Identification of pirinixic acid derivatives bearing a 2-aminothiazole moiety combines dual PPARα/γ activation and dual 5-LO/mPGES-1 inhibition

Article abstract of DOI:10.1016/j.bmcl.2014.06.077

The concept of dual PPARα/γ activation was originally proposed as a new approach for the treatment of the metabolic syndrome. However, recent results indicated that PPARα as well as PPARγ activation might also be beneficial in the treatment of inflammator

Full text of DOI:10.1016/j.bmcl.2014.06.077

Accepted Manuscript
Identification of pirinixic acid derivatives bearing a 2-aminothiazole moiety
combines dual PPARα/γ activation and dual 5-LO/mPGES-1 inhibition
Thomas Hanke, Christina Lamers, Roberto Carrasco Gomez, Gisbert Schneider,
Oliver Werz, Manfred Schubert-Zsilavecz
PII:
S0960-894X(14)00707-0
DOI:
http://dx.doi.org/10.1016/j.bmcl.2014.06.077
BMCL 21796
Reference:
Bioorganic & Medicinal Chemistry Letters
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Received Date:
Revised Date:
Accepted Date:
29 April 2014
24 June 2014
26 June 2014
Please cite this article as: Hanke, T., Lamers, C., Gomez, R.C., Schneider, G., Werz, O., Schubert-Zsilavecz, M.,
Identification of pirinixic acid derivatives bearing a 2-aminothiazole moiety combines dual PPARα/γ activation and
dual 5-LO/mPGES-1 inhibition, Bioorganic & Medicinal Chemistry Letters (2014), doi: http://dx.doi.org/10.1016/
j.bmcl.2014.06.077
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Identification of pirinixic acid derivatives
bearing a 2-aminothiazole moiety combines
dual PPARα/γ activation and dual 5-
LO/mPGES-1 inhibition
Leave this area blank for abstract info.
Thomas Hankea,†, Christina Lamersa,†, Roberto Carrasco Gomeza,b, Gisbert Schneiderb, Oliver Werzc and
Manfred Schubert-Zsilavecza∗
a Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany
b ETH Zürich, Department of Chemistry and Applied Biosciences, Wolfgang-Pauli-Strasse 10, CH-8093 Zürich, Switzerland
c Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University Jena, Philosophenweg 14, D-07743 Jena, Germany

Bioorganic & Medicinal Chemistry Letters
journal homepage: www.els evier.com
Identification of pirinixic acid derivatives bearing a 2-aminothiazole moiety
combines dual PPARα/γ activation and dual 5-LO/mPGES-1 inhibition
Thomas Hankea,†, Christina Lamersa,†, Roberto Carrasco Gomeza,b, Gisbert Schneiderb, Oliver Werzc and
Manfred Schubert-Zsilavecza∗
a Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany
b ETH Zürich, Department of Chemistry and Applied Biosciences, Wolfgang-Pauli-Strasse 10, CH-8093 Zürich, Switzerland
c Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University Jena, Philosophenweg 14, D-07743 Jena, Germany
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
The concept of dual PPARα/γ activation was originally proposed as a new approach for the
treatment of the metabolic syndrome. However, recent results indicated that PPARα as well as
PPARγ activation might also be beneficial in the treatment of inflammatory diseases and cancer.
We have recently identified aminothiazole-featured pirinixic acids as dual 5-lipoxygenase (5-
LO) and microsomal prostaglandin E2 synthase-1 (mPGES-1) inhibitors. Here we present the
structure-activity relationship of these aminothiazole-featured pirinixic acids as dual PPARα/γ
agonists and discuss their advantages with their potential as dual 5-LO/mPGES-1 inhibitors in
inflammatory and cancer diseases. Various pirinixic acid derivatives had already been identified
as dual PPARα/γ agonists. However, within this series of aminothiazole-featured pirinixic acids
we were able to identify the most potent selective PPARγ agonistic pirinixic acid derivative
Keywords:
PPARα
PPARγ
Inflammation
5-LO
mPGES-1
Cancer
(compound 13,
(2-[(4-chloro-6-{[4-(naphthalen-2-yl)-1,3-thiazol-2-yl]amino}pyrimidin-2-
yl)sulfanyl]octanoic acid)). Therefore, docking of 13 on PPARγ was performed to determine the
potential binding mode.
2009 Elsevier Ltd. All rights reserved.
Peroxisome proliferator-activated receptors (PPARs) belong
to the superfamily of the nuclear receptors. They act as ligand-
activated transcription factors and regulate various biological
processes. Three distinct forms have been identified PPARα
(NR1C1), PPARβ/δ (NR1C2) and PPARγ (NR1C3) and each
subtype differs in tissue distribution and expression pattern.1
Several natural and synthetic ligands have been discovered for
each subtype. Selective agonists of PPARα, the drug class of
fibrates, are used for the treatment of dyslipidemia, and selective
PPARγ agonists are used for treatment of type 2 diabetes
mellitus. Much effort has been done in the research and
development of dual PPARα/γ activators as a new approach for
the treatment of the metabolic syndrome (MS). However many of
these so-called glitazars (dual PPARα/γ activators) failed in large
clinical trials, mainly due to undesired side effects and up to now
just one glitazar (Saroglitazar, LipaglynTM, s. figure 1) was able
to enter the market and is approved in India for the therapy of
patients suffering from diabetes and dyslipidemia.2
been identified as natural PPAR ligands, like 15-keto-PGE2 or
15d-PGJ2 as ligands for PPARγ or LTB4 as ligand for PPARα. 24,
25, 26
Their physiological action, triggered through PPAR
activation, is mainly associated with anti-inflammatory effects,
which renders PPAR an attractive therapeutic target in
inflammation-related diseases.4, 5 LTB4 was the first eicosanoid
which has been identified to control inflammation via the PPARα
pathway.6 PPARα activation reduces secretion of LTB4, which
demonstrates that LTB4 has besides its pro-inflammatory action
also anti-inflammatory effects mediated through PPARα.7
Mendez and LaPointe demonstrated that PPARγ activation,
mediated by 15d-PGJ2 or troglitazone, leads to a complete
inhibition of IL-1β-mediated induction of microsomal
prostaglandin E2 synthase-1 (mPGES-1).8
Notwithstanding the above, in the last decade much effort has
been done to elucidate the complex interaction of the lipid
signaling network and the PPARs.1, 3 Various eicosanoids have
Figure 1: Chemical structure of Saroglitazar (LipaglynTM
)
———
∗ Corresponding author. Tel.: +49-69-798 29339; fax: +49-69-798 29332; e-mail: schubert-zsilavecz@pharmchem.uni-frankfurt.de
† Both authors contributed equally to this work.

Figure 2: Various pirinixic acid derivatives with PPARα and PPARγ activity.
Scheme 1: Synthesis of pirinixic acid derivatives; Reagents and Conditions: (Step I) 2-Bromo-(R1)-ethyl acetate (1.2 equiv),
thiobarbituric acid (1 equiv), TEA (1.5 equiv), DMF, 90 °C, 3 h, 21–79%; (Step II) POCl3 (18 equiv), N,N-diethylaniline (1 equiv),
90°C, 6 h, 86–94%; (Step III) Pd2(dba)3 (0.02 equiv), Xantphos (0.06 equiv), Na2CO3 (1.4 equiv), toluene/water, 90 °C, 18 h, 19–66%;
(Step IV) LiOH*H2O (5 equiv), THF/water, 45 °C, 24–48 h, 7–89%.
Dual inhibition of mPGES-1 and 5-lipoxygenase (5-LO) is
considered as a new approach for the treatment of cancer, besides
its anti-inflammatory action.9 In addition Avis et al. have shown
that exposure of breast cancer cells to a 5-LO inhibitor up-
regulated both PPARs expression (PPARα and γ), and exposure
of these cells to PPAR agonists, especially PPARγ agonists, led
to potent growth inhibition of respective cancer cells.10 The
positive effects of PPARγ activation in lung cancer have been
Our lead compound pirinixic acid (compound 1) was first
synthesized by Wyeth as anti-hypercholesterolemic agent in
1974.12 Several attempts have been made in our working group to
optimize this lead structure (s. figure 2). Introduction of bulky
lipophilic residues in α-position to the carboxylic acid such as an
alkyl chain (YS121, compound 2) led to dual PPARα/γ activators
or in case of a naphthyl residue to selective PPARγ activators
(compound 3).13, 14 Further optimization was done by focusing on
the lipophilic backbone and introduction of diphenethoxy-
residues (compound 4),15 or replacement of the xylidine-moiety
by a quinolone (compound 5)16 or by a biphenyl-moiety
(compound 6),17 respectively. Recently we have identified a new
class of aminothiazole-featured pirinixic acid derivatives as dual
5-LO/mPGES-1 inhibitors, which exerts anti-inflammatory
properties in vitro and in vivo.18 Within this work we aimed to
reveal the structure-activity relationship of these aminothiazole-
28
described before.27, Moreover, the combination of a PPARγ
agonist and a 5-LO inhibitor have superadditive effects on
growth inhibition and induction of apoptosis in lung cancer cell
lines, which is superior over a 5-LO inhibitor or PPARγ agonist
alone.11 These results encourage the research for compounds
which are able to interfere within the eicosanoid pathway as well
as with PPARs.

Compound
PPAR EC50 [µM] SEM
(rel. activation compared to
control means SEM)
5-LO IC50 [µM]a
mPGES-1
IC50 [µM]a
cell-based
cell-free
α
β
γ
α-substituted pirinixic acid derivates
R1
R2
R3
-H
6.6 0.9
(57 9%)
6.5 0.3
(57 2%)
3.6 0.4
(51 7%)
r.a. @10
24 7%
ia
@10
ia
6.4 0.2
(90 3%)
7.6 1.1
7
8
4-chlorophenyl
n-hexyl
0.9 0.2
0.9 0.1
3.6 0.8
>10
0.8 0.3
3.8 1.0
6.6 1.4
>10
0.7 0.1
1.2 0.2
1.4 0.3
2.3 0.2
4-chlorophenyl
4-chlorophenyl
4-chlorophenyl
n-butyl
n-ethyl
-H
-H
-H
-H
@10 (136 35%)
ia
@10
ia
3.9 0.04
(95 2%)
r.a. @10
63 13%
9
10
@10
4-substituted 2-aminothiazoles
r.a. @6
55.36
1.87%
ia
5.7 2.0
11
phenyl
n-hexyl
-H
0.6 0.03 2.0 0.04
0.8 0.1
@10 (108 24%)
4-
8.2 0.07
ia 7.2 1.6
@10 (139 48%)
12
13
14
15
16
n-hexyl
n-hexyl
n-hexyl
n-hexyl
n-hexyl
-H
-H
-H
-H
-H
0.2 0.04
0.2 0.1
1.5 0.04
1.5 0.1
1.4 0.1
3.0 0.7
0.3 0.1
2.3 0.7
2.5 0.8
1.8 0.4
0.7 0.2
0.4 0.1
1.6 0.2
1.8 0.1
5.0 1.5
methylphenyl
(125 3%)
r.a. @6
37 8%
5.7 0.04
(70 1%)
r.a. @10
18 8%
2.9 0.1
(89.4%)
r.a. @3
52.94
ia
@10
ia
1.3 0.1
(78 3%)
2.9 0.7
2-naphthyl
3,4-
difluorophenyl
2,4-
difluorophenyl
@10
(94 19%)
ia
3.6 0.6
@10 (145 31%)
ia 3.4 0.7
@10 (130 23%)
4-nitrophenyl
5,6,7,8-
tetrahydro-2-
naphthyl
ia
4.1 0.4
17
n-hexyl
n-hexyl
-H
-H
0.4 0.1
>10
2.3 0.8
>10
0.4 0.1
>10
@3
(107 13%)
7.6%
ia
@10
ia
ia
18
4-benzoic acid
@10
@10
4,5-disubstituted 2-aminothiazoles
r.a. @6
23 5%
ia
@10
2.3 0.1
(99 3%)
3.8 0.2
(143.5
19
phenyl
n-hexyl
n-hexyl
-CH3 0.6 0.02
-CH3 0.2 0.02
1.9 0.2
1.6 0.1
0.7 0.2
1.3 0.1
3.9 0.3
(102 14%)
ia
@3
20
4-bromophenyl
10.3%)
cyclized 2-aminothiazoles
5.4 0.5
(229.4
23.9%)
ia
@3
3.7 0.1
(86 5.3%)
21
0.2 0.03
1.9 0.1
1.9 0.1
Table 1: IC50 values of aminothiazole featured pirinixic acid derivatives regarding 5-LO (cell-based and cell-free) and mPGES-1
a
(recently published in18) and EC50 values regarding PPARα/β/γ; Data are expressed as means SEM of single determinations
obtained in at least three independent experiments; ia: inactive at given concentration; r.a.: remaining activity at given
concentration.

featured pirinixic acids on PPARα and PPARγ. We were able
to identify one derivative (compound 13) which was slightly
superior as PPARγ agonist compared to the previous reported
compound 6. In contrast, 13 shows no PPARα activation which
motivated us to prepare a docking pose of compound 13 on
PPARγ to predict the possible binding mode.
partial agonists on PPARα with a maximal activation of about
50% in comparison to the PPARα ligand GW7647. Likewise, we
were able to identify a superagonist on PPARα (compound 21),
which leads to a maximal activation of about 230% (compared to
GW7647).
The structure-activity relationship of the presented compounds
regarding 5-LO and mPGES-1 have been described previously,18
except of compound 18, which is inactive on 5-LO as well as on
mPGES-1 up to 10 µM. In summary it can be concluded that
most of the compounds have a lower IC50 regarding 5-LO and
mPGES-1 than the corresponding EC50 for PPARα and PPARγ.
Starting from parental compound 7 the difference between the
IC50 (5-LO, mPGES-1) and EC50 (PPARs) values is about one
magnitude, which was an encouraging result for us to obtain
some selectivity between these targets. However, we were not
able to completely diminish the PPAR activity of the presented
compounds. In contrast, the most potent dual 5-LO/mPGES-1
inhibitor (compound 13) is also the most potent PPARγ agonist,
though less active regarding PPARα. Nevertheless, as mentioned
above these dual inhibitory properties in case of pro-
inflammatory mediators (PGE2 and LTs) and activation of anti-
inflammatory pathways through PPAR agonism could enhance
the anti-inflammatory efficiency of the presented compounds.
Together, the compounds can be categorized into at least four
different groups.
The syntheses of the presented compounds (7–17 and 19–21)
have been described previously.18 Compounds 7–17 and 19–21
were synthesized in a four step reaction (s. Scheme 1). For
compound 18 the corresponding 2-aminothiazole derivative was
prepared according to Scheme 2.
The final compounds were tested in a PPAR transactivation
assay as described previously.17 Parental compound of this series
of aminothiazole-featured pirinixic acid derivatives is compound
7 with well-balanced moderate activity on PPARα and PPARγ (s.
Table 1). First investigations focused on the α-position by
shortening the n-alkyl chain. As expected shortening to an n-
butyl residue (compound 8) was slightly less active regarding
PPARγ and the unsubstituted derivative (compound 10) was
dramatically less active at least for PPARα. These results are in
accordance to our previously data on the analysis of the variation
of the α-position.13 However, an interesting feature is, that the n-
ethyl derivative (compound 9) was more potent for PPARα and
PPARγ than parental compound 7. In a second step we
investigated the influence of the p-chlorophenyl residue of the
aminothiazole moiety. Diminishing compound 7 to a phenyl
residue (compound 11) slightly increases the activity for PPARγ,
whereas the 4-tolyl derivative (compound 12) was again less
potent on both receptors. Increasing the lipophilic backbone by
replacement of the p-chlorophenyl moiety with a 2-naphthyl
moiety enhances the activity on PPARγ about a factor of five,
whereas for PPARα compound 13 was less active than parental
compound 7. Fluorinated derivatives (compound 14 and 15)
enhance the activity mainly for PPARγ but did not reach the
potency of the 2-naphthyl moiety. An interesting feature is
migration of one fluorine from position 3 to 2 (compound 15)
that completely diminished the activity regarding PPARα.
Introducing a nitro group in p-position (compound 16) enhanced
the activity on both receptors round about a factor 2. Exchange of
the most potent PPARγ moiety, the 2-naphthyl residue (in
I.
Selective mPGES-1 inhibitors
The most selective compound is the α-unsubstituted derivative
compound 10, which has just minor activity on PPARγ at 10 µM,
and was not able to inhibit the LT production, nor is PPARα
agonism conferred.
II.
Dual 5-LO/mPGES-1 inhibitors
The most selective compound featuring dual 5-LO/mPGES-1
inhibition is compound 12, which is about 36- to 41-fold less
active as PPAR agonist compared to LT inhibition at the cellular
level, and about 10-12-fold less potent PPAR agonist versus
mPGES-1 inhibition.
III. Dual 5-LO/mPGES-1 inhibitors and PPARγ agonists
Compounds 13, 15 and 19 possess most selectivity between
PPARα and PPARγ, besides their dual 5-LO/mPGES-1
inhibition, while 13 is the most potent compound on all three
targets.
compound 13) by
a 5,6,7,8-tetrahydro-2-naphthyl moiety
(compound 17) was again more potent than parental compound 7
but did not reach the potency of 13 regarding PPARγ. To
evaluate the concept of fatty acids and fatty acid analogs as
ligands for PPAR we introduced a second carboxylic acid moiety
in compound 18 yielding dicarboxylic acids. And indeed, this
dicarboxylic acid (compound 18) totally lost activity for PPARα
as well as for PPARγ which is in accordance with the model of
PPAR agonists presented previously.17 In a last step we
investigated the substitution pattern at the aminothiazole by
introducing a methyl-group on position 5 or by a cyclized
aminothiazole moiety. The introduction of the methyl group on
position 5 (compound 19) enhanced the activity on PPARγ in
comparison to compound 11, whereas the activity on PPARα was
slightly impaired. Enlargement of the lipophilic backbone by
introducing a p-bromo-substituent (compound 20), restored the
activity on PPARα and was just slightly less active on PPARγ in
comparison to 19. Further enlargement of the lipophilic backbone
by introducing the 7-methoxy-4,5-dihydronaphtho[1,2-d]thiazole
moiety (compound 21) was also well tolerated by both receptors.
The rigidity of the latter moiety implied that less flexible
compounds are also accepted by both receptors, which is in
accordance with the result of the quite large binding pocket of
PPARs (>1300 Å3).20, 21 An interesting feature of the SAR is the
fact that all the p-chlorophenyl compounds (7, 8 and 9) act as
IV. Dual 5-LO/mPGES-1 inhibitors and PPARα/γ agonist
Compounds 9 and 16 have IC50 and EC50 values in a similar
range on all four targets. However, 9 seems to have more
druglikeness features, due to a smaller molecular weight (441 vs
508) and the lack of the metabolically prone n-hexyl residue.
Because compound 13 was even slightly more potent for
PPARγ than the previously reported compound
6 and
additionally, it was selective for PPARγ with no PPARα activity
in contrast to 6, we were encouraged to predict the possible
binding mode. We used the recently published crystal structure of
PPARγ (PDB ID: 3VSO)22 for molecular docking simulations,
because this crystal structure has a high resolution of 2.00 Å and
a ligand with a similar motif, a α-substituted carboxylic acid
derivative which is closely related to our α-substituted pirinixic
acid derivatives. As a result of the synthesis of the compounds (s.
Scheme 1, Step I) all presented compounds are in racemic form.
In our previous work17 we have shown that the absolute
configuration in α-position has a strong impact on the activity of
the compounds on PPARα. However, the impact of the absolute
configuration on PPARγ was less distinctive. Thus, for our most

potent compound (compound 13), which has negligible activity
on PPARα, we have compared both enantiomers (s. Figure 1 SI)
and it seems that the (S)-enantiomer would be better tolerated by
PPARγ. The possible binding mode of 13 is in accordance with
our previous results14, as well as with the control compound
MEKT21 [(2R)-2-benzyl-3-[4-propoxy-3-({[4-(pyrimidin- 2-
yl)benzoyl]amino}methyl)phenyl]propanoic acid] in 3VSO22.
The carboxylic acid head group interacts with two tyrosines
(Tyr327 and Tyr473) as well as with
Scheme 2: Synthesis of dicarboxylic pirinixic acid derivative (comp. 18); Reagents and Conditions: (Step I) Acetyl benzoic acid (1
equiv), EtOH (21 equiv), H2SO4 (0.2 equiv), reflux, 18 h; (Step II) a) Ethyl 4-acetylbenzoate (1 equiv), Br2 (1.05 equiv), CHCl3, RT,
3 h; b) α-bromo-ketone (1 equiv), thiourea (1.5 equiv), MeOH, 3 h, RT; (Step III) Pd2(dba)3 (0.02 equiv), Xantphos (0.06 equiv),
Na2CO3 (1.4 equiv), toluene/water, 90 °C, 18 h; (Step IV) LiOH*H2O (5 equiv), THF/water, 45 °C, 24 h.
Figure 3: Potential binding mode of compound 13 on PPARγ (PDB ID: 3VSO22). Amino acid which interact with the carboxylic acid are Ser289, His323,
Tyr327 and Tyr473. Helix 3 is marked in blue.
Ser289 and His323 (s. Figure 3). Compound 13 has a U-
shaped binding mode from the n-hexyl residue to the thiazole
moiety, whereas the 2-naphthyl residue is wriggled around helix
3. A remarkable feature of the SAR is the fact, that compound 13
has negligible activity on PPARα, whereas it was the most potent
derivative on PPARγ. Therefore, an alignment of the docking
mode of compound 13 in the ligand binding domain of PPARγ
(PDB ID: 3VSO22) was performed with the ligand binding
domain of PPARα (PDB ID: 3KDT29). Interestingly distinct
differences are identifiable. The 2-naphthyl-moiety of compound
13 seems to be too big to fit into the ligand binding domain of
PPARα whereas it was well tolerated in the PPARγ subpocket (s.
Figure 4). Mainly responsible for the differences in these
subpockets is helix 2´ on the entrance of the ligand binding
pocket which is shifted towards the 2-naphthyl-moiety (s. Figure
5).

Figure 4: Comparison of potential binding mode of compound 13 on PPARγ (PDB ID: 3VSO22; green surface) and alignment with LBD of PPARα (PDB ID:
3KDT29; cyan surface).
Figure 5: Alignment of PPARγ LBD (PDB ID: 3VSO22; green surface) with PPARα LBD (PDB ID: 3KDT29; cyan surface).The varying orientation of helix
2´ is highlighted in different colours. The helix 2´ of PPARα (in magenta) is directed to the 2-naphthyl-moiety of compound 13, whereas helix 2´ of PPARγ (in
orange) is targeted away, so that the bulky 2-naphthyl-moiety is better tolerated from PPARγ than from PPARα.
Particularly three amino acids in PPARα could be identified
(L247, E251 and V255) which are directed to the 2-naphthyl-
moiety of compound 13 and therefore reduce the space in the
lipophilic backbone (s. Figure 2 SI). This feature explains on the
one hand why our previous compound 6 was well tolerated on
PPARα, on the other hand it could be used to explain the
differences between the different classes of our compounds and
how they interact in the LBD. The biphenyl-moiety in compound
6 is smaller than the bulkier 4-(2´-naphthyl)-thiazole-2-yl moiety
in compound 13 and that explain, why compound 6 fits perfectly
into the LBD of PPARα and not compound 13. Additionally
compounds with a long unbranched lipophilic backbone like in
compound 6, 7, 12 or 16 are about equal potent on both enzymes,
whereas more branched compounds like 13, 14 or 15 are better
tolerated from PPARγ. Thus, we can conclude that the selectivity
of the presented compounds on the PPARα or PPARγ subtype
depends on the space of the lipophilic backbone. PPARδ activity
is not induced at 10 µM for all compounds of this series. M453
(M417) (V444 in PPARα, L453 in PPARγ) present in the PPARδ
LBD seems to hinder binding of compounds with bulkier
lipophilic substituents in alpha position of the carbocylic acid.30,
31
In conclusion, within this work we identified PPAR agonistic
activity of a set of aminothiazole-based pirinixic acid derivatives
supporting their suitability as anti-inflammatory or anti-cancer
drugs. Even though anti-inflammatory and anti-proliferative
properties of PPAR agonism have been reported over a decade
ago23, suitable clinical studies are still needed to validate this
concept. Nevertheless an increasing demand has emerged for
design of PPAR agonists to elaborate the PPAR effects in
inflammation and inflammation-related diseases4. In our previous
work we have shown, that aminothiazole-based pirinixic acid
derivatives were highly potent in dual 5-LO and mPGES-1
inhibition. The interference within several pathways at once
might have superadditive effects11, and to the best of our
knowledge no such compounds that combine this dual PPARα/γ
agonism and dual 5-LO/mPGES-1 inhibition have been described
before. Here, we have identified several compounds with distinct
pharmacological profiles on the presented targets. The most

17. Zettl, H.; Dittrich, M.; Steri, R.; Proschak, E.; Rau, O.;
Steinhilber, D.; Schneider, G.; Lämmerhofer, M.; Schubert-
Zsilavecz, M. QSAR Comb. Sci. 2009, 5, 576.
18. Hanke, T.; Dehm, F.; Liening, S.; Popella, S.-D.; Maczewsky, J.;
Pillong, M.; Kunze, J.; Weinigel, C.; Barz, D.; Kaiser, A.;
Wurglics, M.; Lämmerhofer, M.; Schneider, G.; Sautebin, L.;
Schubert-Zsilavecz, M.; Werz, O. J. Med. Chem. 2013, 22, 9031.
19. Yin, J.; Zhao, M. M.; Huffman, M. A.; McNamara, J. M. Org.
Lett. 2002, 20, 3481.
20. Pirard, B. J. Comput. Aided Mol. Des. 2003, 11, 785.
21. Ramachandran, U.; Kumar, R.; Mittal, A. Mini-Rev. Med. Chem.
2006, 5, 563.
22. Ohashi, M; Oyama, T.; Putranto, E. W.; Waku, T.; Nobusada, H.;
Kataoka, K.; Matsuno, K.; Yashiro, M.; Morikawa, K.; Huh, N.-
H.; Miyachi, H. Bioorg. Med. Chem. 2013, 8, 2319.
potent derivative regarding PPARγ (compound 13) has also
shown anti-inflammatory efficacy in vivo. Compound 13 was
able to reduce the PGE2 and LTC4 levels in vitro and in vivo.
Additionally, we have seen
a reduction of the vascular
permeability and an inhibition of neutrophil infiltration in a
zymosan-induced peritonitis model in mice.18 Whether the
PPARγ agonism contributes to these anti-inflammatory effects
need to be further elucidated. Finally, our broad in vitro
pharmacological characterization of these aminothiazole featured
pirinixic acids provides the opportunity to examine their potential
in further in vitro and in vivo models of inflammation and
especially cancer diseases, e.g. lung cancer.
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Acknowledgments
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We thank Katrin Fischer and Monika Listing for expert
technical assistance and Martina Annika Heinrich for synthesis
support.
References and notes
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M. Arch. Pharm. 2007, 7, 367.