Identification of a series of oxadiazole-substituted α-isopropoxy phenylpropanoic acids with activity on PPARα, PPARγ, and PPARδ

Article abstract of DOI:10.1016/S0960-894X(01)00458-9

A series of oxadiazole-substituted α-isopropoxy phenylpropanoic acids with dual agonist activity on PPARα and PPARγ is described. Several of these compounds also showed partial agonist activity on PPARδ. Resolution of one analogue showed that PPARα and PP

Full text of DOI:10.1016/S0960-894X(01)00458-9

Bioorganic & Medicinal Chemistry Letters 11 (2001) 2385–2388
Identification of a Series of Oxadiazole-Substituted ꢀ-Isopropoxy
Phenylpropanoic Acids with Activity on PPARꢀ, PPARꢁ, and
PPARꢂ
Kevin G. Liu,a,* Jennifer S. Smith,b Andrea H. Ayscue,a Brad R. Henke,b
Millard H. Lambert,a Lisa M. Leesnitzer,a Kelli D. Plunket,a Timothy M. Willsona
and Daniel D. Sternbachb
aNuclear Receptor Discovery Research, GlaxoSmithKline, Research Triangle Park, NC 27709, USA
bMetabolic Diseases Drug Discovery, GlaxoSmithKline, Research Triangle Park, NC 27709, USA
Received 15 May 2001; accepted 25 June 2001
Abstract—A series of oxadiazole-substituted a-isopropoxy phenylpropanoic acids with dual agonist activity on PPARa and PPARg
is described. Several of these compounds also showed partial agonist activity on PPARd. Resolution of one analogue showed that
PPARa and PPARg activity resided in mainly one enantiomer, whereas PPARd activity was retained in both enantiomers. # 2001
Elsevier Science Ltd. All rights reserved.
Type 2 diabetes, or non-insulin-dependent diabetes
mellitus, is the most prevalent endocrine disease in the
world. An estimated 120 million people worldwide suf-
fer from this disease.1 Type 2 diabetes is primarily
characterized by peripheral resistance to the actions of
insulin, which leads to hyperglycemia. There is also a
high frequency of concurrent dyslipidemia (e.g., high
levels of triglycerides and low levels of HDL-c), which
may contribute significantly to accelerated coronary
atherosclerosis, the leading cause of death in these indi-
viduals.2,3 Treatment of insulin resistance and dyslipi-
demia simultaneously would provide the great benefit
for type 2 diabetic patients.
of drugs that are effective at lowering serum triglycer-
ides and raising HDL-c.8 Experimental evidence has
indicated that PPARa is the receptor through which
fibrates mediate their effects on lipid metabolism.8,9
Therefore, PPARa/g dual agonists may provide super-
ior therapy to the current PPARg-selective agonists, due
to the additional lipid control afforded by the PPARa
component. Although less is known about the third
PPAR subtype, a selective PPARd agonist GW501516
was recently shown to increase HDL-c and lower tri-
glycerides.10
a-Alkoxy-substituted carboxylic acids have been pre-
viously disclosed as non-TZD insulin sensitizers in
vivo,11ꢀ13 but limited information on activity against the
three PPAR subtypes has been reported. Here we report
a series of a-isopropoxy phenylpropanoic acids con-
taining oxadiazole tails (1 and 2, Fig. 1) that are potent
and efficacious PPARa/g dual agonists. Additionally,
Recently, a new class of insulin-sensitizing drugs called
thiazolidinediones (TZDs) has been found to provide
improvements in glycemic control and hyperlipidemia in
type 2 diabetics. The potency of the marketed insulin
sensitizing drugs rosiglitazone4 and pioglitazone5 has
been correlated with their activity on the orphan nuclear
receptor PPARg.6 This correlation facilitated the dis-
covery of the tyrosine-derived insulin sensitizer farglita-
zar (GI262570), whose structure was optimized by
screening against PPARg in vitro.7 Fibrates are a class
*Corresponding author at current address: Structural GenomiX,
10505 Roselle Street, San Diego, CA 92121, USA. Tel.: +1-858-558-
4850; fax: +1-858-558-4859; e-mail: kevin_liu@stromix.com
Figure 1. PPAR agonists.
0960-894X/01/$ - see front matter # 2001 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(01)00458-9

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K. G. Liu et al. / Bioorg. Med. Chem. Lett. 11 (2001) 2385–2388
Scheme 1. Reagents: (a) (i) Na2CO3; (ii) isoamyl nitrite, cat. HOAc, CHCl3, reflux, 30 min, 100%; (b) Rh2(OAc)4, i-PrOH, rt, overnight, 38%; (c)
H2, 10% Pd/C, EtOH, rt, overnight, 98%; (d) chloroacetonitrile, Cs2CO3, CH3CN, rt, overnight, 79%; (e) acrylonitrile, cat. benzyltrimethyl
ammonium hydroxide, MeOH, reflux, 24 h, 64%; (f) NH2OH, H2O/MeOH, reflux, 4 h, 71% for 9 and 17% for 10; (g) acyl chlorides, pyridine,
reflux, 2 h; or carboxylic acids, 1,10-carbonyl diimidazole, DMF, 110 ꢁC, 24–90%; (h) LiOH, THF/H2O/MeOH, rt, overnight, 90–100%.
some compounds within this series also demonstrate
partial agonist activity on PPARd.
All of the analogues tested profile as potent PPARa and
PPARg dual agonists, with several analogues also dis-
playing submicromolar PPARd partial agonist activity
(e.g., 1m and 2e). The substituents on the oxadiazole tail
affect the PPARa and PPARg potency. The number of
carbon atoms (one for 1 and two for 2) between the
oxadiazole tail and the central phenoxy moiety also
affects the potency. In general, compounds with a two-
carbon linker (e.g., 2a, 2b, 2c, and 2h) are more potent
against PPARg but less potent against PPARa than
their one-carbon linker analogues (1a, 1b, 1c, and 1n,
The general preparation of these PPAR agonists of ser-
ies 1 and 2 is depicted in Scheme 1. The synthesis starts
with commercially available O-benzyl protected tyrosine
methyl ester HCl salt 3. Diazotization of the corre-
sponding free amine following the procedure developed
by Takamura14 provided diazo compound 4 in quanti-
tative yield. Rhodium-catalyzed insertion of iso-
propanol to 4 provided a-isopropoxy methyl ester 5 in
relatively low yield along with the a,b-unsaturated pro-
penoic acid as the major side product via elimination.
The propensity for byproduct formation varied with the
alcohol and reaction conditions. After exploring a
number of different reaction conditions, we found that
three equivalents of isopropanol in toluene at room
temperature provided the highest yield of 5. Debenzy-
lation of 5 by catalytic hydrogenolysis afforded phenol
6, which upon alkylation with chloroacetonitrile and
Cs2CO3 in acetonitrile provided nitrile 7. Michael addi-
tion of 6 to acrylonitrile catalyzed by benzyltrimethyl
ammonium hydroxide provided nitrile 8. Addition of
hydroxylamine to nitriles 7 and 8 provided advanced
intermediates amide oximes 9 and 10, respectively.
Oxadiazole formation via treatment with acid chlorides
in pyridine at reflux or with 1,10-carbonyl diimidazole
(CDI) in DMF using more readily available carboxylic
acids as reported by Deegan15 provided oxadiazoles 11
and 12, which upon saponification furnished target
molecules 1 and 2, respectively.
Table 1. Transient transfectiona data of PPAR agonists 1 and 2
Compd
R
EC50 (nM)
hPPARa
EC50 (nM)
hPPARg
EC50 (nM)
hPPARd
1a
1b
1c
1d
1e
1f
1g
1h
1i
H
3-F
4-F
2-Me
3-Me
4-Me
4-Cl
4-Br
160
79
160
40
79
25
13
40
32
20
13
40
40
6
240
2000
500
790
400
320
200
400
50
79
100
200
100
50
16
20
32
25
63
4
10,000
7900b
7900b
1600b
1600b
2500b
500b
790b
4-CF3
4-CF3O
4-i-Pr
4-t-Bu
3,5-di-F
3,5-di-CF3
Cyclohexyld
H
500b
1j
1k
1l
7900b
7900b
5000b
160b
3
1m
1n
1o
2a
2b
2c
2d
2e
2f
100
32
230
13
2
40
25
4
320b
c
—
—
c
3-F
4-F
4-Cl
3-Cl
4000b
c
—
c
—
100b
500b
The target compounds 1a–o and 2a–h were initially
synthesized in racemic form and were evaluated for
their binding affinity and functional potency against the
three human PPAR subtypes. The details of both the
binding7,16 and the cell-based functional assays6,7 have
been previously reported. In general, compound affi-
nities for the three PPAR subtypes correlated well with
their potency of activation in the functional assay (data not
shown). The latter was used to establish the structure–
activity relationship (SAR) and is depicted in Table 1.
3-CF3
2-CF3
3,5-di-CF3
6
160
4
2g
2h
2500
c
—
a,bCompounds were assayed for agonist activity on PPAR-GAL4 chi-
meric receptors in transiently transfected CV-1 cells as described;6,7,17
EC50=the concentration of test compound that gave 50% of the
maximal reporter activity.
bCompound with percent activation 40–70%.
cCompounds with percent activation <40%.
dCyclohexyl directly attached to oxadiazole. All data ꢂ15% (n=3).

K. G. Liu et al. / Bioorg. Med. Chem. Lett. 11 (2001) 2385–2388
2387
respectively). Most of the compounds listed in Table 1
have an oxadiazole tail substituted with an aromatic
group. Compounds with non-aromatic group-sub-
stituted oxadiazole tails are much less potent (1o). For
compounds with a one-carbon linker (1), the phenyl
derivative 1a was fairly potent (ꢃ100 nM) at both
PPARa and PPARg. While substitution of the phenyl
ring with a fluorine did not improve the potency (1b and
1c), substitution with a larger methyl group especially at
the 4-position was found to improve potency for both
PPARa and PPARg (1f). Substitution at the 4-position
with the sterically more demanding isopropyl group
provided 1k as one of the most potent PPARa/g dual
agonists with EC50=13 nM at PPARa and EC50=4 nM
at PPARg. The 4-t-Bu compound 1l is also a potent
PPARa/g dual agonist with ꢃ15-fold selectivity for
PPARg versus PPARa. Interestingly, substitution with
trifluoromethyl groups at both 3- and 5- positions pro-
vided a potent PPARa/g dual agonist 1n with ꢃ5- fold
selectivity for PPARa over PPARg. Clearly, the selec-
tivity between PPARa and PPARg can be fine-tuned in
this series by changing the substituents on the oxadia-
zole tail. The selectivity between PPARa and PPARg
may be critical in order to achieve the optimal in vivo
PPARa/g dual agonist profile.
In order to determine whether PPAR activity resides in
one or both enantiomers, the racemic methyl ester of 1n
was resolved by chiral HPLC to afford the enantio-
merically pure methyl esters, which upon saponification
with LiOH in THF and H2O provided enantiomerically
pure carboxylic acids (+)-1n and (ꢀ)-1n. No racemiza-
tion was observed during saponification based on chiral
HPLC analysis. The (ꢀ)-enantiomer [[a]2D3 ꢀ18.8 (c 0.43,
MeOH)] is 500-fold more potent on PPARa and 12-fold
more potent on PPARg than its (+)-antipode [[a]2D3 19.5
(c 0.43, MeOH)] (Table 2). Interestingly, there was little
difference in the PPARd activity of the two enantio-
mers. Thus, different levels of enantioselectivity was
observed on each of the three PPAR subtypes. The (ꢀ)-
enantiomer presumably has an (S)-configuration based
on the cocrystal structures of PPARg with related com-
pounds.18
In summary, we have identified a series of oxadiazole-
substituted a-isopropoxy phenylpropanoic acids with
dual agonist activity on PPARa and PPARg. Several of
these compounds also showed partial agonist activity on
PPARd. These oxadiazole-based PPAR agonists may
provide lead compounds to develop new anti-
hyperglycemic agents with an improved lipid-lowering
capability over currently available PPARg agonists.
In contrast to the one-carbon linker compounds 1 that
are approximately equipotent at PPARa and PPARg,
compounds with a two-carbon linker (2) are often >10-
fold more potent at PPARg than at PPARa. Substitu-
tion at both 3- and 5-positions with trifluoromethyl
groups provided the most potent PPARa and PPARg
analogue 2h in the two-carbon linker series with
EC50=50 nM at PPARa and EC50=4 nM at PPARg.
Acknowledgements
The authors would like to thank Melissa Lindsay and
Manon Villeneuve for the separation of enantiomers of 1n.
References and Notes
Certain compounds in both one-carbon (1) and two-
carbon (2) linker series also showed partial agonist
activity at PPARd in the cell-based functional assay.
These compounds stimulated transcription by only 40–
70% as compared to the positive control GW501516.10
Most of the compounds showed weak (EC50>1 mM)
potency at PPARd. However, substitution on the
phenyl ring with electron-withdrawing groups both in
one-carbon series 1 and in two-carbon series 2 increased
the potency (1g–i, 1 m–n, 2e–f). The most potent
PPARd compound 2e has an EC50 of 100 nM in the
functional assay. The in vivo pharmacological sig-
nificance of the observed in vitro partial agonist activity
on PPARd is unknown.
1. Cobb, J.; Dukes, I. Annu. Rep. Med. Chem. 1998, 33, 213.
2. Goldberg, I. J. J. Clin. Endocrinol. Metab. 2001, 86, 965.
3. Garg, A. Am. J. Cardiol. 1998, 81, 47 B.
4. Cantello, B. C. C.; Cawthorne, M. A.; Cottam, G. P.; Duff,
P. T.; Haigh, D.; Hindley, R. M.; Lister, C. A.; Smith, S. A.;
Thurlby, P. L. J. Med. Chem. 1994, 37, 3977.
5. Momose, Y.; Meguro, K.; Ikeda, H.; Hatanaka, C.; Oi, S.;
Sohda, T. Chem. Pharm. Bull. 1991, 39, 1440.
6. Lehmann, J. M.; Moore, L. B.; Simth-Oliver, T. A.; Wilk-
ison, W. O.; Willson, T. M.; Kliewer, S. A. J. Biol. Chem.
1995, 270, 12953.
7. 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.; Szewc-
zyk, J. R.; Willson, T. M. J. Med. Chem. 1998, 41, 5020.
8. Staels, B.; Dallongeville, J.; Auwerx, J.; Schoonjans, K.;
Leitersdorf, E.; Fruchart, J.-C. Circulation 1998, 98, 2088.
9. Brown, P. J.; Winegar, D. A.; Plunket, K. D.; Moore, L. B.;
Lewis, M. C.; Wilson, J. G.; Sundseth, S. S.; Koble, C. S.; Wu,
Z.; Chapman, J. M.; Lehmann, J. M.; Kliewer, S. A.; Willson,
T. M. J. Med. Chem. 1999, 42, 3785.
Table 2. Different PPAR activity of 1n enantiomers in transient
transfection assaya
Compounds
R
EC50 (nM)
hPPARa
EC50 (nM)
hPPARg
EC50 (nM)
hPPARd
(ꢂ)-1n
(ꢀ)-1nc
(+)-1nd
3,5-di-CF3
3,5-di-CF3
3,5-di-CF3
6
4
2500
32
32
630
320b
630b
790b
10. Oliver, W. R., Jr.; Shenk, J. L.; Snaith, M. R.; Russell,
C. S.; Plunket, K. D.; Bodkin, N. L.; Lewis, M. C.; Winegar,
D. A.; Sznaidman, M. L.; Lambert, M. H.; Xu, H. E.; Stern-
bach, D. D.; Kliewer, S. A.; Hansen, B. C.; Willson, T. M.
Proc. Natl. Acad. Sci. U.S.A. 2001, 98, 5306.
a,bSee footnotes to Table 1. All data ꢂ15% (n=3).
c(ꢀ)-1n: [a]2D3 ꢀ18.8 (c 0.43, MeOH).
d(+)-1n: [a]2D3 19.5 (c 0.43, MeOH).

2388
K. G. Liu et al. / Bioorg. Med. Chem. Lett. 11 (2001) 2385–2388
11. Hulin, B.; Newton, L. S.; Lewis, D. M.; Genereux, P. E.;
Gibbs, E. M.; Clark, D. A. J. Med. Chem. 1996, 39, 3897.
12. Aller, E.; Buck, R. T.; Drysdale, M. J.; Ferris, L.; Haigh,
D.; Moody, C. J.; Pearson, N. D.; Sanghera, J. B. J. Chem.
Soc., Perkin Trans. 1 1996, 2879.
13. Haigh, D.; Allen, G.; Birrell, H. C.; Buckle, D. R.; Can-
tello, B. C. C.; Eggleston, D. S.; Haltiwanger, R. C.; Holder,
J. C.; Lister, C. A.; Pinto, I. L.; Rami, H. K.; Sime, J. T.;
Smith, S. A.; Sweeney, J. D. Bioorg. Med. Chem. 1999, 7, 821.
14. Takamura, N.; Mizoguchi, T.; Koga, K.; Yamada, S.
Tetrahedron Lett. 1971, 4495.
15. Deegan, T. L.; Nitz, T. J.; Cebzanov, D.; Pufko, D. E.;
Porco, J. A., Jr. Bioorg. Med. Chem. Lett. 1999, 9, 209.
16. Nichols, J. S.; Parks, D. J.; Consler, T. G.; Blanchard,
S. G. Anal. Biochem. 1998, 257, 112.
17. Willson, T. M.; Cobb, J. E.; Cowan, D. J.; Wiethe, R. W.;
Correa, I. D.; Prakash, S. R.; Beck, K. D.; Moore, L. B.;
Kliewer, S. A.; Lehmann, J. M. J. Med. Chem. 1996, 39, 665.
18. Gampe, R. T., Jr.; Montana, V. G.; Lambert, M. H.;
Miller, A. B.; Bledsoe, R. K.; Milburn, M. V.; Kliewer, S. A.;
Willson, T. M.; Xu, H. E. Mol. Cell 2000, 5, 545.