Aryloxazolidinediones: Identification of potent orally active PPAR dual α/γ agonists

Article abstract of DOI:10.1016/S0960-894X(03)00785-6

A series of novel aryloxazolidine-2,4-diones was synthesized. A structure-activity relationship study of these compounds led to the identification of potent, orally active PPAR dual α/γ agonists. Based on the results of efficacy studies in the db/db mice

Full text of DOI:10.1016/S0960-894X(03)00785-6

Bioorganic & Medicinal Chemistry Letters 13 (2003) 3541–3544
Aryloxazolidinediones: Identification of Potent Orally Active
PPAR Dual ꢀ/ꢁ Agonists
Ranjit C. Desai,a,* Dominick F. Gratale,a Wei Han,a Hiroo Koyama,a Edward Metzger,a
Victoria K. Lombardo,a Karen L. MacNaul,b Thomas W. Doebber,b Joel P. Berger,b
Kwan Leung,c Ronald Franklin,c David E. Moller,b James V. Hecka
and Soumya P. Sahooa,*
aDepartment of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
bDepartment of Metabolic Disorders, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
cDepartment of Drug Metabolism, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
Received 13 February 2003; accepted 7 July 2003
Abstract—A series of novel aryloxazolidine-2,4-diones was synthesized. A structure–activity relationship study of these compounds
led to the identification of potent, orally active PPAR dual a/g agonists. Based on the results of efficacy studies in the db/db mice
model of type 2 diabetes and the desired pharmacokinetic parameters, compound 12 was selected for further profiling.
# 2003 Published by Elsevier Ltd.
Type 2 insulin-resistant diabetes is a heterogeneous dis-
order that accounts for 120 million patients worldwide
and the number is likely to grow over 200 million over
next decade. This is a complex disease and invariably
type 2 diabetic patients population also display cardio-
vascular factors including hypertension and dyslipide-
mia.1,2 In the past 3 years, two new drug candidates,
Avandia (rosiglitazone) and Actos (pioglitazone) have
been introduced in the US market as novel therapy for
type 2 diabetes. Both Avandia and Actos are PPARg
agonists and elicit their insulin sensitizing effect through
binding and activating PPARg nuclear receptor.
Recently, scientists at Kyorin Pharmaceutical Co. have
disclosed a novel antidiabetic KRP-297, a first pub-
lished example of a dual PPARa and PPARg agonist.3
PPARa is the molecular target for the fibrate class of
lipid-modulating drugs4 and incorporation of additional
PPARa activity into compounds with PPARg agonist
activity may offer improved alternatives towards control
of hyperglycemia and hypertriglyceridemia in type 2
diabetic patients.5
of type 1 (X=S) as potent dual PPARa/g agonists.6
Unlike the classical glitazones, 1 has the thiazolidine-
2,4-dione ring directly attached to the phenyl ring.
Based on their excellent efficacy in the established
rodent models of type 2 diabetes and desirable PK pro-
file, we initiated synthesis of various meta linked aryl
TZD analogues to find replacement(s) for the C-40-aryl-
oxy substituents and extended these efforts to include
the synthesis of oxazolidine-2,4-diones (OZDs, 1:
X=O) as bioisosteric replacement for the correspond-
ing TZD ring.7,8
In the earlier structure–activity relationship (SAR)
studies en route to identifying 1, we had established the
need for the three carbon methylene tether and n-propyl
group as the optimal substituent at the C-20 position for
potency and selectivity. Further studies identified C-40
position as an important site for additional structural
modifications. Herein, we report the results of this SAR
study that resulted in the identification of potent and in
vivo efficacious OZD analogues.
In the previous communication, we disclosed the results
of our efforts that led to the identification of compounds
*Corresponding author. Tel.: +1-732-594-3923; fax: +1-732-594-
9556; e-mail: ranjit_desai@merck.com
0960-894X/$ - see front matter # 2003 Published by Elsevier Ltd.
doi:10.1016/S0960-894X(03)00785-6

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R. C. Desai et al. / Bioorg. Med. Chem. Lett. 13 (2003) 3541–3544
Table 1. In vitro human PPAR activities of compounds 1–11
Compd
R
Binding IC50 (mM)13
Transactivation EC50 (mM)10
a
d
g
a
d
g
1
2
0.028
>50
>50
0.057
0.026
0.035
>3
>3
0.014
1.4
0.037
0.085
0.063
0.019
0.144
0.03
0.039
ND
3
0.21
0.042
0.09
>50
0.92
0.17
>50
0.14
>50
>50
>50
>5
ND
ND
ND
ND
>3
>3
ND
>3
>3
>3
>3
4
ND
5
>3
0.167
0.051
ND
6
>10
>3
7
0.037
0.12
ND
8
0.064
0.15
0.13
0.11
0.21
0.08
0.081
9
0.062
0.046
0.08
0.17
10
11
0.059
0.34
0.076
0.053
The preparation of the thiazolidine-2,4-diones (Table 1)
has been described.9 The synthetic route used to prepare
OZD analogues 12–20 (Table 2) is illustrated in Scheme
1 with the synthesis of 12. Commercially available 3-
hydroxybenzonitrile was converted to aldehyde A by
first alkylating with 1,3-dibromopropane and then
reducing the nitrile with DIBALH. The aldehyde was
then transformed to mandelate B via intermediacy of a
cyanohydrin. Coupling of the mandelate with 2-propyl-
4-cyclohexylphenol provided intermediate C. Conver-
sion of the ester to corresponding amide using
methanolic ammonia followed by treatment of the
amide with diethylcarbonate and sodium methoxide in
methanol gave the desired oxazolidine-2,4-dione deri-
vative 12. The preparation of 2-propyl-4-cyclohexyl-
phenol is described in Scheme 2. 4-Cyclohexylphenol
(D, R=cyclohexyl) was first alkylated with allyl bro-
mide and then subjected to Claisen rearrangement to
provide intermediate E. Hydrogenation of the allylic
olefin furnished the desired phenol F. The starting phe-
nols D were either commercially available or could be
easily synthesized using conventional chemistry.
As stated earlier, our initial goal was to find a suitable
replacement for the C-40 phenoxy substituent of com-
pound 1. The obvious starting point would be to
explore the corresponding saturated ring analogue as
shown for compound 2. This analogue, though equi-
potent to 1 in its binding affinity to PPARg receptor,
was 90-fold less active on the PPARa receptor. How-
ever, in the functional GAL4-PPAR transactivation
assay,10 2 was indistinguishable from 1 at both PPARg
and PPARa receptors. This compound unfortunately
suffered from poor PK properties which resulted in
poor in vivo efficacy in lowering glucose and triglycer-
ides in the db/db mice model. Oral administration of
compound 2 to male Sprague–Dawley (SD) rats (2 mg/
kg) resulted in low bioavailability (10%) and dose

R. C. Desai et al. / Bioorg. Med. Chem. Lett. 13 (2003) 3541–3544
Table 2. In vitro human PPAR activities of compounds 12–20
3543
Compd
R
Binding IC50 (mM)13
Transactivation EC50 (mM)10
a
d
g
a
d
g
12
0.29
>50
0.49
0.055
>3
0.019
13
14
15
16
17
18
19
20
2.64
0.61
0.63
1.51
>50
3.85
0.45
0.64
1.06
1.16
0.18
0.54
1.76
0.75
2
>3
>3
0.09
0.035
ND
0.054
ND
ND
ND
ND
ND
ND
>3
>15
>50
>50
>50
>50
>50
ND
>15
ND
0.59
>3
>3
3.3
>3
>3
0.09
ND
2.88
ND
ND
Scheme 1. Reagents: (a) Br(CH2)3Br, K2CO3, DMF; (b) DIBALH; (c) TMSCN, NaCN, 18-crown-6; (d) HCl (gas), EtOH; (e) 2-propyl-4-cyclo-
hexylphenol, K2CO3, DMF; (f) NH3, MeOH; (g) (C2H5O)2CO, MeONa, MeOH.
normalized AUC of 0.3 mM h. The higher homologe 3
also suffered from poor PK in SD rats. As compared to
2, which showed dual PPARg and PPARa receptors
agonism, the corresponding cyclopentyloxy ring analo-
gue 4 displayed non-selective binding to all three PPAR
g, a, and d receptors. Replacement of the oxygen linker
of 1 with carbonyl afforded compound 5, which also
showed non-selective binding. However, an improve-
ment in the binding selectivity favoring PPARg was
noted with analogue 6 bearing a para-chloro substituent
on the phenyl ring. But, this binding selectivity was lost
as observed in compound 7, where the carbonyl group
was masked in a benzisoxazole moiety.
Interestingly, when compared to phenyl ketone 5, the
corresponding cyclohexyl ketone analogue 8 displayed
the desired PPARg and PPARa receptor affinity in both
the binding and functional assays. Despite this good
potency, compound 8 suffered from poor PK in SD rats
with 7.8% bioavailability and dose normalized AUC of
0.07 mM h and a high clearance of 29.47 mL/min/kg. In
an attempt to improve upon the metabolic stability and

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R. C. Desai et al. / Bioorg. Med. Chem. Lett. 13 (2003) 3541–3544
Scheme 2. Reagents: (a) CH2¼CHCH2Br, K2CO3, acetone; (b) 1,2-dichlorobenzene, reflux; (c) H2, Pd/C, MeOH.
Table 3. In vivo efficacy of selected dual agonists in db/db mice
cyclohexyl derivatives 18–19 as well as the tetra-
hydropyran analogue 20 were synthesized.11,12
Compd
Dose
(mpk)
Glucose
correction (%)
Triglyceride
correction (%)
Analogues 16 and 17 were found to be selective PPARg
agonists while 18–20 displayed decreased binding affi-
nity and activation potency for PPARg and PPARa
receptors as compared to compound 12.
2
8
9
10
11
12
14
10
10
10
10
10
10
10
34
29
87
46
91
76
45
7
57
31
41
85
77
53
In summary, we have identified through a systematic
structure–activity relationship study, a novel series of
potent, orally efficacious 5-aryloxazolidine-2,4-diones
(OZDs) as dual PPARa/g agonists.
Rosiglitazone
KRP-297
10
100
67
51
74
60
Male db/db mice (12–13 weeks of age, n=7) and non-diabetic mice
(lean control, n=7) were provided ad libitum access to rodent chow
and water and received once-a-day oral dosing of the sodium-salts of
tested compounds by gavage with vehicle (0.25% methylcellulose) for
11 days. Blood was collected from the tail for measurement of plasma
levels of glucose and triglyceride.10
Acknowledgements
We thank Dr. Peter Meinke for reviewing the manu-
script and Margaret Wu, Neelam Sharma, Ying Li and
Raul Alvaro for the technical support.
also to further probe the SAR, compounds 9–11 were
synthesized. All three compounds displayed dual
PPARg and PPARa binding as well as functional
agonism.
References and Notes
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11. Compounds 16 and 17 were identified as major metabolites
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While 9 and 10 suffered from poor PK profile, com-
pound 11 showed promising PK profile with 27% oral
bioavailability, t1=2 of 3.6 h and dose normalized AUC
of 1.1 mM h for a 2-mpk po dose in SD rats. As seen
from Table 3, compound 11 when dosed orally at
10 mpk for 11 days produced 91% glucose correction
and 85% triglycerides reduction in the db/db mice
model of type 2 diabetes. It is noteworthy that although
weaker in its binding affinity for both PPARg and
PPARa receptors when compared to 1, compound 11
was not significantly different in functional assay, which
was reflected in the excellent in vivo efficacy.
Optimization studies established that the C-40 cyclo-
hexyl was a suitable replacement for the phenoxy group
of 1. Next, we decided to explore the utility of the OZD
as a bioisosteric replacement for the corresponding
thiazolidine-2,4-dione (TZD) ring. With this objective,
the aryl OZD 12 was synthesized and evaluated. Com-
pound 12 was found equipotent in both binding affinity
and functional potency to the corresponding TZD ana-
logue 11. In the db/db mice, 12 produced 76% glucose
correction and lowered triglycerides by 77% reflecting
correlation between in vitro potency and in vivo effi-
cacy. Interestingly, switching cyclohexyl ring of 12 a
with the phenyl ring resulted in non-selective binding as
revealed by compound 13. The effects of the ring size
variations at C-40 were probed with synthesis of analo-
gues 14 and 15. In order to minimize the metabolic oxi-
dation sites of the cyclohexyl ring of 12, the substituted