(-)3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid [(-)DRF 2725]: A dual PPAR agonist with potent antihyperglycemic and lipid modulating activity

Article abstract of DOI:10.1021/jm010143b

(-)DRF 2725 (6) is a phenoxazine analogue of phenyl propanoic acid. Compound 6 showed interesting dual activation of PPARα and PPARγ. In insulin resistant db/db mice, 6 showed better reduction of plasma glucose and triglyceride levels as compared to rosig

Full text of DOI:10.1021/jm010143b

J . Med. Chem. 2001, 44, 2675-2678
2675
(-)3-[4-[2-(P h en oxa zin -10-yl)eth oxy]p h en yl]-2-eth oxyp r op a n oic Acid [(-)DRF
2725]: A Du a l P P AR Agon ist w ith P oten t An tih yp er glycem ic a n d Lip id
Mod u la tin g Activity
Braj B. Lohray,† Vidya B. Lohray,† Ashok C. Bajji,† Shivaramayya Kalchar,† Rajamohan R. Poondra,†
Srinivas Padakanti,† Ranjan Chakrabarti,‡ Reeba K. Vikramadithyan,‡ Parimal Misra,‡ Suresh J uluri,‡
N. V. S. Rao Mamidi,‡ and Ramanujam Rajagopalan‡*
Discovery Synthesis and Discovery Biology, Dr. Reddy’s Research Foundation, 7-1-27, Ameerpet, Hyderabad 500 016, India
Received April 2, 2001
(-)DRF 2725 (6) is a phenoxazine analogue of phenyl propanoic acid. Compound 6 showed
interesting dual activation of PPARR and PPARγ. In insulin resistant db/db mice, 6 showed
better reduction of plasma glucose and triglyceride levels as compared to rosiglitazone. Com-
pound 6 has also shown good oral bioavailability and impressive pharmacokinetic character-
istics. Our study indicates that 6 has great potential as a drug for diabetes and dyslipidemia.
In tr od u ction
panoic acid, which showed dual PPARR and PPARγ
activity in in vitro transactivation assay and also
interesting blood glucose and triglyceride lowering
activity in experimental animal models.
Diabetes mellitus is a polygenic disorder affecting a
significant proportion of the people in industrialized
nations. Insulin resistance is a basic etiological factor
for type 2 diabetes1 and is also linked to a wide spectrum
of other pathophysiologic conditions including hyperten-
sion, hyperlipidemia, atherosclerosis, and obesity which
are collectively called syndrome X or insulin resistance
associated disorders (IRAD).2 Despite intense research,
the understanding of the molecular mechanism of
insulin resistance is not very clear. Troglitazone (1),3
rosiglitazone (2),4 and pioglitazone (3)5 (Figure 1) belong
to the class of thiazolidinedione (TZD) antidiabetic
agents that improve the blood glucose level in type 2
diabetes by an insulin sensitizing mechanism. The
molecular mechanism of TZD is activation of peroxisome
proliferator-activator receptor gamma (PPARγ),6 a mem-
ber of a family of ligand activated nuclear hormone
receptors. Fibrates are another class of drugs that
reduce triglyceride and increase HDL levels through
activation of PPARR, which is present predominantly
in the liver. WY 14,643 (4)7 is a more potent PPARR
specific activator (Figure 1), which is used in this study
for comparative purpose. A drug that improves insulin
sensitivity and effectively decreases hyperlipidemia
would be useful for the management of diabetes and
dyslipidemia. With this aim, a discovery program was
initiated to find novel compounds that activate both
PPARR and PPARγ receptors. A few â-aryl R-hydroxy
propanoic acids, their derivatives, and their analogues
have been reported8 to be useful in the treatment of
hyperglycemia and hyperlipidemia. Structure-activity
relationship to provide novel â-aryl R-oxysubstituted
alkylcarboxylic acids were investigated by substituting
the methylaminobenzoxazole group of SB 213068 (5)8
with different tricyclic ring systems. This lead to the
discovery of 6, a phenoxazine analogue of phenylpro-
Resu lts a n d Discu ssion
Compound 6 is prepared from phenoxazine using a
synthetic route shown in Scheme 1. Phenoxazine 7 upon
reaction with p-bromoethoxy benzaldehyde 89 gave
benzaldehyde derivative 9. Reacting 9 with triethyl
2-ethoxy phosphonoacetate afforded propenoate 10 as
a mixture of geometric isomers. Reduction of 10 using
magnesium methanol gave propanoate 11, which on
hydrolysis using aqueous sodium hydroxide gave pro-
panoic acid 12 in racemic form. Resolution of 12 using
(S)(+)-2-phenyl glycinol followed by hydrolysis using
sulfuric acid afforded the propanoic acid 6 in (-) form.
In an in vitro transactivation assay, 6 showed dual
activation of PPARR and PPARγ as shown in Table 1.
On the other hand, the (+) isomer of 6 showed weak
activation for both the isoforms (Table 1). As mentioned
in the literature,6,10 rosiglitazone and WY 14,643 showed
PPAR isoform specific activation.
In genetically diabetic, insulin resistant, hyperlipi-
demic db/db mice, 9 days treatment with 6 showed 56%
reduction in plasma glucose and 62% reduction in
triglyceride as compared to 33% reduction in glucose
and 16% reduction in triglyceride by rosiglitazone at the
same dose. (Figure 2).
In pharmacokinetic studies in male wistar rats, 6
showed very good oral bioavailability and impressive
pharmacokinetic characteristics (Table 2).
In conclusion, the transactivation assay results showed
that 6 is a dual activator of PPARR and PPARγ. In
insulin resistant db/db mice, the compound treatment
showed much better antidiabetic and hypolipidemic
activity than rosiglitazone. The pharmacokinetic profile
of this molecule is also quite impressive. Thus treatment
with 6 showed interesting blood glucose and triglyceride
lowering activity through dual activation of PPARR and
γ receptors. Consequently, 6, which belongs to a differ-
ent chemical class from thiazolidinediones, has great
* Correspondence: Ramanujam Rajagopalan, Ph.D., Dr. Reddy’s
Research Foundation, Bollaram Road, Miyapur, Hyderabad 500 050,
India. Tel: 91-40-304 5387. Fax: 91-40-304 5438. E-mail: rajagopalanr@
drreddys.com. DRF publication no. 149.
† Discovery Synthesis.
‡
Discovery Biology.
10.1021/jm010143b CCC: $20.00 © 2001 American Chemical Society
Published on Web 07/11/2001

2676 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 16
Brief Articles
F igu r e 1. Structures of known PPAR activators and compound 6.
Sch em e 1a
a
(a) NaH, DMF, 0-25 °C, 12 h; (b) triethyl 2-ethoxy phosphosphonoacetate, NaH, THF, 0-25 °C, 12 h; (c) Mg/CH3OH, 25 °C, 12 h; (d)
10% aq NaOH, CH3OH, 25 °C, 6 h; (e) (1) pivaloyl chloride, Et3N, DCM, 0 °C, (2) (S)-2-phenyl glycinol/Et3N; (f) 1 M H2SO4, dioxane/
water, 90-100 °C, 80 h.
Ta ble 1. PPAR Transactivation Studya
P P AR Tr a n sa ctiva tion Assa y. The reporter construct
used for luciferase assay included (UASGAL4 × 5) response
element upstream of pFR-Luc reporter under the Simian virus
40 early promoter. GAL4 fusions were made by fusing human
PPARγ or PPARR ligand binding domain (amino acids: 174-
475) to the C-terminal end of yeast GAL4 DNA binding domain
(amino acids: 1-147) of pM1 vector. pAdVantage vector was
used to enhance luciferase expression.
HEK 293T cells were transfected with relevant plasmids
by Superfect as per the instruction manual.11 Forty-two hours
after transfection, cells were treated for 18 h with test com-
pounds. DMSO (0.1%) was used as blank. Luciferase activity
was determined as “fold activation” relative to untreated cells
using the Luclite kit (Packard Instrument Co, Meriden, CT)
in a Packard Top Count (Packard Instrument Co.)
PPARR
fold activation
PPARγ
fold activation
(1 µM)
compd
(50 µM)
(-) isomer of 6
(+) isomer of 6
rosiglitazone
WY 14,643
10.87 ( 1.2
2.9 ( 0.3
1.77 ( 0.07
12.5 ( 0.45
16.67 ( 1.24
1.23 ( 0.15
18.4 ( 1.18
0.75 ( 0.07
a
Values are expressed as mean ( SE (n ) 4).
potential as a drug in the management of insulin resis-
tance and dyslipidemia.
Exp er im en ta l Section
Biology. Ma ter ia ls. The standard compounds, rosiglita-
zone (2) and WY 14,643 (4), were synthesized in-house using
published procedures4,7 and were found to be 99% pure. Plasma
glucose and triglyceride levels were measured spectrophoto-
metrically using commercially available kits (Point Scientific,
USA). Carboxymethylcellulose (CMC) was obtained from
LOBA Chemicals Pvt. Ltd., Mumbai, India.
An im a l Exp er im en ts. Experiments were carried in ac-
cordance with internationally valid guidelines, with prior
approval from Dr. Reddy’s Research Foundation (DRF) animal
ethics committee. Male C57 BL/Ks J -db/db mice were from the
breeding stock of DRF animal house, generated from the
breeding stock of J ackson Laboratories, ME. Animals were
maintained under 12 h light and 12 h dark cycle at 25 ( 1 °C

Brief Articles
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 16 2677
Ch em istr y. Thin-layer chromatography was performed on
precoated silica gel plates (F254, Merck). 1H and 13C NMR
spectra were recorded on a Varian Gemini 200 MHz spectrom-
eter and are reported as parts per million (ppm) from downfield
to TMS. The mass spectra were recorded on a HP 5989A mass
spectrometer. p-Bromoethoxy benzaldehyde9 and triethyl-2-
ethoxyphosphonoacetate were prepared according to the re-
ported methods. Phenoxazine is procured from commercial
sources. The chiral centers are fixed based on the optical
rotation for appropriate compounds.
4-[2-(P h en oxa zin -10-yl)eth oxy]ben za ld eh yd e (9). To a
suspension of sodium hydride (60% mineral oil, 7.86 g, 164
mmol) in dimethyl formamide (20 mL) was added a solution
of phenoxazine (25 g, 136 mmol) in dimethyl formamide (250
mL) at 0 °C under nitrogen atmosphere. The reaction mixture
was heated at 60-80 °C for 1 h. The reaction mixture was
cooled to 0 °C, and a solution of 4-(2-bromoethoxy)benzalde-
hyde (46.9 g, 204 mmol) in dry dimethyl formamide (100 mL)
was added at 0 °C, and the stirring was continued for a further
12 h at ca. 25 °C. Water (250 mL) was added, and the mixture
was extracted with ethyl acetate (2 × 150 mL). The combined
organic extracts were washed with water (100 mL) and brine
solution (100 mL), dried (Na2SO4), and filtered, and the solvent
evaporated under reduced pressure. The residue was chro-
matographed over silica gel using a mixture of ethyl acetate
and petroleum ether (1:9) as eluent to afford the title com-
pound (25 g, 92%) as a greenish solid. 1H NMR (CDCl3, 200
MHz): δ 3.67 (t, J ) 6.2 Hz, 1H), 4.05 (t, J ) 6.2 Hz, 1H), 4.28
(t, J ) 6.3 Hz, 1H), 4.38 (t, J ) 6.2 Hz, 1H), 6.75 (m, 8H), 7.02
(m, 2H), 7.87 (m, 2H), 9.90 (s, 1H). Mass m/z (relative intensity)
331 (M+, 49), 196 (100), 182 (23), 167 (10), 127 (7).
F igu r e 2. Comparative effect of compound 6 and rosiglitazone
in db/db mice. Animals were treated for 9 days. All values are
expressed as mean ( SE, n ) 5.
Ta ble 2. Pharmacokinetic Parameters of 6 in Male Wistar
Ratsa
pharmacokinetic parameter
oral
iv
Eth yl (E/Z)-3-[4-[2-(P h en oxa zin -10-yl)eth oxy]p h en yl]-
2-eth oxyp r op en oa te (10). A solution of triethyl-2-ethoxy-
phosphonoacetate (24.2 g, 90.0 mmol) prepared by the method
of Grell and Machleid (Ann. Chemie, 1996, 699, 53) in dry
tetrahydrofuran (30 mL) was added slowly to a stirred ice
cooled suspension of sodium hydride (60% dispersion of oil)
(4.32 g, 94.4 mmol) in dry tetrahydrofuran (100 mL), under a
nitrogen atmosphere. The mixture was stirred at 0 °C for 30
min. followed by addition of a 4-[2-(phenoxazin-10-yl)ethoxy]-
benzaldehyde (25.0 g, 75.5 mmol) in dry tetrahydrofuran (100
mL). The mixture was allowed to warm to room temperature
and stirred at that temperature for further 12 h. The excess
NaH was quenched with a few drops of cold water. The solvent
was evaporated under reduced pressure and was distilled with
water (150 mL) and extracted with ethyl acetate (2 × 200 mL).
The combined organic extracts were washed with water (100
mL) and brine (100 mL), dried (Na2SO4), and filtered, and the
solvent was evaporated under reduced pressure. The crude
product was chromatographed over silica gel using a mixture
of ethyl acetate and petroleum ether (1:9) as an eluent to afford
the title compound (28.0 g, 83%) as a white solid, mp: 110-
112 °C. 1H NMR (CDCl3, 200 MHz): δ 1.16 and 1.38 (combined,
6H, isomeric -OCH2CH3 triplet signals), 3.89-4.05 (m, 4H),
4.14-4.31 (m, 4H), 6.06 (s, 0.36H, olefinic proton of E isomer),
6.66-6.95 (m, 10.6H), 7.75 (d, J ) 8.8 Hz, 2H). Mass m/z
(relative intensity): 445 (M+, 50), 196 (100), 182 (29), 167 (7),
127 (5).
dose
10 mg/kg
71.40 ( 12.86
17.17 ( 4.22
1.50 ( 0.58
0.25 ( 0.0
2.81 ( 0.06
-
3 mg/kg
AUC(0-∞) (µg h/mL)
Cmax (µg/mL)
Tmax (h)
27.81 ( 5.85
18.33 ( 7.26#
-
0.15 ( 0.03
4.69 ( 0.77
36.92 ( 19.9
21.32 ( 4.99
-
Kel (h-1
T1/2 (h)
Vd (mL)
Cl (mL/h)
f (%)
)
-
77.02
a
Each value is mean ( SD, n ) 4; #C0.
and were given standard chow supplied by National Institute
of Nutrition, Hyderabad, India (NIN) and water ad libitum.
db/db mice (8-9 weeks) were grouped according to blood sugar
levels and treated with test compound at a dose of 1 mg/kg
administered orally for 9 days. Animals in the control group
received vehicle only (0.25% CMC, dose 10 mL/kg). Blood
samples were collected from animals (in fed state) under mild
ether anesthesia from the retro-orbital sinus 1 h after drug
administration. Plasma samples were separated for glucose
and triglyceride measurement. The percent reduction was
calculated as per the formula:
1 - [(9 day treated/0 day
treated)/(9 day control/0 day control)] × 100
Met h yl 3-[4-[2-(P h en oxa zin -10-yl)et h oxy]p h en yl]-2-
eth oxyp r op a n oa te (11). A mixture of ethyl (E/Z)-3-[4-[2-
(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropenoate (1.3 g,
2.9 mmol) and magnesium turnings (1.4 g, 58 mol) in dry
methanol (50 mL) was stirred at 25 °C for 10 h. Water (100
mL) was added, and pH of the solution was adjusted to 6.5-
7.5 with 2 N hydrochloric acid. The solution was extracted with
ethyl acetate (3 × 75 mL). The organic layers were washed
with water (50 mL) and brine (50 mL), dried (Na2SO4), and
filtered, and solvent was evaporated under reduced pressure.
The crude product was chromatographed over silica gel using
a mixture of ethyl acetate and petroleum ether (2:8) as an
eluent to afford the title compound (0.68 g, 52%) as a white
Pharmacokinetic studies were carried out in male Wistar
rats (weight range 200-300 g) (NIN). For oral study, animals
were fasted for 14 h and test compound was administered in
0.25% CMC suspension. For intravenous study, the compound
was dissolved in a cocktail consisting of DMSO (6.6%), Cre-
mophor ELP (6.6%), ethanol (3.3%), and saline (83.3%) and
administered through tail vein. Blood samples were drawn
from the retro-orbital sinus at 0.05, 0.5, 1, 2, 4, 6, 8, 10, and
21 h. The plasma was separated, processed with a suitable
internal standard, extracted, and analyzed by a validated
reverse phase HPLC method. The parameters were calculated
based on noncompartmental model analysis. The oral bioavail-
ability was calculated by the following formula:
1
solid, mp: 88-90 °C. H NMR (CDCl3, 200 MHz): δ 1.16 (t, J
) 6.9 Hz, 3H), 2.96 (d, J ) 6.6 Hz, 2H), 3.22-3.40 (m, 1H),
3.51-3.66 (m, 1H), 3.68 (s, 3H), 4.00 (t, J ) 7.0 Hz, 1H), 4.18
f ) [AUC(0-
× iv dose] × 100/[AUC(0-
× oral dose]
)oral
)iv

2678 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 16
Brief Articles
(m, 4H), 6.55-6.89 (m, 10H), 7.12 (d, J ) 8.6 Hz, 2H). Mass
m/z (relative intensity): 433 (M+, 35), 196 (100), 182 (28), 167
(7), 127 (4). Purity by HPLC: 86.19%.
solution. The mixture was extracted with ethyl acetate (2 ×
25 mL), and the organic extract was washed with water (50
mL) and brine (25 mL), dried (Na2SO4), and evaporated. The
residue was chromatographed over silica gel using a gradient
of 50-75% ethyl acetate in petroleum ether to afford the title
compound (0.19 g, 54%) as a white solid, mp: 89-90 °C. [R]D
3-[4-[2-(P h en oxa zin -10-yl)eth oxy]p h en yl]-2-eth oxyp r o-
p a n oic Acid (12). To a solution of methyl 3-[4-[2-(phenoxazin-
10-yl)ethoxy]phenyl]-2-ethoxypropanoate (62 g, 139 mmol) in
methanol (1000 mL) was added aqueous 10% sodium hydrox-
ide (300 mL). The reaction mixture was stirred at ca. 25 °C
for 6 h. The methanol was evaporated under reduced pressure,
and water (200 mL) was added and acidified with 2 N hydro-
chloric acid. The mixture was extracted with ethyl acetate (3
× 500 mL). The combined ethyl acetate layers were washed
with water (2 × 50 mL) and brine (500 mL), dried (Na2SO4),
and filtered, and solvent was evaporated under reduced
pressure. The residue was triturated with petroleum ether to
afford the title compound (56 g, 96%) as a white solid, mp:
25
1
) - 12.6 (c ) 1.0%, CHCl3). H NMR (CDCl3, 200 MHz): δ
1.16 (t, J ) 7.0 Hz, 3H), 1.42-1.91 (bs, 1H, D2O exchangeable),
2.94-3.15 (m, 2H), 3.40-3.65 (m, 2H), 3.86-4.06 (m, 3H), 4.15
(t, J ) 6.6 Hz, 2H), 6.63-6.83 (m, 10H), 7.13 (d, J ) 8.5 Hz,
2H). Mass m/z (relative intensity): 419 (M+, 41), 197 (15), 196
(100), 182 (35), 167 (7), 127 (6), 107 (19). Purity by HPLC:
chemical purity: 99.5%; chiral purity: 94.6% (RT 27.5).
Ack n ow led gm en t. We thank Drs. K. Anji Reddy
and A. Venkateswarlu for their support and encourage-
ment. We also thank the IPM group in manuscript
preparation and the analytical research group for their
excellent support.
1
89-91 °C. H NMR (CDCl3, 200 MHz): δ 1.19 (t, J ) 7.0 Hz,
3H), 2.90-3.18 (m, 2H), 3.41-3.62 (m, 2H), 3.90-4.10 (m, 3H),
4.18 (t, J ) 6.2 Hz, 2H), 6.58-6.89 (m, 10H), 7.16 (d, J ) 8.4
Hz, 2H), COOH proton is too broad to observe. Mass m/z
(relative intensity): 419 (M+, 26), 373 (5), 197 (16), 196 (100),
182 (38), 167 (5), 121 (16), 107 (37). Purity by HPLC: 98.52%.
[(2S),N(1S)]-3-[4-[2-(P h en oxa zin -10-yl)eth oxy]p h en yl]-
2-eth oxy-N-(2-h yd r oxy-1-p h en yleth yl)p r op a n a m id e (13).
To an ice cooled solution of 3-[4-[2-(phenoxazin-10-yl)ethoxy]-
phenyl]-2-ethoxypropanoic acid (1.2 g, 2.9 mmol) and triethyl-
amine (0.58 g, 5.8 mmol) in dry dichloromethane (25 mL) was
added pivaloyl chloride (0.38 g, 3.19 mmol), and stirring was
continued for further 30 min at 0 °C. A mixture of (S)(+)-2-
phenyl glycinol (0.39 g, 2.9 mmol) and triethylamine (0.58 g,
5.8 mmol) in dichloromethane (20 mL) was added to the above
reaction mixture at 0 °C, and stirring was continued for 2 h
at 25 °C. Water (50 mL) was added and extracted with di-
chloromethane (2 × 50 mL). The organic extracts were washed
with water (2 × 25 mL) and brine (25 mL), dried (Na2SO4),
and evaporated. The residue was chromatographed over silica
gel using a gradient of 40-60% ethyl acetate in petroleum
ether as an eluent to afford first a diastereomer tentatively
assigned as [2R,N(1S)]-3-[4-[2-(Phenoxazin-10-yl)ethoxy]phen-
yl]-2-ethoxy-N-(2-hydroxy-1-phenylethyl)propanamide followed
by [2S,N(1S)]-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy-
N-(2-hydroxy-1-phenylethyl)propanamide (0.5 g, 32%), mp:
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139-141 °C. [R]D ) -13.3 (c ) 1.00%, CHCl3). 1H NMR
25
(CDCl3, 200 MHz): δ 1.18 (t, J ) 6.9 Hz, 3H), 2.05 (bs, 1H,
D2O exchangeable), 2.80-3.14 (m, 2H), 3.54 (q, J ) 7.0 Hz,
2H), 3.85 (bs, 2H), 3.97 (m, 3H), 4.14 (t, J ) 6.2 Hz, 2H), 4.92-
5.01 (m, 1H), 6.62-6.85 (m, 9H), 7.02-7.20 (m, 5H), 7.26-
7.30 (m, 3H), CONH is too broad to observe. Mass m/z (relative
intensity): 538 (M+, 65), 492 (6), 210 (8), 196 (100), 182 (12).
Purity by HPLC: 99.4%.
(S)-3-[4-[2-(P h e n oxa zin -10-yl)e t h oxy]p h e n yl]-2-e t h -
oxyp r op a n oic Acid (6). A solution of [(2S,N(1S)]-3-[4-[2-
(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy-N-(2-hydroxy-1-
phenyl)propanamide (0.45 g, 0.84 mmol) in a mixture of 1 M
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J M010143B