Novel Phenyldiazenyl Fibrate Analogues as PPAR α/γ/δ Pan-Agonists for the Amelioration of Metabolic Syndrome

Article abstract of DOI:10.1021/acsmedchemlett.8b00574

The development of PPARα/γ dual or PPARα/γ/δ pan-agonists could represent an efficacious approach for a simultaneous pharmacological intervention on carbohydrate and lipid metabolism. Two series of new phenyldiazenyl fibrate derivatives of GL479, a previously reported PPARα/γ dual agonist, were synthesized and tested. Compound 12a was identified as a PPAR pan-agonist with moderate and balanced activity on the three PPAR isoforms (α, γ, δ). Moreover, docking experiments showed that 12a adopts a different binding mode in PPARγ compared to PPARα or PPARδ, providing a structural basis for further structure-guided design of PPAR pan-agonists. The beneficial effects of 12a were evaluated both in vitro, on the expression of PPAR target key metabolic genes, and ex vivo in two rat tissue inflammatory models. The obtained results allow considering this compound as an interesting lead for the development of a new class of PPAR pan-agonists endowed with an activation profile exploitable for therapy of metabolic syndrome.

Full text of DOI:10.1021/acsmedchemlett.8b00574

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Letter
Novel Phenyldiazenyl Fibrate Analogues as PPAR #/#/
# Pan-Agonists for the Amelioration of Metabolic Syndrome
Letizia Giampietro, Antonio Laghezza, Carmen Cerchia, Rosalba Florio, Lucia Recinella,
Fabio Capone, Alessandra Ammazzalorso, Isabella Bruno, Barbara De Filippis, Marialuigia
Fantacuzzi, Claudio Ferrante, Cristina Maccallini, Paolo Tortorella, Fabio Verginelli, Luigi
Brunetti, Alessandro Cama, Rosa Amoroso, Fulvio Loiodice, and Antonio Lavecchia
ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.8b00574 • Publication Date (Web): 25 Feb 2019
Downloaded from http://pubs.acs.org on February 28, 2019
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Novel Phenyldiazenyl Fibrate Analogues as PPAR α/γ/δ Pan-Agonists
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Letizia Giampietroa,*, Antonio Laghezzab, Carmen Cerchiac, Rosalba Florioa,d, Lucia Recinellaa, Fabio
Caponec, Alessandra Ammazzalorsoa, Isabella Brunoa, Barbara De Filippisa, Marialuigia Fantacuzzia,
Claudio Ferrantea, Cristina Maccallinia, Paolo Tortorellab, Fabio Verginellia,d, Luigi Brunettia,
Alessandro Camaa,d, Rosa Amorosoa, Fulvio Loiodiceb,**, Antonio Lavecchiac,***
a Department of Pharmacy, University of Chieti “G. d.Annunzio”, Via Dei Vestini, 31, 66100, Chieti, Italy.
b Department of Pharmacy-Drug Science, University of Bari “Aldo Moro”, Via E. Orabona, 4, 70126, Bari, Italy.
c Department of Pharmacy, “Drug Discovery” Laboratory, University of Napoli “Federico II”, Via D. Montesano, 49, 80131,
Napoli, Italy.
dCenter of Aging Science and Translational Medicine (CeSI-MeT), University of Chieti "G. d'Annunzio, Via Luigi Polacchi
11, 66100 Chieti, Italy
KEYWORDS PPARs, pan agonist, docking, metabolic syndrome, type 2 diabetes mellitus, gene expression, PGE2.
ABSTRACT: The development of PPARα/γ dual or PPAR α/γ/δ pan-agonists could represent an efficacious approach for a
simultaneous pharmacological intervention on carbohydrate and lipid metabolism. Two series of new phenyldiazenyl fibrate
derivatives of GL479, a previously reported PPAR α/γ dual agonist, were synthesized and tested. Compound 12a was identified as a
PPAR pan-agonist with moderate and balanced activity on the three PPAR isoforms (α, γ, δ). Moreover, docking experiments showed
that 12a adopts a different binding mode in PPARγ compared to PPARα or PPARδ, providing a structural basis for further structure-
guided design of PPAR pan-agonists. The beneficial effects of 12a were evaluated both in vitro, on the expression of PPAR target
key metabolic genes, and ex vivo in two rat tissues inflammatory models. The obtained results allow considering this compound as
an interesting lead for the development of a new class of PPAR pan-agonists endowed with an activation profile exploitable for
therapy of metabolic syndrome.
Peroxisome proliferator-activated receptors (PPARs) are
members of the nuclear receptor superfamily and play a
decisive role in the regulation of lipid metabolism and glucose
homeostasis. PPARs exist as three subtypes with different
localizations and physiological functions, designated as PPAR
α, PPARγ, and PPARδ.1 These receptors are targets for the
therapy of metabolic syndrome, a group of risk factors for
cardiovascular disease and type 2 diabetes mellitus (T2DM)
including insulin resistance, elevated fasting blood glucose,
hypertension, obesity and atherogenic dyslipidemia.1
Furthermore, metabolic syndrome is accompanied by a low-
grade inflammatory state in white adipose tissue and liver,
which may exacerbate insulin resistance and diabetes.2 Fibrates
(e.g., fenofibrate and gemfibrozil), a class of lipid-lowering
drugs, are PPARα ligands.3 Thiazolidinediones (TZDs), such as
rosiglitazone and pioglitazone, are insulin-sensitizing agents
that activate PPARγ.4 PPARδ agonists have not yet reached the
market, but some of them, for example GW501516, GW0741,
L165,041, GFT505 and MBX8025, are being investigated for a
possible therapeutic usefulness in the treatment of metabolic
disorders, inflammation and angiogenesis (Figure S1).5
However, due to the adverse effects associated with these drug
treatments,3,4 new research strategies have been undertaken
with the aim to obtain new PPAR ligands with reduced side
effects and improved beneficial effects. One of these strategies
consists in the synthesis of PPARα/γ dual or PPAR α/γ/δ pan-
agonists, which beneficially alter carbohydrate and lipid
metabolism in a coordinated manner.6-8 In particular, pan-
agonists would merge the agonist activities with regard to
PPAR α , - γ and –δ in a unique ligand but with a balanced
activation profile, which could be useful for treatment of
metabolic syndrome and T2DM. In the search for new PPAR
ligands with these properties, we have recently discovered a
series of derivatives of the antilipidemic drugs gemfibrozil or
clofibric acid, in which the clofibric acid skeleton was
combined with the lipophilic scaffolds derived from natural
products, such as α -asarone, stilbene, chalcone and their
bioisosters.9-12 In particular, the combination of the clofibric
acid with a phenyldiazenyl function resulted in GL479 (R = H,
X = O, Y = CH2; Figure 1), a PPAR α/γ dual agonist.13 Co-
crystal structures of GL479 with PPARα and -γ revealed that
the ligand adopts different binding modes at these receptor
subtypes, reflecting the distinct activation profile observed for
each receptor.14
Herein we wish to report the synthesis and biological
evaluation of a series of derivatives of GL479 (compound 11a,
Table 1) in which i) small substituents with different
stereochemical properties were inserted at the para position of
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the distal aromatic ring of phenyldiazenyl moiety (compounds
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11b-g) and ii) the oxygen atom of the linker was moved to the
para position of the phenoxy-propanoic acid (compounds 12a-
f). Such design strategy was planned taking into account the
crystallographic pose of GL479 into both PPAR α and –γ: the
hydrophobic tail binds upward into arm II of PPARα, where it
explores a relatively large accessible volume. Instead, this
group bends downward into arm III of PPARγ, surrounded by
hydrophobic residues such as I388, I325, M329 and F266.
Therefore, with the aim of probing further binding interactions
in this region of the protein, we further explored the
introduction of small substituents at para position of the
phenyldiazenyl group. Furthermore, C285 on H3, which
assumes two possible conformations, reflecting a certain degree
of flexibility, and the oxygen in the linker of GL479 are at a
favorable distance for H-bonding. This cysteine residue is also
conserved in PPARα. Thus, in the attempt to promote possible
interactions with cysteine residues on H3, we varied the
position of the oxygen atom on the linker.
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aReagents and conditions: (a) NaNO2, 6N HCl, H2O, 0-5°C, 1h; (b)
Phenol, 4N NaOH, 0-5°C, 1h; (c) oxone, CH2Cl2, H2O, r.t., 4h; (d)
2-(4-aminophenyl)ethanol, CH3COOH, r.t., 24-48h.
Esters 7 and 8 were obtained by SN2 reaction of phenols 4 or
5 with ethyl 2-bromo-2-methylpropanoate (6), in presence of
dry K2CO3 in DMF at reflux (7) or in the presence of KOH in
EtOH at reflux (8) as reported in Scheme 2.
Scheme 2. Synthetic pathways of compounds 4-6, 11a-g,
Aromatic
center
R
12a-f
Acidic head
group
N
O
COOH
N
X
Y
Skeleton of clofibrate
Phenyldiazenyl group
Cyclic tail
Aliphatic
chain
linker
Figure 1. General features of synthetic PPAR agonists and
structural development of the presented compounds.
Phenyldiazenyl derivatives 11a-g and 12a-f (Table 1) were
easily obtained in good yields using simple synthetic
procedures (see Supporting Information for the detailed
procedures). The intermediates 2a-g and 3a-f were synthesized
according to Scheme 1. Phenols 2a-g were synthesized by
diazotization of p-substituted anilines with NaNO2 in 6N HCl
at 0°C and copulation of the obtained diazonium salts with
phenol in 4N NaOH at 0°C. The alcohols 3a-f were synthesized
by oxidation of p-substituted anilines by oxone in
dichloromethane/water at r.t. and subsequent reaction with 2-
(4-aminophenyl)ethanol in CH3COOH at r.t. (Scheme 1).
aReagents and conditions: (a) dry K2CO3, DMF, reflux, 4h,
(Y=CH2CH2OH) (4  7); (b) KOH, EtOH, reflux, N2, 72h,
(Y=OH) (5  8); (c) PPh3, DIAD, N2, THF dry, r.t., 10-12h; (d)
1N NaOH, EtOH, r.t., 15-24h.
Scheme 1. Synthetic Pathways of Compounds 2a-g and 3a-
fa
Esters 9a-g and 10a-f were synthesized by Mitsunobu reaction
between 2a-g or 3a-f and the appropriate alcohol 7 or phenol 8.
These esters were hydrolyzed in basic condition with 1N NaOH
in EtOH at room temperature to obtain the target acids 11a-g
and 12a-f (Scheme 2).
Table 1. In Vitro Transactivation Activity of Compounds With Various Lipophilic Tails and Linkers.
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hPPARα
hPPARγ
hPPARδ
compd
R
H
X
O
Y
1
2
3
4
5
6
7
8
EC50 (μM)a (Emax
)
EC50 (μM)a (Emax
)
EC50 (μM)a (Emax
)
b
b
b
11a
(GL479)
11b
CH2
2.1±0.6 (56±9)
n.d. (13±1)
6.4±1.2 (39±4)
Cl
Br
O
O
CH2 0.38±0.05 (60±6)
CH2 0.81±0.06 (71±10)
n.d. (12±1)
n.d. (12±3)
n.d. (8±1)
n.d. (12±1)
n.d. (14±1)
n.d. (10±1)
6.0±1.5 (24±3)
n.d. (10±1)
n.d. (8±1)
n.d. (9±1)
n.d. (12±2)
n.d. (10±1)
-
3.1±0.4 (23±2)
3.9±0.4 (29±2)
1.8±0.4 (24±3)
6.5±1.2 (20±4)
4.1±1.0 (21±3)
1.4±0.2 (23±2)
2.8±0.3 (35±2)
1.2±0.3 (41±6)
1.1±0.2 (29±3)
n.d. (12±4)
11c
11d
CF3
CN
NO2
OCH3
H
O
CH2
CH2
CH2
CH2
O
2.3±1.3 (35±8)
2.6±0.8 (25±7)
n.d. (11±7)
9
11e
O
10
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12
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11f
O
11g
O
2.4±0.8 (32±2)
0.25±0.07 (69±12)
0.51±0.12 (52±9)
1.9±0.2 (35±4)
2.2±1.2 (37±7)
1.4±0.1 (61±11)
n.d. (19±8)
12a
CH2
CH2
CH2
CH2
CH2
12b
Cl
O
12c
Br
O
12d
CF3
CN
O
12e
O
2.8±0.3 (50±3)
2.3±0.4 (28±3)
-
12f
NO2 CH2
O
Clofibric acid
Rosiglitazone
L165,041
50 ± 6 (100 ± 10)
-
0.04 ± 0.02 (100 ± 9)
-
-
-
0.21 ± 0.04 (100 ± 4)
a EC50 values were determined by testing compounds in at least three separate experiments at five concentrations ranging from 1 to 50 or 100
μM. The results are expressed as the mean ± SEM. bEfficacy values were calculated as percentage of the maximum fold induction obtained
with clofibric acid, rosiglitazone and L165,041 as reference compounds for PPAR, PPAR and PPAR, respectively. n.d.: EC50 not
determined.
All synthesized compounds were evaluated for their agonist
activity toward the three subtypes of human PPARs (hPPARs)
by a cell-based transactivation assay, according to a previously
reported procedure.15 The results were compared with those
obtained with clofibric acid (100 μM), rosiglitazone (2 μM), L-
165,041 (2 μM), used as reference compounds for PPAR α, - γ
GL479, EC50 = 2.1 ± 0.6 μM) and a slight increase of efficacy,
suggesting a favorable influence of the weak electron-
withdrawing properties of these substituents on the activity. In
contrast, the introduction of stronger electron-withdrawing
substituents, such as trifluoromethyl and cyanide, afforded
compounds with potency comparable to GL479 (11d, EC50
=
and -
δ, respectively (Table 1). Maximum fold induction
2.3±1.3 μM; 11e, EC50 = 2.6±0.8 μM), but a concomitant loss
of efficacy from 56% to about 30%. The presence of the highly
hydrophilic nitro group caused an almost complete loss of
PPAR α activation (11f). Compound 11g, bearing the electron-
donating group methoxy, showed a similar activity to the
derivative 11d. Therefore, we argued that the electronic
properties of the substituent in the para position of the distal
aromatic ring of phenydiazenyl moiety do not seem to exert a
crucial role on the activity. Surprisingly, compounds 11b-g
showed poor PPAR γ activity as well as a weak activation of
PPAR δ. In particular, the substitution with trifluoromethyl or
methoxy increased the potency toward
obtained with the reference agonists was set at 100%. The
activity of all compounds was evaluated at 25 μM and only
those showing efficacy percentage (Emax) higher than 20% were
selected for determination of EC50. Because of the different cell
line used in this assay, GL479 turned out to be a partial agonist
instead of a full agonist, as reported earlier13; moreover, this
ligand displayed a significant activation of PPARδ subtype that
had not been previously investigated. Derivatives 11b-g
displayed partial agonist activity towards PPAR
α. The
introduction of a chlorine or bromine resulted in about 3- and
5-fold increase of potency compared to lead compound GL479
(11b, EC50 = 0.38 ± 0.05 μM; 11c, EC50 = 0.81 ± 0.06 μM;
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Figure 2. Binding mode of compound 12a (magenta sticks) into the PPAR (A) and - (B) LBDs, represented as green and dirty violet
ribbon models, respectively. Only amino acids located within 4.5 Å of the bound ligand are displayed (white sticks) and labeled. H-bonds
discussed in the text are depicted as dashed grey lines. H12 is shown in slate.
this receptor subtype, with 11d and 11g being the most potent.
Derivatives 12a-f displayed partial agonism on PPAR α.
Compound 12a, a close analogue of GL479, showed about 8-
fold potency increase and a concomitant slight increase of Emax
(about 70%). Substitutions at the para position of the
phenyldiazenyl moiety afforded compounds displaying lower
potency and efficacy compared to 12a. The chloro (12b) and
cyano (12e) derivatives were the most active. Again, the
presence of the hydrophilic and strong electron-withdrawing
PPAR modulator (SPPARM), that is a ligand that, compared
with a full agonist, differentially induces specific receptor
effects, ideally uncoupling the benefits of PPAR activation from
the adverse side effects.19 Until few years ago, SPPARM
activity was pursued only for PPAR γ agonist, but nowadays it
is considered desirable also for the other two subtypes.20 As far
as we know, 12a is one of the few pan-agonists showing
moderate activity toward all three PPAR subtypes. This is
noteworthy if one considers that most pan-agonists introduced
and then discontinued in clinical trials (e.g. indeglitazar, etc.)21
were full agonists at least toward one of the three subtypes.
To help interpretation of SAR data and to increase our
understanding of the molecular basis for the observed partial
agonism of 12a towards PPAR α, - γ and - δ, we undertook
docking simulations and cluster analysis (see details in
Supporting Information). 12a occupies arms I and II in both
PPARα and -δ (Figure 2), whereas it interacts mainly with arms
II and III in PPARγ (Figure S7). As illustrated in Figure 2A, B,
the clofibric acid moiety of 12a is located in the arm I, making
conventional interactions with the polar side chains (S280,
Y314, H440, and Y464 for PPARα and T253, H287, H413, and
Y437 for PPAR δ), the central phenoxy ring is placed in the
center and the hydrophobic tail part is buried in the arm II. In
the PPAR α LBD complex, the gem-dimethyl substituents are
directed into the lipophilic “benzophenone pocket”, lined by
F273, Q277, V444, and L456.22 However, in PPAR δ V444 is
substituted with a methionine, which has a bulkier side chain
and is less prone to accommodate the fibrate head group.23 This
might account for the potency increase of 12a towards PPARα
and for the decrease of PPAR δ potency. Noteworthy, the
nitro group caused an almost complete loss of PPAR
α
activation (12f). As the activity is not strikingly affected from
the electronic properties of the para-substituent of the distal
aromatic ring of phenyldiazenyl moiety, and given that the
preparation of the derivative bearing the methoxy was
somewhat troublesome, this last compound was not
synthesized. Derivatives 12b-f displayed very weak activation
of PPARγ; only the unsubstituted derivative 12a showed higher
potency and efficacy than the lead compound GL479.
Regarding PPAR δ, all derivatives 12a-f, displayed a partial
agonism profile toward this receptor subtype. Introduction of
chlorine or bromine increased potency with respect to the
unsubstituted derivative 12a, whereas the introduction of
trifluoromethyl group was detrimental. The cyano and nitro
derivatives displayed a similar potency to 12a. Overall, this
second series of derivatives (12a-f) displayed higher potency
and a slightly higher efficacy than the corresponding derivatives
of the first series (11a-f) towards PPARδ. This suggests that the
shift of the oxygen of the linker to the para position of phenoxy
group is more favorable to the interaction and resulting
activation of PPAR δ. Interestingly, 12a resulted more potent
than GL479 but with basically the same significant and well-
balanced activity on all three PPAR subtypes. In fact, 12a
exhibits a weak/moderate efficacy, which is desirable given that
moderately effective PPAR agonists demonstrate good
tolerability and safety in a large population of patients.16-18 In
addition, the partial agonist activity of 12a allows
hypothesizing that this compound behaves like a selective
phenyldiazenyl moiety in PPAR
α forms sulfur-aromatic
interactions24 with C275, C276, M355, and M330. This
remarkable environment might rationalize the augmented
potency of 12a in the PPAR α pocket, which is more lipophilic
and less solvent-exposed than the corresponding pocket of
PPARδ.25
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Figure 3. Expression of PDK4 (panel A), CPT1A (panel B) and GLUT1 (panel C) after treatment with PPAR agonist 12a (100 μM). The
enhanced activity on the gene expression is compared with the commercial compounds L165,041 (2 μM, panel A), GW7647 (2 μM, panel
B) or rosiglitazone (10 μM, panel C) as reference positive controls.
In fact, with the exception of C276, sulfur-containing residues
are not conserved in PPARδ. The 10-fold potency decrease of
11a compared to 12a in PPARα can be explained based on the
valence-bond (or resonance) theory (see details in Supporting
information).
12a binds to PPARγ LBD in a different binding mode as
compared to that of either PPARα LBD or PPAR δ LBD,
because it does not interact directly with H12 (Supporting
information, Figure S7). Therefore, the low affinity and the
attenuated transcriptional response of 12a and its derivatives
towards PPARγ might be ascribed to the peculiar binding mode,
which is not able to replicate the spectrum of contacts of full
agonists.26
significant in the case of metabolic syndrome and
atherosclerosis, which present an inflammatory component.2
This allows hypothesizing that the beneficial effects of PPAR
activation on insulin sensitivity are mediated, at least in part, by
its anti-inflammatory activities. For this reason, we conducted
ex vivo experiments for evaluating the ability of 12a to reduce
the LPS-induced PGE2 production in liver and cortex of male
adult Sprague-Dawley rats. LPS is often used as a stimulus for
the induction of inflammation-related disorders simulating
metabolic diseases.29
Next, we evaluated whether 12a could affect the expression
of three PPAR target genes involved in the control of lipid and
carbohydrate
metabolism,
namely
carnitine
palmitoyltransferase 1A (CPT1A), pyruvate dehydrogenase
kinase 4 (PDK4) and glucose transporter 1 (GLUT1).27 CPT1A
is a molecular component of the carnitine shuttle system that
catalyzes the entry of fatty acids into the mitochondrial matrix
and their subsequent enzymatic oxidation. Importantly, CPT1A
gene expression is enhanced by PPARα agonists.27 PDK4 is a
well-established PPAR δ target gene and contributes to the
regulation of glucose and fatty acid metabolism and
homeostasis.27 GLUT1 is a constitutive glucose transporter
whose expression is increased by PPARγ ligands, resulting in
enhanced glucose uptake and utilization into adipocytes.28
Therefore, a screening of gene activation by RTqPCR (real-time
quantitative PCR analysis) was performed for compound 12a in
HepG2 human hepatocellular carcinoma cell line, using the
PPARδ agonist L165,041, the PPARα agonist GW7647 and the
PPARγ agonist rosiglitazone as reference positive controls. As
illustrated in Figure 3, treatment with 12a (100 μM) showed
enhanced activity on the expression of PDK4 and CPT1A
similar to the agonists L165,041 (2 μM) and GW7647 (2 μM,
Figure 3, panels A and B). Moreover, 12a significantly
increased the mRNA expression level of GLUT1 as compared
to rosiglitazone (10 μM, P< 0.01; Figure 3, panel C). The choice
of performing the experiment at the fixed concentration of 100
μM was based on the lower potency and/or efficacy of 12a in
the transactivation assay compared to the reference compounds
as reported in Table 1. However, these results indicate that 12a,
even though less potent than positive controls, through its
simultaneous and balanced activation of the three PPAR
subtypes may have a beneficial outcome on carbohydrate and
lipid metabolism. In the light of these results, for a deeper
investigation of the biological properties of 12a, we decided to
evaluate its anti-inflammatory activity. Numerous studies
indicate that the role of PPARs in inflammation is particularly
Figure 4. Effects of 12a (0.1–10 μM) on LPS-induced production
of PGE2 (pg/mg) in rat liver (A) and cortex (B), ex vivo. Data were
reported as means ± SEM. Results were analyzed by analysis of
variance (ANOVA) followed by Newman-Keuls post-hoc test.
ANOVA, p < 0.0001; post-hoc ***p < 0.001 vs. LPS-treated group.
To assess the degree of inflammation, we measured the levels
of prostaglandin PGE2, which can contribute to diabetes by
inhibiting insulin secretion, leading to impaired glucose
tolerance and insulin sensitivity.30 Rats were sacrificed and both
liver and cortex specimens were immediately collected and
maintained in a humidified incubator in RPMI (Roswell Park
Memorial Institute) buffer with added bacterial LPS (10
μg/mL). During the incubation period, tissues were treated
alternatively with 1 μM WY14643, pioglitazone, and L165,041
as selective PPARα, -γ, and -δ agonists, respectively, or with
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(2)
Rehman, K.; Akash, M. S. Mechanisms of inflammatory
scalar concentrations of 12a (0.1-10 μM). Compound 12a was
able to significantly inhibit LPS-induced PGE2 production in
both rat liver (Figure 4, panel A) and cortex (Figure 4, panel B),
two tissues that play a central role in the regulation of glucose
homeostasis and metabolism, in a non-dose-dependent manner.
The efficacy of 12a was comparable with that of WY14643 and
pioglitazone, whereas the PPAR δ agonist L165,041 did not
cause any decrease of the LPS-induced PGE2 production in
both tissues.
In conclusion, this study led to the identification of 12a
endowed with moderate activity on the three PPAR subtypes (
α , γ , δ ), which might represent a potential lead for the
development of a new class of PPAR pan-agonists for treatment
of metabolic syndrome and T2DM.
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Boubia, B.; Poupardin, O.; Barth, M.; Binet, J.; Peralba, P.;
ASSOCIATED CONTENT
Supporting Information
(7)
Piemontese, L.; Cerchia, C.; Laghezza, A.; Ziccardi, P.;
Sblano, S.; Tortorella, P.; Iacobazzi, V.; Infantino, V.; Convertini, P.;
Dal Piaz, F. New diphenylmethane derivatives as peroxisome
proliferator-activated receptor alpha/gamma dual agonists endowed
with anti-proliferative effects and mitochondrial activity. Eur. J. Med.
Chem. 2017, 127, 379-397.
The Supporting Information is available free of charge on the ACS
Publications website.
Complete experimental procedures, characterization data for all
compounds, biological procedures, docking and cluster analysis,
and spectra (PDF)
(8)
Piemontese, L.; Fracchiolla, G.; Carrieri, A.; Parente, M.;
Laghezza, A.; Carbonara, G.; Sblano, S.; Tauro, M.; Gilardi, F.;
Tortorella, P. Design, synthesis and biological evaluation of a class of
bioisosteric oximes of the novel dual peroxisome proliferator-activated
receptor α/γ ligand LT175. Eur. J. Med. Chem. 2015, 90, 583-594.
AUTHOR INFORMATION
Corresponding Authors
* E-mail: l.giampietro@unich.it
** E-mail: fulvio.loiodice@uniba.it
*** E-mail: antonio.lavecchia@unina.it
(9)
Giampietro, L.; Ammazzalorso, A.; Bruno, I.; Carradori, S.;
De Filippis, B.; Fantacuzzi, M.; Giancristofaro, A.; Maccallini, C.;
Amoroso, R. Synthesis of Naphthyl‐, Quinolin‐and Anthracenyl
Analogues of Clofibric Acid as PPAR α Agonists. Chem. Biol. Drug
Des. 2016, 87, 467-471.
(10) De Filippis, B.; Agamennone, M.; Ammazzalorso, A.;
Bruno, I.; D'Angelo, A.; Di Matteo, M.; Fantacuzzi, M.; Giampietro,
L.; Giancristofaro, A.; Maccallini, C.; Amoroso, R. PPARα agonists
based on stilbene and its bioisosteres: biological evaluation and
docking studies. MedChemComm 2015, 6, 1513-1517.
(11) Giampietro, L.; D’Angelo, A.; Giancristofaro, A.;
Ammazzalorso, A.; De Filippis, B.; DiMatteo, M.; Fantacuzzi, M.;
Linciano, P.; Maccallini, C.; Amoroso, R. Effect of stilbene and
chalcone scaffolds incorporation in clofibric acid on PPARα agonistic
activity. Med. Chem. 2014, 10, 59-65.
(12) Amoroso, R.; Leporini, L.; Cacciatore, I.; Marinelli, L.;
Ammazzalorso, A.; Bruno, I.; De Filippis, B.; Fantacuzzi, M.;
Maccallini, C.; Menghini, L. Synthesis, Characterization and
Evaluation of Gemfibrozil-stilbene Hybrid as Antioxidant Agent. Lett.
Drug Des. Discov. 2018, 15, 1230-1238.
(13) Giampietro, L.; D’Angelo, A.; Giancristofaro, A.;
Ammazzalorso, A.; De Filippis, B.; Fantacuzzi, M.; Linciano, P.;
Maccallini, C.; Amoroso, R. Synthesis and structure–activity
relationships of fibrate-based analogues inside PPARs. Bioorg. Med.
Chem. Lett. 2012, 22, 7662-7666.
(14) dos Santos, J. C.; Bernardes, A.; Giampietro, L.;
Ammazzalorso, A.; De Filippis, B.; Amoroso, R.; Polikarpov, I.
Different binding and recognition modes of GL479, a dual agonist of
Peroxisome Proliferator-Activated Receptor α/γ. J. Struct. Biol. 2015,
191, 332-340.
(15) Laghezza, A.; Pochetti, G.; Lavecchia, A.; Fracchiolla, G.;
Faliti, S.; Piemontese, L.; Di Giovanni, C.; Iacobazzi, V.; Infantino, V.;
Montanari, R. New 2-(aryloxy)-3-phenylpropanoic acids as
peroxisome proliferator-activated receptor α/γ dual agonists able to
upregulate mitochondrial carnitine shuttle system gene expression. J.
Med. Chem. 2012, 56, 60-72.
(16) Fernández-Miranda, C.; Pérez-Carreras, M.; Colina, F.;
López-Alonso, G.; Vargas, C.; Solís-Herruzo, J. A. A pilot trial of
fenofibrate for the treatment of non-alcoholic fatty liver disease. Dig.
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ORCID
Letizia Giampietro: 0000-0002-8483-1885
Fulvio Loiodice: 0000-0003-3384-574X
Antonio Lavecchia: 0000-0002-2181-8026
Author Contributions
The manuscript was written through contributions of all authors.
All authors have given approval to the final version of the
manuscript.
Notes
The authors declare no conflict of interest.
ACKNOWLEDGMENT
This study was supported by University of Chieti “G. d’Annunzio”
local grants.
ABBREVIATIONS
PPARs, peroxisome proliferator-activated receptors; T2DM, type
2 diabetes mellitus; TZDs, thiazolidinediones; SAR, structure–
activity relationship; CPT1A, carnitine palmitoyltransferase 1A;
PDK4, pyruvate dehydrogenase kinase 4; GLUT1, glucose
transporter 1; LPS, lipopolysaccharide; LBD, ligand binding
domain.
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