Characterization of Telmisartan-Derived PPARγ Agonists: Importance of Moiety Shift from Position6 to5 on Potency, Efficacy and Cofactor Recruitment

Article abstract of DOI:10.1002/cmdc.201200337

Selective modulation of the peroxisome proliferator-activated receptor gamma (PPARγ) by direct binding of small molecules demonstrates a promising tool for treatment of insulin resistance and type2 diabetes mellitus. Besides its blood pressure-lowering properties, the AT₁-receptor blocker telmisartan has been shown to be a partial agonist of PPARγ with beneficial metabolic effects in vitro and in mice. In our previous work, comprehensive structure-activity relationship (SAR) studies discussed the different parts of the telmisartan structure and various moieties. Based on these findings, we designed and synthesized new PPARγ ligands with a benzimidazole (agonists 4-5 and 4-6), benzothiophene (agonists 5-5 and 5-6) or benzofuran (agonists 6-5 and 6-6) moiety either at position5 or6 of the benzimidazole core structure. Lipophilicity and EC₅₀ values were improved for all new compounds compared with telmisartan. Regarding PPARγ activation, the compounds were characterized by a differentiation assay using 3T3-L1 cells and a luciferase assay with COS-7 cells transiently transfected with pGal4-hPPARgDEF, pGal5-TK-pGL3 and pRL-CMV. A decrease in both potency and efficacy was observed after the shift of either the benzothiophene or the benzofuran moiety from position6 to position5. Selective recruitment of the coactivators TRAP220, SRC-1 and PGC-1α, and release of corepressor NCoR1 determined by time-resolved fluorescence resonance energy transfer (TR-FRET) was detected depending on residues in position5 or6.

Full text of DOI:10.1002/cmdc.201200337

MED
DOI: 10.1002/cmdc.201200337
Characterization of Telmisartan-Derived PPARg Agonists:
Importance of Moiety Shift from Position 6 to 5 on
Potency, Efficacy and Cofactor Recruitment
Lena Herbst,[a] Matthias Goebel,[b] Sebastian Bandholtz,[c] Ronald Gust,[d] and
Ulrich Kintscher*[a]
Selective modulation of the peroxisome proliferator-activated
receptor gamma (PPARg) by direct binding of small molecules
demonstrates a promising tool for treatment of insulin resist-
ance and type 2 diabetes mellitus. Besides its blood pressure-
lowering properties, the AT1-receptor blocker telmisartan has
been shown to be a partial agonist of PPARg with beneficial
metabolic effects in vitro and in mice. In our previous work,
comprehensive structure–activity relationship (SAR) studies dis-
cussed the different parts of the telmisartan structure and vari-
ous moieties. Based on these findings, we designed and syn-
thesized new PPARg ligands with a benzimidazole (agonists
4-5 and 4-6), benzothiophene (agonists 5-5 and 5-6) or benzo-
furan (agonists 6-5 and 6-6) moiety either at position 5 or 6 of
the benzimidazole core structure. Lipophilicity and EC50 values
were improved for all new compounds compared with telmi-
sartan. Regarding PPARg activation, the compounds were char-
acterized by a differentiation assay using 3T3-L1 cells and a luci-
ferase assay with COS-7 cells transiently transfected with
pGal4-hPPARgDEF, pGal5-TK-pGL3 and pRL-CMV. A decrease in
both potency and efficacy was observed after the shift of
either the benzothiophene or the benzofuran moiety from po-
sition 6 to position 5. Selective recruitment of the coactivators
TRAP220, SRC-1 and PGC-1a, and release of corepressor NCoR1
determined by time-resolved fluorescence resonance energy
transfer (TR-FRET) was detected depending on residues in posi-
tion 5 or 6.
Introduction
Activation of the peroxisome proliferator-activated receptor
gamma (PPARg) exhibits beneficial effects on the regulation of
genes involved in glucose and lipid metabolism.[1] Therefore,
synthetic high-affinity ligands for PPARg, known as thiazolidine-
diones (TZDs)/glitazones are currently used for the treatment
of type2 diabetes mellitus and insulin resistance. However, full
activation of PPARg frequently goes along with an increase in
body weight, fluid retention, and an increased risk for heart
failure and loss of bone mineral density.[2] Occurrence of seri-
ous side effects accelerated the interest for further investiga-
tion of favorable PPARg ligands. The inhibition of the CDK5-
mediated phosphorylation of some PPARg ligands is currently
discussed to ameliorate an anti-diabetic effect independent of
the PPARg agonism.[3] Meanwhile, nearly all of the initially ap-
proved TZDs have been withdrawn from the market.[4] During
the last years, the concept of selective or “partial activation” of
the receptor, which is reported to be correlated with promising
metabolic efficacy without being tempered by adverse actions,
resulted in the development of a new group of ligands: the se-
lective PPARg modulators (SPPARgMs).[5] Upon binding, these
compounds induce a specific conformational change of the re-
ceptor, resulting in conformation-dependent recruitment or re-
lease of cofactors, and activation of a ligand-specific PPARg
gene-expression profile. The crucial factor is the binding mode
of compounds to the receptor, influencing cofactor interaction
and receptor activation. According to the current understand-
ing, stabilizing helix 12 is required for full agonist activity,[6]
while partial agonists bind via independent mechanisms of
helix 12.[7] NMR studies performed by Hughes et al. revealed
that a conformational disorientation, due to the ability of li-
gands to sample different binding modes, contributes to re-
duced receptor activation and therefore leads to an unfavora-
ble conformation for cofactor binding.[8]
Beside its antihypertensive properties, the angiotensin
type 1 (AT1)-receptor blocker telmisartan has been shown to
act as partial agonist of PPARg in vitro with an excellent side-
effect profile in vivo.[9] In previous studies, we focused on the
analysis of structure–activity relationships (SARs) and modifica-
tion of structural components of telmisartan to develop new
[a] Dr. L. Herbst, Prof. Dr. U. Kintscher
Institute of Pharmacology, Center for Cardiovascular Research
Charitꢀ-Universitꢁtsmedizin Berlin
Hessische Str. 3-4, 10115 Berlin (Germany)
E-mail: ulrich.kintscher@charite.de
[b] Dr. M. Goebel
Institute of Pharmacy, Free University of Berlin
Koenigin-Luise Strasse 2+4, 14195 Berlin (Germany)
[c] S. Bandholtz
Department of Medicine/Hepatology and Gastroenteroloy/Tumor targeting
Charitꢀ-Universitꢁtsmedizin Berlin
Augustenburger Platz 1, 13353 Berlin (Germany)
[d] Prof. Dr. R. Gust
Institute of Pharmacy, Department of Pharmaceutical Chemistry
University of Innsbruck
Innrain 80/82, 6020 Innsbruck (Austria)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/cmdc.201200337.
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therapeutic strategies against in-
sulin resistance.[10] We demon-
strated that a “backbone” part
of telmisartan containing the
basic scaffold of the 1-(biphenyl-
4-ylmethyl)-1H-benzimidazole is
necessary to meet the minimum
requirements for PPARg activa-
tion.[10a] Moreover, elongation of
the alkyl chain at position 2 of
the benzimidazole core, espe-
cially the propyl chain, was im-
portant for potency and activa-
tion.[10b] Furthermore, changes at
positions 5 and 6 of the core
scaffold were shown to have
a strong influence on receptor
activity.[10c] Based on this knowledge, we intended to create
substances with high potency, but we also wanted to gain
more information about the SAR between telmisartan and
PPARg. Accordingly, we synthesized PPARg ligands with a benzi-
midazole, benzothiophene or benzofuran moiety either at po-
sition 5 or 6 of the benzimidazole core. The synthesized com-
pounds exert partial (compounds 4-5, 4-6, 5-5 and 6-5) and
full (compounds 5-6 and 6-6) agonistic receptor-activation
properties, and show a selective recruitment/release pattern of
Scheme 1. Synthesis of compounds 4-5 and 4-6. Reagents and conditions: a) EtOH, concd H2SO4, reflux, 5 h;
b) THF, valeryl chloride, RT, 1 h; c) toluene, pTsOH·H2O, reflux, 3 h; d) MeOH, aq NaOH (10%), reflux, 2 h; e) poly-
phosphoric acid, 1508C, 2 h; f) NaH, 4’-(bromomethyl)-2-biphenylcarbonitrile, DMF, 08C–RT, 5 h; g) ethylene glycol,
KOH, 1858C, 6 h.
polyphosphoric acid at 1508C yielded compound 3.[12] Com-
pounds 4-5 and 4-6 were prepared by N-alkylation of 3 with
4’-(bromomethyl)-2-biphenylcarbonitrile followed by saponifi-
cation of the carbonitrile with potassium hydroxide in ethylene
glycol at 1858C.
The preparation of compound 5 and 6 was described befor-
e.[10c] Compounds 5-5, 5-6 and 6-5 and 6-6 were prepared with
the respective boronic esters by a Suzuki reaction in acetoni-
trile and aqueous sodium carbonate (0.4m) catalyzed by palla-
dium complex (Ph3P)4Pd (Scheme 2).[10c]
cofactors
(thyroid-hormone-receptor-associated
protein
[TRAP220], steroid-receptor coactivator 1 [SRC-1], PPARg co-
activator 1a [PGC-1a], nuclear-receptor corepressor 1 [NCoR1]).
Metabolic efficacy and the influence of these compounds on
the AT1 receptor need to be elucidated in the future.
Separation of the regioisomers was carried out by a combina-
tion of column chromatography (silica gel) and fractional crys-
tallization in methanol or ethanol, respectively. The assignment
of the moieties to position 5 or 6 was performed by differential
1H NMR nuclear Overhauser effect experiments (NOE-Diff) on
the basis of a saturation transfer from the C-7-positioned
proton (H-7) at the central benzimidazole to the benzylic
methylene group.
Result and Discussion
Synthesis
After esterification of 3,4-diaminobenzoic acid with ethanol/
sulfuric acid, the free amino groups were acylated with valeryl
chloride in dry tetrahydrofuran (THF) at room temperature, fol-
lowed by cyclocondensation in toluene and p-toluenesulfonic
acid to give compound 2 (Scheme 1).[11] The ester cleavage
was carried out in a 1:1 mixture of methanol and aqueous
sodium hydroxide solution (10%). The cyclocondensation of
the free carboxyl group with N-methyl-1,2-benzenediamine in
In vitro SAR studies
The AT1-receptor blocker telmisartan has been identified as
a partial PPARg agonist with low potency. In order to optimize
the PPARg-activating properties and develop more potent
PPARg agonists, we synthesized a series of new telmisartan-
based compounds, and performed structure–PPARg-activity re-
lationship studies. Accordingly, compounds were characterized
Scheme 2. Synthesis of compounds 5-5, 5-6, 6-5 and 6-6. Reagents and conditions: a) (Ph3P)4Pd, MeCN, aq Na2CO3 (0.4m), 908C, 6 h; b) ethylene glycol, KOH,
1858C, 6 h.
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Telmisartan-Derived PPARg Agonists
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for PPARg activation in vitro by luciferase transactivation assay
(Figure 1). Pioglitazone, known as a full agonist, was used as
positive control, and maximum activation was defined as
Table 1. clogD, EC50 and maximum activation of the hPPARg-LBD in tran-
sient transfection.
[b,d]
[c,d]
Compd
clogD[a]
(pH 7.4)
EC50
[mm]
Amax
[%]
Pioglitazone
Telmisartan
4-5
4-6
5-5
5-6
6-5
6-6
1.97
2.34
4.51
4.51
5.39
5.39
4.46
4.46
0.83Æ0.16
2.53Æ0.40
0.55Æ0.12
1.99Æ0.34
0.14Æ0.07
0.09Æ0.04
0.23Æ0.12
0.37Æ0.08
98Æ4
62Æ4
42Æ5
70Æ6
27Æ4
87Æ13
34Æ6
90Æ9
[a] Calculated logD (clogD) values were determined with MarvinSketch
5.4.0.0. [b] EC50 values were calculated by the use of the dose–response
curves (Figure 1). [c] The maximal activation shows the highest relative
PPARg-activation triggered by the compounds in comparison to pioglita-
zone (100%). [d] Data points represent the mean (ÆSD) of threefold de-
termination of three independent experiments.
had similar potency for PPARg as our compounds presented in
this publication.[13] However, replacement of the central benzi-
midazole with an indole dramatically increased potency to the
picomolar range under partial receptor activation, but com-
pletely abolished AT1 antagonism.[14] Previous studies by our
group (data not published), and also other groups[13] showed
a negative correlation between PPARg activation and AT1 an-
tagonism. Conclusively, agonists with low efficacy for PPARg
might still be able to block the AT1 receptor.
The shift of a benzimidazole, benzothiophene or benzofuran
moiety from position 6 to position 5 decreased potency and ef-
ficacy (Figure 1). While compounds 4-5 and 4-6 are both partial
agonists, the relocation of the benzothiophene or benzofuran
substituent from position 6 to 5 transformed a full agonist with
higher potency than pioglitazone into a partial agonist. Both,
compounds 5-5 and 6-5 showed reduced maximum activation
values (27Æ4% for 5-5 and 34Æ6% for 6-5) and demonstrat-
ed improved potency relative to telmisartan (Table 1). Com-
pounds corresponding to agonists 4-5 and 4-6 with an
n-propyl chain also resulted in a decrease in efficacy, as pub-
lished by Goebel et al.[10a] Moreover and also shown by Goebel
et al., a one-carbon extension at position 2 is able to increase
potency and efficacy.[10b] In order to generate more potent ag-
onists, compounds 4-5 and 4-6 were synthesized with an
n-butyl chain. Although compounds 4-5 and 4-6 with an
n-propyl or n-butyl chain were not analyzed in the same exper-
imental approach, the extension of the alkyl chain did not
seem to increase potency.
Figure 1. PPARg activation measured with the transactivation assay. COS-7
cells transiently transfected with pGal4-hPPARgDEF and pGal5-Tk-pGL3 were
*
stimulated with pioglitazone ( ; max. activation was set to 100%), telmisar-
~
!
*
*
tan ( ), or DMSO ( ), or synthesized compounds a) 4-5 ( ), 4-6 ( ); b) 5-5
~
!
~
!
(
), 5-6 ( ); and c) 6-5 ( ), 6-6 ( ) in a dose-dependent manner. Firefly luci-
ferase activity was measured after 36 h and normalized with activity of co-
transfected pCMV-Renilla. Data points represent the mean (ÆSD) of three-
fold determination of three independent experiments.
100%. Table 1 shows an overview of lipophilicity, EC50 values
and maximum activation of the ligand binding domain (LBD)
of PPARg. All of the newly synthesized compounds exhibit lipo-
philicity values of about twofold or more than that of telmisar-
tan (clogD=2.34). Best results were obtained with compounds
5-5 and 5-6 merged with a benzothiophene moiety (clogD=
5.39). Relative to telmisartan and even pioglitazone, EC50
values were improved with the modifications at position 5
or 6: telmisartan (EC50 =2.53Æ0.40)>4-6 (EC50 =1.99Æ0.34);
pioglitazone (EC50 =0.83Æ0.16)>4-5 (EC50 =0.55Æ0.12)>6-6
The adipocyte-differentiation assay represents a well-estab-
lished assay for the assessment of cellular PPARg activation.[15]
Thus, the degree of differentiation closely correlates with
PPARg activity. The differentiation grade of 3T3-L1 cells was an-
alyzed by Oil-Red O staining and results are shown in Figure 2.
Oil-Red O staining confirmed the results of the luciferase assay.
Absence of triglyceride accumulation in 3T3-L1 cells after di-
methyl sulfoxide (DMSO) treatment confirmed that activation
is only triggered by pioglitazone, telmisartan or the new com-
pounds. In accordance with results from the PPARg-LBD activi-
(EC50 =0.37Æ0.08)>6-5
(0.23Æ0.12)>5-5
(EC50 =0.14Æ
0.07)>5-6 (EC50 =0.09Æ0.04). Telmisartan analogous with
a central imidazolpyridine published by Casimiro-Garcia et al.
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ies,[16] one may speculate that compound 5-6 and 6-6 behave
in the same manner. However, the mechanisms underlying
TZD-induced weight gain are not completely understood.
TZDs also increase weight via fluid retention resulting in
edema formation.[17] These processes could, at least partially,
be explained by activation of PPARg in the collecting duct of
the kidney, followed by up regulation of the sodium transport-
er, ENaC, or water channels (aquaporins), and subsequent fluid
retention.[18] The effect of the new compounds on fluid reten-
tion remains unclear and has to be addressed in future in vivo
studies.
In vitro cofactor interaction
For further characterization of compounds 4-5 and 4-6, 5-5
and 5-6, and 6-5 and 6-6, nuclear cofactor–PPARg-LBD binding
studies using time-resolved fluorescence resonance energy
transfer (FRET) were performed with the corepressor NCoR1
and co-activators SRC1, PGC-1a and 220TRAP220. Binding of
the indicated compounds to the PPARg-LBD consistently result-
ed in dose-dependent release of the corepressor (Figure 3) and
selective coactivator recruitment (Figure 4). Furthermore,
PPARg activity seems to have a strong impact on the degree of
cofactor recruitment/release. Compounds with strong PPARg
activation properties, like 5-6 and 6-6, showed a strong dose-
dependent release of NCoR1, and recruitment of SRC1, PGC-1a
and TRAP220, while partial PPARg activators (compounds 5-5
and 6-5) hardly interacted with the indicated cofactors
(Figure 3 and Figure4). Compounds with a benzimidazole
moiety at position 5 or 6 (4-5 and 4-6) and with a similar
degree of PPARg activity as telmisartan also showed a telmisar-
tan-like cofactor-recruitment/release pattern (Figure 3a and
Figure 4a, d, andg). These findings suggest a different binding
mode of compound 4-6 compared with compounds 5-6 and
6-6.
Figure 2. PPARg–ligand-dependent adipocyte differentiation. 3T3-L1 cells
were differentiated with the indicated compounds at 0.1 mm, 1 mm and
10 mm. Pioglitazone and telmisartan served as positive controls and DMSO
as vehicle. Oil-RedO staining was performed after 9 days. Pictures are repre-
sentative of three independent experiments.
ty assay, cells treated with the full agonists 5-6 and 6-6 exhibit-
ed the highest degree of adipocyte differentiation. All other
partial agonists showed a similar differentiation pattern to the
one of telmisartan.
Development of selective modulators targeting PPARg for
therapeutic purposes without significant side effects still repre-
sents a pharmacological challenge. Nevertheless, selective
binding of compounds in a different way compared with TZDs
could result in distinct receptor confirmation followed by selec-
tive cofactor release/recruitment. Such selective PPARg modu-
As full PPARy agonism and strong adipocyte differentiation
has been associated with body weight gain in clinical stud-
Figure 3. Corepressor release by TR-FRET. Fluorescein-labeled corepressor NCoR1 was incubated with PPARg-LBD protein labeled with terbium in the presence
~
!
~
!
~
!
*
*
of increasing concentrations of pioglitazone ( ), telmisartan ( ), or synthesized compounds a) 4-5 ( ), 4-6 ( ); b) 5-5 ( ), 5-6 ( ); and c) 6-5 ( ), 6-6 ( ).
FRET signal was calculated as a ratio of 520 nm (fluorescein) to 495 nm (terbium). Data points represent the mean (ÆSD) of threefold determination of three
independent experiments.
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Telmisartan-Derived PPARg Agonists
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Figure 4. Coactivator recruitment by TR-FRET. Fluorescein-labeled coactivators a–c) SRC1, d–f) PGC-1a and g–i) TRAP220 were incubated with PPARg-LBD pro-
~
!
*
*
tein labeled with terbium in the presence of increasing concentrations of pioglitazone ( ), telmisartan ( ), or synthesized compounds a, d, g) 4-5 ( ), 4-6 ( );
~
!
~
!
b, e, h) 5-5 ( ), 5-6 ( ); and c, f, i) 6-5 ( ), 6-6 ( ). FRET signal increases when terbium and fluorescein are in close proximity. Recruitment of coactivators was
calculated as a ratio of 520 nm (fluorescein) to 495 nm (terbium). Data points represent the mean (ÆSD) of threefold determination of three independent
experiments.
lators (SPPARgMs) have already been tested in animal models
demonstrating promising metabolic effects in vivo.[19]
Experimental Section
Chemistry
Conclusions
General: All reagents and solvents were purchased from Acros Or-
We gained knowledge about the structure–PPARg-activity rela-
ganics, Sigma–Aldrich, Alfa Aesar or Merck (Darmstadt, Germany).
tionship for telmisartan-like PPARg ligands after modification of
All reactions were monitored by thin-layer chromatography (TLC),
position 5 or 6 of the central 1-(biphenyl-4-ylmethyl)-1H-benzi-
performed on silica gel plates 60 F254 (Merck). Visualization on TLC
was achieved using UV light. Column chromatography was per-
midazole core of telmisartan. The shift of a substituent from
position 6 to 5 showed a strong influence on potency and effi-
cacy, and induced a selective recruitment/release pattern of co-
factors. The effect was more pronounced with a benzothio-
phene or benzofuran moiety. Thus, these new PPARg ligands
act like SPPARMs. In vivo function and side effect profile of our
compounds has to be elucidated in the future.
formed with silica gel 60H, grain size <0.063 mm, 230 mesh ASTM
(Merck). Melting points were determined using a B545 Bꢁchi capil-
1
lary melting point apparatus (Flawil, Switzerland). H NMR measure-
ments were performed on Avance DPX-400 spectrometer (Bruker,
Karlsruhe, Germany) at 400 MHz (internal standard: TMS). Elemental
analyses were performed in a microlaboratory of the Freie Universi-
tꢂt Berlin (Germany) with elemental analyzer Vario EL (Elementar,
Hanau). The analytical results are within 0.4% of the theoretical
values. Electron ionization (EI) mass spectra were collected using
a CH-7-A-Varian MAT, 70 eV (Melbourne, Australia). A microplate
reader FLASHScan S12 (Analytik Jena AG, Jena, Germany) and a
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microlumat Victor 2 1420 multilabel counter (Wallac, PerkinElmer,
Life sciences, Turku, Finnland) were used.
was removed by filtration, and the soution was recrystallized from
CH2Cl2/MeOH to give compound 3 as colorless crystals (34%; 31%
1
overall yield): H NMR ([D6]DMSO): d=12.4 (s, 1H), 7.9 (d, 1H), 7.63
General procedure for N-alkylation with 4’-(bromomethyl)bi-
phenyl-2-carbonitrile: NaH (2 mmol) was added to a stirred solu-
tion of the appropriate secondary amine (1 mmol) in dry N,N-dime-
thylformamide (DMF; 3 mL) at 08C (ice cooling). After approx.
30 min (or after no more visible emergence of hydrogen), 4’-(bro-
momethyl)biphenyl-2-carbonitrile (0.3 g, 1.1 mmol) was added
slowly and first stirred for 1 h at 08C and then 2–5 h at RT. The re-
action mixture was poured into 6n HCl (1 mL) with crushed ice
(25 g) and extracted with CHCl3 (3ꢃ15 mL). The organic layers
were combined and dried over Na2SO4. After filtration, the solvent
was removed in vacuo, and the resulting crude product was puri-
fied by column chromatography (SiO2) with stepwise gradient elu-
tion (CH2Cl2/MeOH, 99:1, 98:2, 95:5).
(m, 4H), 7.26 (m, 2H), 3.9 (s, 3H), 2.87 (t, J=7.5 Hz, 2H), 1.79 (quin-
tet, J=7.5 Hz, 2H), 1.39 (sextet, J=7.4 Hz, 2H), 0.94 ppm (t, J=
7.4 Hz, 3H); MS (EI, 1758C): m/z (%): 304 (89) [M]+ , 275 (28), 262
C
(100).
4’-[(1’-Methyl-2-propyl-2’,5-bi-1H-benzo[d]imidazole]-1-yl)meth-
yl]biphenyl-2-carboxylic acid (4-5) and 4’-[(1’-Methyl-2-butyl-
2’,6-bi-1H-benzo[d]imidazole]-1-yl)methyl]biphenyl-2-carboxylic
acid (4-6): Compound 3 (0.38 g, 1.26 mmol) was N-alkylated by
a general procedure with 4’-(bromomethyl)biphenyl-2-carbonitrile
(0.38 g, 1.38 mmol). The resulting isomeric mixture of 4’-[(1’-
methyl-2-propyl-2’,5-/6-bi-1H-benzo[d]imidazole]-1-yl)methyl]bi-
phenyl-2-carbonitrile (89%, 0.56 g, 1.12 mmol) was treated with
KOH (0.31 g, 5.6 mmol) as described for the general procedure for
saponification to give a colorless solid. Separation of the 5- and 6-
regioisomers was carried out by a combination of column chroma-
tography (SiO2, CH2Cl2/MeOH, 95:5) and fractional crystallization.
General procedure for saponification of carbonitriles: A solution
of the respective carbonitrile (1 mmol), KOH (5 mmol) in H2O
(1 mmol), and ethylene glycol (4 mL) was stirred and heated to
1858C. Every hour of the reaction time period H2O (1 mmol) has to
be added cautiously. After 5–6 h, the reaction mixture was cooled
to 1008C, and H2O (8 mL) was added. The solution was acidified
with HCl (6n, pH 5–6) and stirred for 15 min to complete precipita-
tion. The obtained solid was purified by column chromatography
(SiO2) with stepwise gradient elution (CH2Cl2/MeOH, 95:5, 9:1, 8:2)
and recrystallization from MeOH.
Compound 4-5 was isolated (CH2Cl2/MeOH, 9:1) as a colorless solid
1
(34%): mp: 1598C; H NMR ([D6]DMSO): d=12.73 (s, 1H), 8.07 (m,
1H), 7.72–7.67 (m, 4H), 7.61 (d, J=7.6 Hz, 1H), 7.55 (td, J=7.6,
1.2 Hz, 1H), 7.44 (td, J=7.5, 1.1 Hz, 1H), 7.36–7.23 (m, 5H), 7.23–
7.19 (m, 2H), 5.63 (s, 2H), 3.92 (s, 3H), 2.93 (t, J=7.5 Hz, 2H), 1.78
(quintet, J=7.4 Hz, 2H), 1.41 (sextet, J=7.4 Hz, 2H), 0.91 ppm (t,
J=7.4 Hz, 3H); MS (EI, 3008C): m/z (%): 514 (8) [M]+ , 470 (100),
C
428 (59), 211 (48), 167 (56), 44 (68); Anal. calcd for C33H30N4O2 ꢃ
0.75H2O: C 75.05, H 6.01, N 10.61, found: C 75.17, H 6.31, N 10.82.
Ethyl-2-butyl-1H-benzo[d]imidazole-6-carboxylate (2): A solution
of 3,4-diaminobenzoic acid (1 g, 6.57 mmol) in dry EtOH (20 mL)
and concd H2SO4 (0.35 mL, 6.6 mmol) was heated under reflux.
After 5–10 h, the reaction was cooled, poured into a NaHCO3 solu-
tion (5%, 40 mL) and extracted with CHCl3 (3ꢃ25 mL). The aque-
ous phase was kept at pH 8 to solely extract the desired ethyl-3,4-
diaminobenzoate. The organic layers were combined and dried
over Na2SO4. After filtration, the solvent was removed in vacuo,
and the resulting crude product (1.05 g, 5.8 mmol, 89%) was dis-
solved in tetrahydrofuran (THF; 10 mL). Valeryl chloride (1.38 mL,
11.6 mmol) was added dropwise and stirred for 1 h at RT. The reac-
tion was poured into a NaHCO3 solution (5%, 15 mL) and extracted
with CHCl3 (3ꢃ20 mL). The organic layers were combined and
dried over Na2SO4. After filtration, the solvent was removed under
reduced pressure, and the resulting crude product (ethyl-3,4-dipen-
tanamidobenzoate, 1.92 g, 5.51 mmol, 95%) was dissolved in a sus-
pension of toluene (55 mL) and p-toluenesulfonic acid monohy-
drate (2.1 g, 11 mmol), and refluxed for 3 h. The reaction work up
was performed as described in the previous step, and the crude
product was purified by column chromatography (SiO2) with step-
wise gradient elution (CH2Cl2/MeOH, 98:2, 95:5, 9:1) to give the
Compound 4-6 was isolated (CH2Cl2/MeOH, 9:1) as a colorless solid
1
(38%): mp: 2208C; H NMR ([D6]DMSO): d=12.82 (s, 1H), 7.93 (d,
J=1.1 Hz, 1H), 7.77 (d, J=8.3 Hz, 1H), 7.72–7.68 (m, 2H), 7.65 (dd,
J=8.3, 1.5 Hz, 1H), 7.60 (d, J=7.4 Hz, 1H), 7.54 (td, J=7.6, 1.4 Hz,
1H), 7.43 (td, J=7.5, 1.2 Hz, 1H), 7.34 (dd, J=7.6, 0.9 Hz, 1H), 7.32–
7.22 (m, 4H), 7.19 (d, J=8.2 Hz, 2H), 5.65 (s, 2H), 3.84 (s, 3H), 2.96
(t, J=7.5 Hz, 2H), 1.79 (quintet, J=7.4 Hz, 2H), 1.42 (sextet, J=
7.4 Hz, 2H), 0.92 ppm (t, J=7.4 Hz, 3H); MS (EI, 2208C): m/z (%)=
514 (6) [M]+ , 469 (100), 211 (32); Anal. calcd for C33H30N4O2: C
C
77.02, H 5.88, N 10.89, found: C 77.11, H 5.87, N 10.75.
4’-[(5-(1-Benzothiophen-2-yl)-2-propyl-1H-benzo[d]imidazol-1-yl)-
methyl]biphenyl-2-carboxylic acid (5-5): 1-Benzothiophen-2-ylbor-
onic acid (0.413 g, 2.32 mmol), Pd(PPh3)4 (0.126 g, 0.12 mmol), and
an aq Na2CO3 solution (5.8 mL, 0.4m, 2.32 mmol) was added to
a solution of 4’-[(5-bromo-2-propyl-1H-benzo[d]imidazol-1-yl)me-
thyl]biphenyl-2-carbonitrile (0.5 g, 1.16 mmol) in MeCN (4.5 mL).
The mixture was stirred at 908C under N2 atmosphere for 5–6 h,
cooled to RT and diluted with H2O (25 mL). The reaction mixture
was extracted with CHCl3 (3ꢃ25 mL). The organic layers were com-
bined and dried over Na2SO4. After filtration, the solvent was
evaporated in vacuo, and the resulting crude product was purified
by column chromatography (SiO2) with stepwise gradient elution
(CH2Cl2/MeOH, 98:2, 95:5, 9:1). The resulting 4’-[(5-(1-benzothio-
phen-2-yl)-2-propyl-1H-benzo[d]imidazol-1-yl)methyl]biphenyl-2-
carbonitrile (74%, 0.415 g, 0.86 mmol) was treated with KOH
(0.24 g, 4.3 mmol) as described in the general procedure for sapo-
nification to give a colorless solid (85%; 63% overall): mp: 2728C;
1H NMR ([D6]DMSO): d=12.73 (s, 1H), 7.99 (s, 1H), 7.96 (d, J=
7.8 Hz, 1H), 7.83–7.81 (m, 2H), 7.7 (dd, J=7.5, 1 Hz, 1H), 7.65–7.60
(m, 2H), 7.54 (td, J=7.26, 1.34 Hz, 1H), 7.45–7.29 (m, 6H), 7.15 (d,
J=8.2 Hz, 2H), 5.58 (s, 2H), 2.87 (t, J=7.4 Hz, 2H), 1.80 (sextet, J=
7.3 Hz, 2H), 0.98 ppm (t, J=7.3 Hz, 3H); MS (EI, 2508C): m/z (%):
1
compound 2 as a colorless solid (93%; 78% overall yield): H NMR
([D6]DMSO): d=12.50 (s, 1H), 8.05 (s, 1H), 7.75 (dd, J=8.4, 1.2 Hz,
1H), 7.52 (s, 1H), 4.30 (quintet, J=7.1 Hz, 2H), 2.82 (t, J=7.5 Hz,
2H), 1.74 (sextet, J=7.4 Hz, 2H), 1.32 (m, 5H), 0.90 ppm (t, J=
7.4 Hz, 3H); MS (EI, 1508C): m/z (%): 246 (43) [M]+ , 217 (17), 202
C
(100), 188 (14).
2-Butyl-1’-methyl-1’H,3H-2’,5-bibenzo[d]imidazole (3): After ester
cleavage of 2 (1 g, 4.06 mmol) in MeOH/aq NaOH (10%) (1:1,
18 mL) at reflux temperature for 2 h, the resulting 2-butyl-1H-ben-
zimidazole-6-carboxylic acid (0.8 g, 3.7 mmol, 91%) was dissolved
in polyphosphoric acid (16 g) at 1508C, and N-methyl-benzene-1,2-
diamine (0.5 g, 4.09 mmol) was added in small portions. After stir-
ring at 1508C for 24 h, the mixture was allowed to cool and H2O
was added in small portions. The solution was adjusted to pH 9 by
addition of concd NH3 under ice cooling. The precipitated solid
502 (36) [M]+ , 458 (61), 211 (41), 167 (100); Anal. calcd for
C
C32H26N2O2S: C 76.47, H 5.21, N 5.57, found: C 76.61, H 5.37, N 5.76.
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Telmisartan-Derived PPARg Agonists
MED
4’-[(6-(1-Benzothiophen-2-yl)-2-propyl-1H-benzo[d]imidazol-1-yl)-
methyl]biphenyl-2-carboxylic acid (5-6): The synthesis was per-
formed as described for compound 5-5, however, starting with 4’-
[(6-bromo-2-propyl-1H-benzo[d]imidazol-1-yl)methyl]biphenyl-2-
carbonitrile (0.5 g, 1.16 mmol) to receive compound 5-6 as a color-
and differentiated by a modified protocol previously described.[21]
Briefly, postconfluent preadipocytes were treated with complete
medium containing dexamethasone (1 mm) and insulin (0.17 mm)
for 3 days. After medium change, cells were incubated with com-
plete medium containing only insulin (0.17 mm) for further 3 days
and with solely complete medium for another 3 days. During the
whole stimulation period, the medium contained either one of the
synthesized compounds, pioglitazone, telmisartan or vehicle
(DMSO) at three different concentrations (0.1 mm, 1 mm and 10 mm).
At day 9 of differentiation, cells were washed with phosphate buf-
fered saline and stained with Oil-RedO for 1 h.
1
less solid (58% overall): mp: 2678C; H NMR ([D6]DMSO): d=12.69
(s, 1H), 7.99 (s, 1H), 7.93 (d, J=7.8 Hz, 1H), 7.81–7.79 (m, 2H),
7.69–7.66 (m, 2H), 7.58 (td, J=8.3, 1.69 Hz, 1H), 7.51 (td, J=
7.56 Hz, J=1.45 Hz, 1H), 7.41 (td, J=7.57 Hz, J=1.28 Hz, 1H),
7.37–7.28 (m, 5H), 7.17–7.15 (m, 2H), 5.63 (s, 2H), 2.83 (t, J=7.4 Hz,
2H), 1.78 (sextet, J=7.3 Hz, 2H), 0.95 ppm (t, J=7.3 Hz, 3H); MS
(EI, 2508C): m/z (%): 502 (100) [M]+ , 211 (93); Anal. calcd for
C
Time-resolved fluorescence resonance energy transfer in vitro: Cell-
free LanthaScreen TR-FRET PPARg coactivator assay (Invitrogen)[22]
was used according to the manufacturer’s protocol. Briefly, the re-
combinant ligand binding domain of PPARg (PPARg-LBD) is tagged
with glutathione S-transferase (GST), and can be recognized by an
anti-GST antibody. Dilution series of the synthesized compounds,
pioglitazone and telmisartan were produced in triplicates and com-
bined with PPARg-LBD and anti-GST antibody in black 384-well
plates (Corning). Maximum concentration of pioglitazone repre-
sented the positive assay control and DMSO served as a negative
control. Binding of the agonist induced a conformational change
of the PPARg-LBD, resulting in an increased affinity for coactivator
peptides. In this assay, cofactor peptides are labeled with fluores-
cein (coactivators: SRC1-GPQTPQAQQKSLLQQLLTE, PGC-1a-
C32H26N2O2S: C 76.47, H 5.21, N 5.57, found: C 76.32, H 5.45, N 5.78.
4’-[(5-(1-Benzofuran-2-yl)-2-propyl-1H-benzo[d]imidazol-1-yl)-
methyl]biphenyl-2-carboxylic acid (6-5): The synthesis was per-
formed as described for compound 5-5, however, starting with 4’-
[(5-bromo-2-propyl-1H-benzo[d]imidazol-1-yl)methyl]biphenyl-2-
carbonitrile (0.5 g, 1.16 mmol) and 1-benzofuran-2-ylboronic acid
(0.376 g, 2.32 mmol). After saponification, compound 6-5 was iso-
lated as a colorless solid (70% overall): mp: 2868C; 1H NMR
([D6]DMSO): d=12.75 (s, 1H), 8.40 (s, 1H), 8.08 (d, J=8.4 Hz, 1H),
7.91 (d, J=8.5 Hz, 1H), 7.73–7.68 (m, 2H), 7.64 (d, J=8.3, 1H),
7.56–7.53 (m, 2H), 7.44 (td, J=7.5 Hz, J=1.2 Hz, 1H), 7.37–7.26 (m,
7H), 5.89 (s, 2H), 3.13 (t, J=7.4 Hz, 2H), 1.80 (sextet, J=7.3 Hz,
2H), 0.98 ppm (t, J=7.3 Hz, 3H); MS (EI, 2758C): m/z (%)=486 (96)
[M]+ , 247 (50), 211 (73), 167 (100); Anal. calcd for C32H26N2O3 ꢃ
EAEEPSLLKKLLLAPANTQ,
TRAP220-NTKNHPMLMNLLKDNPAQD
C
0.5H2O: C 77.56, H 5.49, N 5.65, found: C 77.26, H 5.86, N 5.73.
and corepressor: NCoR1-DPASNLGLEDIIRKALMGSFDDK). Close
proximity of terbium and fluorescein increased the FRET signal.
Fluorescence intensities were measured with a filter-based EnVision
plate reader (PerkinElmer) and FRET signal was calculated by the
ratio of the emission signal at 520 nm (fluorescein) and 495 nm
(terbium). Instrument settings were consistent with the specifica-
tions of the manufacturer for LanthaScreen assays and were tested
with LanthaScreen Tb instrument control kit (Invitrogen).
4’-[(6-(1-Benzofuran-2-yl)-2-propyl-1H-benzo[d]imidazol-1-yl)-
methyl]biphenyl-2-carboxylic acid (6-6): The synthesis was per-
formed as described for compound 5-5, however, starting with 4’-
[(6-bromo-2-propyl-1H-benzo[d]imidazol-1-yl)methyl]biphenyl-2-
carbonitrile (0.5 g, 1.16 mmol) and 1-benzofuran-2-ylboronic acid
(0.376 g, 2.32 mmol). After saponification, compound 6-6 was iso-
lated as a colorless solid (59% overall): mp: 2728C; 1H NMR
([D6]DMSO): d=12.74 (s, 1H), 8.15 (d, J=1.3 Hz, 1H), 7.79 (dd, J=
8.4 Hz, J=1.6 Hz, 1H), 7.71 (dd, J=7.7 Hz, J=1.3 Hz, 1H), 7.66–7.61
(m, 3H), 7.55 (td, J=7.6, J=1.4 Hz, 1H), 7.44 (td, J=7.6, J=1.4 Hz,
1H), 7.38–7.22 (m, 6H), 7.18–7.14 (m, 2H), 5.59 (s, 2H), 2.87 (t, J=
7.4 Hz, 2H), 1.81 (sextet, J=7.3 Hz, 2H), 0.98 ppm (t, J=7.3 Hz,
Acknowledgements
We thank Bart Staels (Institute Pasteur, Lille, France) for pGal4-
hPPARgDEF, and pGal5-TK-pGL3pGL plasmids. This work was sup-
ported by Research Grants Gu285/7-2 and Ki712/3-2 from the
Deutsche Forschungsgemeinschaft (DFG).
3H); MS (EI, 2608C): m/z (%): 486 (100) [M]+ , 247 (35), 211 (63);
C
Anal. calcd for C32H26N2O3: C 78.99, H 5.39, N 5.76, found: C 78.91,
H 5.37, N 5.84.
Keywords: cofactors · PPARg · SPPARMs · structure–activity
relationships · telmisartan
Biology
General: Pioglitazone was obtained from Enzo Life Sciences (Ger-
many) and telmisartan was extracted as previously described.[10a]
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USA) were maintained in DMEM supplemented with FBS (10%)
ChemMedChem 0000, 00, 1 – 9
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Received: July 9, 2012
Published online on && &&, 0000
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FULL PAPERS
Changes to the core: The AT1-receptor
blocker telmisartan is a partial PPARg
agonist with promising in vitro and in
vivo properties for the treatment of in-
sulin resistance. However, potency and
efficacy need to be optimized to accom-
plish sufficient plasma levels for PPARg
activation. Therefore, we performed
modifications at position 2, 5 and 6 in
order to increase potency, but also to
analyze the structure–activity relation-
ship and its influence on cofactor
recruitment.
L. Herbst, M. Goebel, S. Bandholtz,
R. Gust, U. Kintscher*
&& – &&
Characterization of Telmisartan-
Derived PPARg Agonists: Importance
of Moiety Shift from Position 6 to 5 on
Potency, Efficacy and Cofactor
Recruitment
ChemMedChem 0000, 00, 1 – 9
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemmedchem.org
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These are not the final page numbers!