 2H), 7.91 (d, J = 8.0 Hz, 2H); 13C NMR: (100 MHz, DMSO-d6): d 9.69,
20.93, 24.93, 26.10, 27.25, 27.69, 28.42, 48.16, 50.22, 55.30, 113.90, 114.08,
122.45, 122.84, 124.70, 125.35, 129.49, 135.69, 139.57, 142.95, 145.03, 154.44,
154.82, 156.23, 158.32.; ESI-S m/z: 481.3 [M+H]+; 13a: 4-[4-(5-methyl-2-(4-
methylphenyl)oxazol-4-yl)-butoxyimino]-4-phenylbutyric acid: white solid;
mp: 102–104 °C; yield: 85%; purity by HPLC: 99%; IR (KBr): 3429, 2922, 1649,
1596, 1577, 1307, 1265, 1147 cmÀ1 1H NMR (CDCl3): d 1.76–1.82 (bm, 4H),
;
2.31 (s, 3H), 2.36 (s, 3H), 2.47–2.54 (m, 4H), 3.17 (t, J = 6.8 Hz,2H), 4.26 (bt, 2H),
7.21 (d, J = 8.0 Hz, 2H), 7.32–7.38 (m, 3H), 7.60–7.66 (m, 2H), 7.84 (d, J = 8.0 Hz,
2H).; 13C NMR (100 MHz, DMSO-d6): d 9.94, 20.93, 21.93, 24.76, 24.97, 28.49,
30.46, 73.41, 124.75, 125.39, 126.08, 128.44, 129.08, 129.46, 135.00, 135.57,
139.81, 143.09, 154.93, 158.40, 173.51; ESI-MS m/z: 421.2 [M+H]+; 13b: 4-[5-
(5-methyl-2-(4-methylphenyl)oxazol-4-yl)-pentyloxyimino]-4-phenylbutyric
acid: off white solid; mp: 91–93 °C; yield: 86%; purity by HPLC: 97%; IR (KBr):
´
J. A.; Brooks, D. A.; Prieto, L.; Gonzalez, R.; Torrado, A.; Rojo, I.; Uralde, B. L.;
Lamas, C.; Ferritto, R.; Martın-Ortega, M. D.; Agejas, J.; Parra, F.; Rizzo, J. R.;
Rhodes, G. A.; Robey, R. L.; Alt, C. A.; Wendel, S. R.; Zhang, T. Y.; Reifel-Miller, A.;
Montrose-Rafizadeh, C.; Brozinick, J. T.; Hawkins, E.; Misener, E. A.; Briere, D.
A.; Ardecky, R.; Fraserd, J. D.; Warshawsky, A. M. Bioorg. Med. Chem. Lett. 2005,
15, 51; (c) Lu, Y.; Guo, Z.; Guo, Y.; Feng, J.; Chu, F. Bioorg. Med. Chem. Lett. 2006,
16, 915; (d) Das, S. K.; Reddy, K. A.; Abbineni, C.; Iqbal, J.; Suresh, J.; Premkumar,
M.; Chakrabarthi, R. Bioorg. Med. Chem. Lett. 2003, 13, 399; (e) Madhavan, G. R.;
Chakrabarthi, R.; Reddy, K. A.; Rajesh, B. M.; Balaraju, V.; Rao, P. B.; Rajagopalan,
R.; Iqbal, J. Bioorg. Med. Chem. 2006, 14, 584.
3413, 2931, 1718, 1500, 1269, 1163, 732 cmÀ1 1H NMR (CDCl3): d 1.47–1.54
;
(m, 2H), 1.64–1.69 (m, 2H), 1.72–1.79 (m, 2H), 2.30 (s, 3H), 2.36 (s, 3H), 2.52 (t,
J = 7.5 Hz, 2H), 2.58 (t, J = 7.5 Hz, 2H), 3.11 (t, J = 7.5 Hz, 2H), 4.20 (t, J = 6.0 Hz,
2H), 7.22 (d, J = 8.1 Hz, 2H), 7.34–7.36 (m, 3H), 7.60–7.63 (m, 2H), 7.85 (d,
J = 8.1 Hz, 2H); 13C NMR (100 MHz, DMSO-d6): d 9.67, 20.92, 21.90, 24.90,
28.25, 28.56, 30.40, 73.55, 124.72, 125.36, 126.05, 128.40, 129.08, 129.47,
133.88, 134.97, 135.61, 139.54, 143.02, 156.33, 158.36, 173.33; ESI-MS m/z:
6. Henke, B. R.; Blanchard, S. G.; Brackeen, M. F.; Brown, K. K.; Cobb, J. E.; Collins, J.
L., ; Harrington, W. W., Jr.; Hashim, M. A.; Hull-Ryde, E. A.; Kaldor, I.; Kliewer, S.
A.; Lake, D. H.; Leesnitzer, L. M.; Lehmann, J. M.; Lenhard, J. M.; Orband-Miller,
L. A.; Miller, J. F.; Mook, R. A.; Noble, S. A.; Oliver, W.; Parks, D. J.; Plunket, K. D.;
Szewczyk, J. R.; Willson, T. M. J. Med. Chem. 1998, 41, 5020.
7. Lohray, B. B.; Lohray, V. B.; Bajji, A. C.; Kalchar, S.; Poondra, R. R.; Padakanti, S.;
Chakrabarti, R.; Vikramadithyan, R. K.; Misra, P.; Juluri, S.; Mamidi, N. V. S. R.;
Rajagopalan, R. J. Med. Chem. 2001, 44, 2675.
435.1
[M+H]+;
13c:
4-[6-(5-methyl-2-(4-methylphenyl)oxazol-4-yl)-
hexyloxyimino]-4-phenyl-butyric acid: white solid; mp: 79–81 °C; yield:
63%; purity by HPLC: 99%; IR (KBr): 3020, 1714, 1625, 1402, 1217, 771 cmÀ1
;
1H NMR (CDCl3): d 1.43–1.45 (m, 2H), 1.59–1.64 (m, 4H), 1.71–1.74 (m, 2H),
2.31 (s, 3H), 2.38 (s, 3H), 2.53 (t, J = 7.5 Hz, 2H), 2.64 (t, J = 7.5 Hz, 2H), 3.09 (t,
J = 7.4 Hz, 2H), 4.22 (t, J = 5.7 Hz, 2H), 7.21–7.25 (m, 2H), 7.35–7.37 (m, 3H),
7.61–7.63 (m, 2H), 7.85 (d, J = 8.1 Hz, 2H); 13C NMR (100 MHz, DMSO-d6): d
9.65, 20.89, 21.86, 24.84, 25.18, 28.26, 28.65, 73.56, 124.70, 125.32, 126.02,
128.40, 129.04, 129.44, 134.95, 135.67, 139.51, 142.94, 156.29, 158.29, 173.27;
8. Hegarty, B. D.; Furler, S. M.; Oakes, N. D.; Kraegen, E. W.; Cooney, G. J.
Endocrinology 2004, 145, 3158.
9. Devasthale, P. V.; Chen, S.; Jeon, Y.; Qu, F.; Shao, C.; Wang, W.; Zhang, H.; Cap,
M.; Farrelly, D.; Golla, R.; Grover, G.; Harrity, T.; Ma, Z.; Moore, L.; Ren, J.;
Seethala, R.; Cheng, L.; Sleph, P.; Sun, W.; Tieman, A.; Wetterau, J. R.; Doweyko,
A.; Chandrasena, G.; Chang, S. Y.; Humphreys, W. G.; Sasseville, V. G.; Biller, S.
A.; Ryono, D. E.; Selan, F.; Hariharan, N.; Cheng, P. T. W. J. Med. Chem. 2004, 48,
2248.
ESI-MS
m/z:
449.1
[M+H]+;
20:
2-methyl-c-5-[4-(5-methyl-2-(4-
methylphenyl)oxazol-4-ylmethoxy)benzyl]-1,3 dioxane-r-2-carboxylic acid:
white solid; mp: 197–198 °C; yield: 95%; purity by HPLC: 99%; IR (KBr):
2929, 1759, 1610, 1502,1286, 1226, 1182, 827 cmÀ1 1H NMR (DMSO-d6): d
;
1.32 (s, 3H), 2.09–2.13 (m, 1H), 2.27 (d, J = 6.9 Hz, 2H), 2.36 (s, 3H), 2.42 (s, 3H),
3.42 (t, J = 11.4 Hz, 2H), 3.69–3.74 (dd, J = 11.6 and 4.1 Hz, 2H), 4.94 (s, 2H),
6.94 (d, J = 8.4 Hz, 2H), 7.11 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 8.1 Hz, 2H), 7.83 (d,
J = 8.1 Hz, 2H); 13C NMR (DMSO-d6): d 9.93, 20.96, 25.52, 32.87, 34.86, 61.38,
67.07, 97.56, 114.64, 124.24, 125.57, 129.62, 130.58, 131.85, 140.15, 146.95,
156.65, 158.98, 171.31; ESI-MS m/z: 438.4 [M+H]+.
10. (a) Guerre-Millo, M.; Gervois, P.; Raspe, E.; Madsen, L.; Poulain, P.; Derudas, B.;
Herbert, J.; Winegar, D.; Willson, T.; Fruchart, J.; Staels, B. J. Biol. Chem. 2000,
275, 16638; (b) Ye, J.; Doyle, P.; Iglesias, M.; Watson, D.; Cooney, G.; Kraegen, E.
Diabetes 2001, 50, 411.
11. (a) Lohray, B. B.; Bhushan, V.; Reddy, A. S.; Rao, P. B.; Reddy, N. J.; Harikishore,
P.; Vikramadityan, R. K.; Chakrabarti, R.; Rajagopalan, R.; Katneni, K. J. Med.
Chem. 1999, 42, 2569; (b) Reddy, K. A.; Lohray, B. B.; Bhushan, V.; Reddy, A. S.;
Harikishore, P.; Rao, V. V.; Saibaba, V.; Bajji, A. C.; Rajesh, B. M.; Reddy, K. V.;
Chakrabarti, R.; Rajagopalan, R. Bioorg. Med. Chem. Lett. 1998, 8, 999; (c) Tudor,
17. Xu, H. E.; Lambert, M. H.; Montana, V. G.; Plunket, K. D.; Moore, L. B.; Collins, J.
L.; Oplinger, J. A.; Kliewer, S. A.; Gampe, R. T.; McKee, D. D.; Moore, J. T.;
Willson, T. M. Proc. Natl. Acad. U.S.A. 2001, 98, 13919.