Revisiting glitazars: Thiophene substituted oxazole containing α-ethoxy phenylpropanoic acid derivatives as highly potent PPARα/γ dual agonists devoid of adverse effects in rodents

Article abstract of DOI:10.1016/j.bmcl.2011.03.020

In an effort to develop safe and efficacious compounds for the treatment of metabolic disorders, novel thiophene substituted oxazole containing α-alkoxy-phenylpropanoic acid derivatives are designed as highly potent PPARα/γ dual agonists. These compounds were found to be efficacious at picomolar concentrations. Lead compound 18d has emerged as very potent PPARα/γ dual agonist demonstrating potent antidiabetic and lipid lowering activity at a very low dose and did not exhibit any significant signs of toxicity in rodents.

Full text of DOI:10.1016/j.bmcl.2011.03.020

Bioorganic & Medicinal Chemistry Letters 21 (2011) 3103–3109
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Revisiting glitazars: Thiophene substituted oxazole containing
a-ethoxy
phenylpropanoic acid derivatives as highly potent PPAR
a/c dual agonists
devoid of adverse effects in rodents q
Preeti Raval a,b, , Mukul Jain a, Amitgiri Goswami a, Sujay Basu a, Archana Gite a, Atul Godha a,
Harikishore Pingali a, Saurin Raval a, Suresh Giri a, Dinesh Suthar a, Maanan Shah a, Pankaj Patel a
⇑
a Zydus Research Centre, Sarkhej-Bavla N.H 8A Moraiya, Ahmedabad 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:
In an effort to develop safe and efficacious compounds for the treatment of metabolic disorders, novel
Received 19 August 2010
Revised 17 February 2011
Accepted 7 March 2011
Available online 11 March 2011
thiophene substituted oxazole containing
highly potent PPAR dual agonists. These compounds were found to be efficacious at picomolar con-
centrations. Lead compound 18d has emerged as very potent PPAR dual agonist demonstrating potent
a-alkoxy-phenylpropanoic acid derivatives are designed as
a/c
a/c
antidiabetic and lipid lowering activity at a very low dose and did not exhibit any significant signs of tox-
icity in rodents.
Keywords:
Ó 2011 Elsevier Ltd. All rights reserved.
Metabolic syndrome
PPAR
Oxazole
Type 2 diabetes
a/c dual agonist
Last decade and a half had witnessed a rapid advancement in
the biological roles of Peroxisome proliferator-activated receptors
(PPARs) in metabolic syndrome, a cluster of disturbance of glucose
& lipid metabolism and tremendous efforts towards the develop-
ment of PPAR ligands for the treatment of this complex syndrome.
Hyperglycemia, dyslipidemia and obesity are the major manifesta-
tions of metabolic syndrome and these abnormalities individually
or in combination can lead to a high risk of developing type 2 dia-
betes and cardiovascular desease.1
However treatment with glitazones is associated with adverse ef-
fects such as weight gain and edema whereas fibrates are poor acti-
vators of PPARa and high dose is needed to be administered to exert
therapeutic effect. As the metabolic syndrome is associated with
defects in glucose as well as lipid metabolism, the concept of discov-
ering dual agonists, which can activate both PPARa and PPARc
simultaneously has emerged as a fascinating target by a logical
hypothesis that these dual agonists may not only control both
glucose and lipid levels but also mitigate the weight gain induced
Peroxisome proliferator-activated receptors (PPAR) are members
of group of nuclear receptor super family and till date three sub-
by PPAR
addition to their hypolipidemic effects, reduce body weight gain in
rodents without affecting food intake.7 Several PPAR
dual ago-
c activation based on the observation that fibrates in
types (PPAR
including humans. The distinct tissue distribution and physiological
roles of PPARs are well documented.2 PPAR
mainly controls the
expression of genes involved in b-oxidation of fatty acids3 and acti-
vation of PPAR with endogenous or synthetic ligands reduces tri-
glycerides (TG) and elevates high density lipoprotein cholesterol
a,
c
, and d) are identified and cloned in several species
a/c
nists, commonly termed as glitazars (Fig. 1) were developed by
a
many pharmaceutical companies.
As reported by Agnes et al.8 typical PPAR agonists have follow-
ing skeleton (Fig. 2).
a
Oxazole group as lipophilic tail and
acidic pharmacophore are extensively studied during the develop-
ment of PPAR agonists. Few PPAR dual agonists containing oxa-
zole group as lipophilic tail and non- -alkoxy carboxylic acid
a-alkoxy carboxylic acid as
(HDL-c) levels. Activation of PPARc is known to improve insulin sen-
sitivity and thereby control glucose homeostasis.4 Two classes of
compounds namely thiazolidinediones (popularly known as glitaz-
ones, e.g., Rosiglitazone and Pioglitazone) (Fig. 1) as antidiabetic
agents5 and fibrates as antihyperlipedimic agents6 (Fig. 1) are
a/c
a
group as acidic head have been advanced to clinical trials, for
example, Imiglitazar 1, muraglitazar 2, Farglitazar 3 (Fig. 3) and
several other compounds having oxazoles as cyclic tail are also re-
currently marketed and are PPARc and a agonists, respectively.
ported to be potent dual agonists.9 Further non oxazole
a-Alkoxy
carboxylic acid derivatives like Tesaglitazar (4) and Naveglitazar
(5) (Fig. 3) have proven to be efficacious in animal models and in
humans.10
q
ZRC Communication # 315.
Corresponding author. Tel.: +91 2717 665555; fax: +91 2717 250606.
E-mail address: preetiraval@zyduscadila.com (P. Raval).
⇑
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.03.020

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P. Raval et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3103–3109
PPAR agonists
α
O
COOEt
O
Cl
O
O
Cl
Clofibrate
O
Fenofibrate
O
COOH
O
N
H
Cl
Bezafibrate
PPAR agonists
γ
Et
S
S
O
O
NH
N
N
N
NH
O
O
O
O
S
Rosiglitazone
Pioglitazone
/
PPAR
dual agonists
α γ
O
O
COOH
OEt
O
N
NH
O
H
MeO
N
O
F3C
KRP-297
Ragaglitazar
Figure 1. Structure of PPAR agonists.
cal development due to carcinogenicity in rodent toxicity models
and elevated serum creatinine & associated decrease in glomer-
ular filtration rate, respectively. The only dual agonist that has
been advanced to NDA filing, Muraglitazar15 was also dropped
very recently due to the higher incidence of edema, heart failure
and cardiovascular deaths amongst the patients taking muraglit-
azar compared with those receiving placebo or treated with
Pioglitazone.16 These facts though appears to be discouraging
to the scientists engaged in the development of PPAR agonists,
the fact that the reasons for the failure of all these compounds
are quite different from each other has left a ray of hope of
developing new agents with modifications in these compounds
in order to develop efficacious and relatively safer PPAR agonists
as the medical need for metabolic disorders is largely remain
unmet.
Acid
Componant
Aromatic
Center
Linker
Linker
Tail
Figure 2. Common structural features of PPAR agonists.
In addition to this
a-alkoxy arylpropanoic acids containing 2-
phenyloxazole-4ylalkyl moiety are also reported to be potent
dual agonists.11 But none of the fore mentioned dual agonists
has been marketed. The first dual agonist Farglitazar12 which is
a potent PPAR
dropped in an advanced stage due to the emergence of edema.
Two more dual agonists with substantial PPAR activity Rag-
aglitazar13 and Tesaglitazar14 were also dropped from late clini-
c agonist with a moderate PPARa activation was
a/c
N
Ph
O
MsO
COOEt
OEt
N
O
Ph
O
COOH
O
Imiglitazar 1
Tesaglitazar 4
PhO
OMe
O
COOEt
OEt
O
N
O
O
O
Ph
N
O
COOH
Naveglitazar 5
Muraglitazar 2
COOH
O
Ph
HN
N
O
O
Farglitazar 3
Figure 3. PPARa/c dual agonists containing oxazole and a-alkoxy carboxylic acid groups.

P. Raval et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3103–3109
3105
O
O
OH
OH
OEt
OEt
N
N
O
n
R
O
n
S
O
O
n=1,2 n=1,2
Figure 4. Designing PPARa/c agonists containing thiophene substituted oxazole.
As a part of our research endeavor on PPARs17 to develop effi-
cacious and safe dual agonists, we hypothesized that administra-
tion of very low dose of potent compounds would probably a
practical approach to minimise at least some of the adverse ef-
fects as these adverse effects exerted by this class of compounds
are dose dependent. Our next goal obviously was to discover the
compounds with very high invitro potency that translates to invi-
Two sets of thiophene substituted oxazole containing
acid derivatives12a–e and 18a–e are reported as dual PPARa/c
a
-alkoxy
agonists. Compounds 12a–e contain methylene spacer between
aromatic center and cyclic tail where as compounds 18a–e repre-
sent corresponding analogues containing ethylene spacer (Fig. 4).
Synthetic route to compounds 12a–e is outlined in Scheme 1.
Synthesis of intermediate 9 was accomplished in two steps follow-
ing the reported method.18 Benzaldehydes 6 were reacted with
diacetyl mono-oxime 7 in acetic acid in presence of dry HCl (gas)
to afford N-Oxides 8. Treatment of 8 with POCl3 gave the corre-
sponding chloromethyl oxazole 9. Nucleophilic substitution of 9
with (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)propanoate 1019
using K2CO3 as base in DMF afforded precursor esters 11. Hydroly-
sis of these ester compounds 11 under aqueous basic conditions
yielded final acid derivatives 12a–e.
vo efficacy. In order to achieve this 2-phenyloxazole containing
a
alkoxyphenylpropanoic acid derivative (Fig. 4) was chosen as
chemical lead and we initially intended to study the effect of sub-
stitution on oxazole at 2-position and we eventually found by
molecular modeling analysis (data not shown) that thiophene is
the best fit. In the present Letter, we report few thiophene
substituted oxazole containing
a-alkoxyphenylpropanoic acid
derivatives as potent PPAR dual agonists and established our
a/c
hypothesis of administering low dose of a potent dual agonist
would minimize the adverse effects.
The synthesis of compounds 18a–e is outlined in Scheme 2.
Intermediate mesylate derivatives 16 were prepared from their
O
O
R
O
O
6
O
b
a
OEt
R
+
+
Cl
N
N
OEt
OH
R
H
O
HO
N
OH
10
9
8
7
O
O
OEt
d
c
OEt
N
OEt
N
O
O
R
R
O
O
12 a-e
11
Scheme 1. Reagents and conditions: (a) AcOH/HCl gas, 0 °C, 1 h, 20–25%; (b) POCl3, dichloroethane, reflux, 14 h, 50–70%; (c) K2CO3, DMF, 80–90 °C, 2 h, 40–50%; (d) NaOH/
MeOH–H2O, 20–25 °C, 16 h, 60–80%.
O
N
O
N
O
N
c
O
N
a
b
R
R
R
R
COOMe
Cl
CN
OH
9
13
14
15
O
O
O
N
O
e
OEt
d
+
OEt
R
R
N
OEt
OEt
O
OMs
HO
16
10
17
O
O
f
OH
R
OEt
N
O
18 a-e
Scheme 2. Reagents and conditions: (a) NaCN, DMF, 25–30 °C, 4 h, 80–90%; (b) MeOH, H2SO4, catalytic H2O, reflux, 16 h, 60–70%; (c) LAH, THF, 0–10 °C, 70–80%; (d) MeSO2Cl,
NEt3, CH2Cl2, 25 °C, 2 h, 85–90%; (e) K2CO3, DMF, 80–90 °C, 2 h, 40–50%; (f) NaOH/MeOH–H2O, 20–25 °C, 16 h, 60–70%.

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P. Raval et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3103–3109
Table 1
In vitro hPPAR transactivation and TG lowering activity of compounds 12a–e and 18a–e
O
OH
OEt
N
O
n
R
O
12 a-e (n=1)
18 a-e (n=2)
Compd
R
hPPAR trans activationa
EC50 (nM) (%max)b EC50 (nM) (%max)b
% Change TGc
a
c
12a
12b
0.026 (134)
3 (147)
0.0015 (107)
2.7 (99)
À72
À70
S
S
S
12c
12d
0.00006 (106)
0.00005 (151)
0.0003 (88)
À72
À69
0.0002 (120)
S
S
12e
20 (93)
3 (104)
À57
18a
18b
0.1 (126)
1.9 (114)
0.05 (104)
0.6 (87)
À78
À62
S
S
S
18c
18d
0.00007 (96)
0.0001 (192)
0.018 (165)
À67
À88
0.00031 (116)
S
S
18e
22
4.5
À62
WY-14643
Rosiglitazone
4800 (100)
ND
ND
50 (100)
ND
ND
a
HepG2 cells transfected with pSG5 expression vector containing the cDNA of hPPARa or hPPARc or hPPARd and cotransfected with PPRE3-TK-luc. The Luciferase activity
determined using commercial fire-fly luciferase assay and b-galactosidase activity determined in ELISA reader. None of the compound showed activation above basal level
against PPARd.
b
Percent of maximal efficacy (%max) of all compounds compared to reference compounds (WY-14643 for
a
and Rosiglitazone for
The test compounds were administered orally at a dose of 10 mg/kg/day to male swissalbino mice (SAM) of 6–8 weeks of age for 6 days. Mean values (n = 6) are the %
change in serum triglyceride (TG) concentration of the compound-treated mice versus vehicle controls. All values are the mean of n = 6. ND denotes not determined.
c) normalized to 100%.
c
corresponding lower homologues 9 in four steps. Chloromethyl
oxazoles 9 were converted to corresponding cyano derivatives 13
using NaCN in DMF at ambient temperature in good yields. Cyano
derivatives 13 were refluxed in a mixture of methanol, sulfuric acid
and water (catalytic amount) to yield corresponding esters 14
which were then reduced to alcohols 15 using LiAlH4 . Alcohols
15 were converted to corresponding mesylates 16. Coupling of
16 with (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)propanoate as
shown in Scheme 1 afforded ester compounds 17. Aqueous basic
hydrolysis of 17 gave the corresponding acids 18. The structure
of all the final compounds and intermediates are confirmed by
their and spectral analysis and are found to be in conformity with
the structures assigned.
tor transfected HEPG2 cells as per the procedure described in our
earlier publication.21 WY14643, Rosiglitazone and GW501516
were used as control for PPARa, c and d, respectively. In vitro
transactivation activities and triglyceride (TG) lowering potential
of compounds 12 and 18 are presented in Table 1. In general
in vitro potency of all the test compounds are in the range of low
nM to pM and subtype selectivity ranges between 1- and 15-folds.
The initial compound 12a possessing unsubstituted thiophene
linked through 2nd position to oxazole showed 26 and 1.5 pM po-
tency towards PPAR
a and c, respectively, whereas its higher
homologue 18a is found detrimental in terms of in vitro potency
as compared to 12a. Both the compounds demonstrated significant
TG lowering effect. When the linkage of thiophene was changed to
3rd position, resulting compounds 12b and 18b showed relatively
poor in vitro potency but still exhibited comparable TG reduction
All the compounds synthesized20 were screened for human
PPARa, PPARc and PPARd transactivation assay using hPPAR recep-

P. Raval et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3103–3109
3107
Table 2
In vivo glucose lowering effect of 12d and 18d in db/db micea
270
250
230
210
190
170
Compd
Dose (mg/kg/day)
% change in glucosea
12d
18d
Tesaglitazar
3
3
3
À67
À72
À55
a
Male db/db mice of 6–8 weeks old were dosed with test compounds daily for
6 days and Plasma glucose, triglycerides were measured. Values reported are %
change of compound-treated mice versus vehicle controls.
Control
3 mg/kg
30 mg/kg
to their 2nd position analogues 12a and 18a. These results indicate
that linkage of thiophene through its 2nd position is favorable over
3rd position. Then we intended to substitute 3rd & 5th position of
thiophene and synthesized compounds 12c–e and 18c–e. Com-
pound 12c bearing methyl group at 3rd position of thiophene
Day 1
Week 1
Week 2
Week 3
Week 4
showed remarkable increase in potency (0.06 pM for
a and
Figure 5. Body weight values of male Wistar rats treated with 18d for 28 days.
0.3 pM for ) and also reduced TG by 72%. When the methyl group
c
was introduced at 5th position of thiophene, the resulting com-
pound 12d demonstrated similar in vitro potency as well as TG
lowering effect. When chain length of the spacer of 12c was in-
creased to ethylene group the resulting compound 18c showed
similar profile as exhibited by 12c. But compound 18d which is
higher homologue of 12d though showed marginally inferior PPAR
potency as compared to 12d, demonstrated 88% of TG reduction
and emerged as a lead compound in the series. To know the effect
of bulkier substituent, we have introduced phenyl group at 5th po-
sition of thiophene and synthesized compounds 12e and 18e. Both
the compounds are found detrimental in terms of in vitro potency
with respect to other compounds of the series. Based on in vitro
activity and TG lowering results, compound 18d and its methylene
analogue 12d were selected for further in vivo evaluation.
Compounds 12d and 18d were subjected for glucose lowering
effect in db/db mice and the results are summarized in Table 2.
Compounds 12d and 18d produced excellent glucose reduction of
67% and 72%, respectively, when dosed orally at 3 mg/kg/day dose.
Finally 18d is selected as the lead compound of the series and its
pharmacokinetic parameters were determined (Table 3) where this
200
190
180
170
160
Control
150
3 mg/kg
140
30 mg/kg
130
Day 1
Week 1
Week 2
Week 3
Week 4
Figure 6. Body weight values of female Wistar rats treated with 18d for 28 days.
ED50 was found to be 0.01 mg/kg. In db/db mice the ED50 values
for the reduction of PG and TG were 0.1657 and 0.0188 mg/kg,
respectively.
compound exhibited excellent profile with a Cmax of 91.7
l
g/mL
and 455.8 h
lg/mL of AUC. This compound exhibited extended
T1/2 of 7.4 h.
Having achieved the primary goal of identifying potent and effi-
Subsequently 18d was then evaluated for its dose dependent
hypolipidemic and anti-hyperglycemic activity in swissalbino mice
(SAM) and db/db mice and the data is presented in Table 4. In SAM
model 18d reduced TG by 41.5% at a dose of 0.003 mg/kg and the
cacious PPARa/c dual agonist, our next end point of this endeavor
is to study the toxicity profile of the lead compound 18d. Oral
acute toxicity of this molecule was studied in male and female wis-
tar rats at 3, 30 mg/kg for 28 days. 15x and 150x doses were se-
Table 3
Mean pharmacokinetic parametersa of 18d in fasted male Wistar rat
Compd
Route
Oral
Dose (mg/kg)
30
Tmax (h)
Cmax
(
lg/mL)
T1/2 (h)
AUC(0–
a) (h lg/mL)
18d
0.667
91.7
7.4
455.8
a
Values indicate mean SD for n = 3.
Table 4
Dose dependent effect of 18d on TG and PG in SAM and db/db mice
Dose (mg/kg)
SAM
db/db
ED50 (mg/kg)
0.1657
% change in TG
ED50 (mg/kg)
0.01
% change in PG
% change in TG
ED50
0.003
0.01
0.03
0.1
0.3
1
À41.5
À61.9
À65.6
À71.8
À80.8
À82.0
À83.1
À47.1
À52.7
À52.1
À51.7
À58.2
À59.7
À62.2
À7.2
À6.6
0.0188
À25.9
À49.4
À51.8
À64.2
À55.1
3

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P. Raval et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3103–3109
Table 5
Relative organ weightsa of wistar rats administered orally with 18d for 28 days
Dose
(mg/
kg)
Heart
Liver
Kidney
Spleen
Adrenal
Brain
Testes
Epididymine
Thymus
% change
in body
wt.
Males
Control 0.383 0.012 3.257 0.069 0.745 0.012 0.215 0.007 0.018 0.001 0.658 0.015 1.075 0.106 0.391 0.017 0.081 0.013 38.25
3
30
0.412 0.006 7.505 0.151 0.807 0.007 0.223 0.004 0.015 0.001 0.720 0.024 1.152 0.033 0.360 0.018 0.089 0.013 33.99
0.479 0.007 8.099 0.124 0.955 0.024 0.252 0.005 0.018 0.001 0.757 0.021 1.356 0.043 0.432 0.016 0.075 0.008 24.01
Females
Ovary
Uterus
Control 0.403 0.010 3.091 0.087 0.733 0.007 0.237 0.012 0.028 0.001 0.970 0.023 0.039 0.005 0.233 0.041 0.094 0.01
11.13
0.460 0.010 6.221 0.165 0.804 0.024 0.257 0.024 0.020 0.001 0.947 0.034 0.020 0.002 0.176 0.011 0.101 0.013 21.77
0.501 0.009 7.075 0.314 0.915 0.037 0.260 0.011 0.022 0.001 0.939 0.050 0.024 0.002 0.189 0.029 0.066 0.005 21.71
3
30
a
Presented as organ-to-body weight percent ratio.
Table 6
Biochemical parameters of wistar rats administered orally with 18d for 28 days
Dose (mg/kg)
HGB (g/dl)
Glu (mg/dl)
CREA (mg/dl)
ALP (U/L)
SGOT (U/L)
SGPT (U/L)
ALB (g.dl)
Urea (mg/dl)
Males
Control
3
13.66 0.23
12.20 0.18
12.46 0.21
70 3.49
75.74 2.65
83.28 2.90
0.47 0.03
0.36 0.04
0.37 0.02
243.88 20.34
470.50 23.93
679.13 59.03
135.14 6.89
193.51 9.76
245.24 26.13
34.24 2.13
28.54 0.89
33.03 3.19
3.66 0.10
3.91 0.15
4.12 0.10
30.52 0.79
31.24 1.19
34.58 1.14
30
Females
Control
3
11.90 0.19
11.84 0.18
11.83 0.19
69.94 2.30
91.88 5.71
91.79 9.14
0.42 0.04
0.36 .03
0.41 0.03
172.38 7.18
248.13 18.00
248.38 32.75
155.70 6.56
157.09 10.32
224 41.94
30.44 1.59
22.46 0.77
35.21 4.41
3.92 0.18
4.03 0.10
4.12 0.12
33.05 2.02
29.19 1.48
37.39 7.93
30
lected based on the ED50 (considering as ꢀ0.2 mg) values in SAM
and db/db mice. There were no significant treatment related clini-
cal manifestations noted in any of the treated group animals and
there was no treatment related mortality occurred. Food consump-
tion was comparable to that of control groups throughout the
study period in both the treated groups of both male and female
animals. Animals were sacrificed on day 29 and data analysis of
blood biochemical parameters, organ weight ratios and histopa-
thological findings.
even at 150 times higher dose than ED50 value. The evaluation of
the toxicity of this molecule in non-rodent species will be carried
out and the results will be published subsequently.
In summary we have designed a series of highly potent and effi-
cacious PPARa/c dual agonists and the lead candidate 18d showed
excellent anti-hyperglycemic, hypolipidemic effects than Rosiglit-
azone and Tesaglitazar. Further evaluation of the lead compound
for its toxicity profile in rodents was encouraging the further
development of this compound for the treatment of metabolic
syndrome.
Body weights were recorded weekly and the data is presented
in Figure 5 (male) and Figure 6 (female). No increase in body
weight was observed due to compound treatment in male animals
while in female animals an increase in body weight was observed
till week 3 and thereafter marginal decrease was observed by the
end of the treatment. These results clearly indicate that 18d does
not cause significant weight gain, the main side effect of PPAR class
of compounds even at a dose of 15x and 150x of ED50 values. Anal-
ysis of organ to body weight ratios (Table 5) did not show evidence
of toxicity attributed to compound treatment at least at 3 mg/kg
dose, which is 15x of ED50, except the liver weights. The results
clearly indicate the hepatomegaly (liver enlargement) in both male
and female animals treated with 18d at 3 and 30 mg/kg. However
it is well established by now that this phenomenon is specific to ro-
dents and the literature precedence clearly established that such
an effect does not occur in non-rodents.22 There was marginal in-
crease (7%) in heart weight at 3 mg dose and significant increase
(25%) at 30 mg dose which is 150 times of ED50 was observed, Sim-
ilarly no significant alterations were observed in biochemical
parameters (Table 6) except the increase in liver enzymes (ALP,
SGOT, SGPT) which are in correlation with rodent specific hepato-
megaly. No significant changes were observed in hemoglobin,
albumin urea and creatinine at 3 mg/kg while at 30 mg/kg dose
an increase in urea levels was observed. More interestingly a mar-
ginal decrease in creatinine was observed at both the doses in male
and female animals, while elevation of creatinine is common side
effect of PPAR agonists. These results clearly indicate that treat-
ment with 18d in rodents did not exert any significant side effects
Acknowledgments
Authors are thankful to Pankaj Makadia for his help in prepar-
ing the manuscript, management of the Zydus Group for encour-
agement and the analytical department for support.
References and notes
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J = 8.5 Hz, 2H), 7.35–7.38 (m, 1H), 7.59–7.61 (m, 1H), 7.91–7.92 (m, 1H); ESI-
MS: 387; 12c: (S)-2-ethoxy-3-(4-((5-methyl-2-(3-methylthiophen-2-
yl)oxazol-4-yl)methoxy)phenyl) propanoic acid: 1H NMR (300 MHz, CDCl3): d
1.16 (t, J = 7.0 Hz, 3H), 2.4 (s, 3H), 2.57 (s, 3H), 2.90–2.98 (m, 1H), 3.05–3.10 (m,
1H), 3.41–3.46 (m, 1H), 3.58–3.61 (m, 1H), 4.02–4.13 (m, 1H), 4.95 (s, 2H), 6.9
(d, J = 5.0 Hz, 1H), 6.94 (d, J = 8.6 Hz, 2H), 7.18 (d, J = 8.5 Hz, 2H), 7.27 (d,
J = 4.9 Hz, 1H); ESI-MS: 401; 12d: (S)-2-ethoxy-3-(4-((5-methyl-2-(5-
methylthiophen-2-yl)oxazol-4-yl)methoxy)phenyl) propanoic acid: 1H NMR
(300 MHz, CDCl3): d 1.16 (t, J = 7.0 Hz, 3H), 2.38 (s, 3H), 2.51 (s, 3H), 2.90–2.97
(m, 1H), 3.03–3.09 (m, 1H), 3.38–3.43 (m, 1H), 3.57–3.62 (m, 1H), 4.00–4.04
(m, 1H), 4.92 (s, 2H), 6.73–6.75 (m, 1H), 6.92 (d, J = 8.6 Hz, 2H), 7.18 (d,
J = 8.6 Hz, 2H), 7.44 (d, J = 3.6 Hz, 1H); ESI-MS: 401; 12e: (S)-2-ethoxy-3-(4-
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((5-methyl-2-(5-phenylthiophen-2-yl)
oxazol-4-yl)methoxy)phenyl)
propanoic acid: 1H NMR (300 MHz, CDCl3): d 1.16 (t, J = 7.0 Hz, 3H), 2.41 (s,
3H), 2.96 (d, J = 6.7 Hz, 2H), 3.32–3.63 (m, 2H), 3.97 (t, J = 6.7 Hz, 1H), 4.95 (s,
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J = 3.9 Hz, 1H), 7.63 (d, J = 7.14 Hz, 2H); ESI-MS: 463; 18a: (S)-2-ethoxy-3-(4-
(2-(5-methyl-2-(thiophen-2-yl)oxazol-4-yl)ethoxy)phenyl)propanoic acid: 1H
NMR (300 MHz, CDCl3): d 1.17 (t, J = 7.0 Hz, 3H), 2.35 (s, 3H), 2.92–2.97 (m,
1H), 2.95 (t, J = 6.6 Hz, 2H), 3.04–3.09 (m, 1H), 3.41–3.47 (m, 1H), 3.55–3.60 (m,
1H), 4.01–4.05 (m, 1H), 4.18 (t, J = 6.6 Hz, 2H), 6.81 (d, J = 8.6 Hz, 2H), 7.06–7.09
(m, 1H), 7.13 (d, J = 8.4 Hz, 2H), 7.37 (dd, J = 4.2 Hz, 1H), 7.48 (m, 1H); ESI-MS:
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401; 18b
:
(S)-2-ethoxy-3-(4-(2-(5-methyl-2-(thiophen-3-yl)oxazol-4-
1.15 (t,
yl)ethoxy) phenyl)propanoic acid: 1H NMR (300 MHz, CDCl3):
d
15. Devasthale, P. V.; Chen, S.; Jeon, Y.; Qu, F.; Shao, C.; Wang, W.; Zhang, H.; Cap,
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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.
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WO2003009841.
J = 7.0 Hz, 3H), 2.34 (s, 3H), 2.89–3.08 (m, 4H), 3.40–3.45 (m, 1H), 3.55–3.60
(m, 1H), 4.0–4.04 (m, 1H), 4.19 (t, J = 6.66 Hz, 2H), 6.83 (d, J = 8.5 Hz, 2H), 6.88
(d, J = 5.01 Hz, 1H), 7.14 (d, J = 8. 5 Hz, 2H), 7.23 (d, J = 5.0 Hz, 1H), 7.86 (d,
J = 2.58 Hz, 1H); ESI-MS: 401; 18c; (S)-2-ethoxy-3-(4-(2-(5-methyl-2-(3-
methylthiophen-2-yl)oxazol-4-yl)ethoxy) phenyl) propanoic acid: 1H NMR
(300 MHz, CDCl3): d 1.15 (t, J = 7.0 Hz, 3H), 2.34 (s, 3H), 2.55 (s, 3H), 2.89–3.08
(m, 4H), 3.40–3.49 (m, 1H), 3.55–3.60 (m, 1H), 4.0–4.04 (m, 1H), 4.19 (t,
J = 6.7 Hz, 2H), 6.83 (d, J = 8.5 Hz, 2H), 6.88 (d, J = 5.01 Hz, 1H), 7.14 (d,
J = 8.6 Hz, 2H), 7.23 (d, J = 5.01 Hz, 1H); ESI-MS: 415; 18d: (S)-2-ethoxy-3-(4-
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S.; Kauffman, R. F.; Broderick, C. L.; Oldham, B. A.; Montrose-Rafizadeh, C.;
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20. Spectroscopic data of compounds 12a–e and 18a–e: 12a: (S)-2-ethoxy-3-(4-
((5-methyl-2-(thiophen-2-yl)oxazol-4-yl)methoxy)phenyl)propanoic acid: 1H
NMR (300 MHz, CDCl3): d 1.16 (t, J = 7.0 Hz, 3H), 2.40 (s, 3H), 2.91–2.98 (m,
2H), 3.35–3.49 (m, 1H), 3.54–3.64 (m, 1H), 4.03 (m, 1H), 4.95 (s, 2H), 6.93 (d,
J = 8.5 Hz, 2H), 7.01 (t, J = 3.7 Hz, 1H), 7.15 (d, J = 8.5 Hz, 2H), 7.40 (d, J = 4.9 Hz,
1H), 7.65 (d, J = 3.4 Hz, 1H); ESI-MS: 387; 12b: (S)-2-ethoxy-3-(4-((5-methyl-
2-(thiophen-3-yl)oxazol-4-yl)methoxy)phenyl)propanoic acid: 1H NMR
(2-(5-methyl-2-(5-methyl
thiophen
-2-yl)oxazol-4-yl)ethoxy)
phenyl)
propanoic acid: 1H NMR (300 MHz, CDCl3): d 1.15 (t, J = 7.0 Hz, 3H), 2.32 (s,
3H), 2.50 (s, 3H), 2.89–2.96 (m, 4H), 3.40–3.43 (m, 1H), 3.56–3.59 (m, 1H),
3.99–4.03 (m, 1H), 4.16 (t, J = 6.6 Hz, 2H), 6.72 (d, J = 3.54 Hz, 1H), 6.81 (d,
J = 8.5 Hz, 2H), 7.15 (d, J = 8. 5 Hz, 2H), 7.39 (d, J = 3.6 Hz, 1H); ESI-MS: 415;
18e: (S)-2-ethoxy-3-(4-(2-(5-methyl-2-(5-pheny lthiophen-2-yl)oxazol-4-
yl)ethoxy) phenyl) propanoic acid: 1H NMR (300 MHz, CDCl3):
d 1.16 (t,
J = 6.4 Hz, 3H), 2.89 (s, 3H), 2.93–3.05 (m, 4H), 3.41–3.58 (m, 2H), 4.01–4.05 (m,
1H), 4.20 (t, J = 6.6 Hz, 2H), 6.81 (d, J = 8.6 Hz, 2H), 7.14 (d, J = 8.5 Hz, 2H), 7.26–
7.42 (m, 4H), 7.54 (d, J = 3.9 Hz, 1H), 7.62 (d, J = 7.3 Hz, 2H); ESI-MS : 477.
21. Pingali, H.; Jain, M.; Shah, S.; Makadia, P.; Zaware, P.; Goel, A.; Patel, M.; Giri, S.;
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(300 MHz, CDCl3):
d
1.16 (t, J = 7.0 Hz, 3H), 2.4 (s, 3H), 2.90–2.97 (dd,
22. Palmer, C. N. A.; Hsu, M. H.; Griffin, K. J.; Raucy, J. L.; Johnson, E. F. Mol.
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J = 7.6 Hz, 1H), 3.03–3.09 (dd, J = 4.7 Hz, 1H), 3.39–3.44 (m, 1H), 3.57–3.62
(m, 1H), 4.01–4.05 (m, 1H), 4.94 (s, 2H), 6.93 (d, J = 8.5 Hz, 2H), 7.18 (d,