Discovery of novel indazole derivatives as dual angiotensin II antagonists and partial PPARγ agonists

Article abstract of DOI:10.1016/j.bmcl.2014.01.004

Identification of indazole derivatives acting as dual angiotensin II type 1 (AT₁) receptor antagonists and partial peroxisome proliferator-activated receptor-γ (PPARγ) agonists is described. Starting from Telmisartan, we previously described that indole derivatives were very potent partial PPARγ agonists with loss of AT₁ receptor antagonist activity. Design, synthesis and evaluation of new central scaffolds led us to the discovery of pyrrazolopyridine then indazole derivatives provided novel series possessing the desired dual activity. Among the new compounds, 38 was identified as a potent AT₁ receptor antagonist (IC₅₀ = 0.006 μM) and partial PPARγ agonist (EC₅₀ = 0.25 μM, 40% max) with good oral bioavailability in rat. The dual pharmacology of compound 38 was demonstrated in two preclinical models of hypertension (SHR) and insulin resistance (Zucker fa/fa rat).

Full text of DOI:10.1016/j.bmcl.2014.01.004

Accepted Manuscript
Discovery of novel indazole derivatives as dual angiotensin II antagonists and
partial PPARγ agonists
Yann Lamotte, Nicolas Faucher, Julien Sançon, Olivier Pineau, Stéphane Sautet,
Marie-Hélène Fouchet, Véronique Beneton, Jean-Jacques Tousaint, Yannick
Saintillan, Nicolas Ancellin, Edwige Nicodeme, Didier Grillot, Paul Martres
PII:
S0960-894X(14)00023-7
DOI:
http://dx.doi.org/10.1016/j.bmcl.2014.01.004
BMCL 21239
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
4 December 2013
2 January 2014
5 January 2014
Please cite this article as: Lamotte, Y., Faucher, N., Sançon, J., Pineau, O., Sautet, S., Fouchet, M-H., Beneton, V.,
Tousaint, J-J., Saintillan, Y., Ancellin, N., Nicodeme, E., Grillot, D., Martres, P., Discovery of novel indazole
derivatives as dual angiotensin II antagonists and partial PPARγ agonists, Bioorganic & Medicinal Chemistry
Letters (2014), doi: http://dx.doi.org/10.1016/j.bmcl.2014.01.004
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Discovery of novel indazole derivatives as dual angiotensin II antagonists and partial
PPARγ agonists
Yann Lamotte*, Nicolas Faucher, Julien Sançon, Olivier Pineau, Stéphane Sautet, Marie-
Hélène Fouchet, Véronique Beneton, Jean-Jacques Tousaint, Yannick Saintillan, Nicolas
Ancellin, Edwige Nicodeme, Didier Grillot, Paul Martres†
Centre de Recherches François Hyafil, GlaxoSmithKline R&D, 25 avenue du Québec, 91140
Villebon-sur-Yvette, France.
* Corresponding author. E-mail: yann.2.lamotte@gsk.com
† Present address: LFB Biotechnologies, 3 avenue des Tropiques BP50052 91942 Courtaboeuf
cedex, France.
Abstract : Identification of indazole derivatives acting as dual angiotensin II type 1 (AT1)
receptor antagonists and partial peroxisome proliferator-activated receptor-γ (PPARγ)
agonists is described.
Starting from Telmisartan, we previously described that indole derivatives were very potent
partial PPARγ agonists with loss of AT1 receptor antagonist activity.
Design, synthesis and evaluation of new central scaffolds led us to the discovery of
pyrrazolopyridine then indazole derivatives provided novel series possessing the desired dual
activity.
Among the new compounds, 38 was identified as a potent AT1 receptor antagonist (IC50
=
0.006 µM) and partial PPARγ agonist (EC50 = 0.25 µM, 40% max) with good oral
bioavailability in rat.
The dual pharmacology of compound 38 was demonstrated in two preclinical models of
hypertension (SHR) and insulin resistance (Zucker fa/fa rat).
Keywords
Telmisartan
PPARγ
Peroxisome proliferator-activated receptor
Angiotensin

Metabolic syndrome refers to a cluster of metabolic disorders such as high blood pressure,
obesity, insulin resistance, and dyslipidaemia that constitutes a major risk factor for
cardiovascular diseases.1-2 A drug that could simultaneously address several of these diseases
would have a significant health benefit effect. The angiotensin II receptor antagonist (AT1
receptor antagonist) Telmisartan (Micardis®) (Fig. 1), a marketed blood pressure reducing
drug was found to exhibit unexpected beneficial metabolic properties on serum glucose levels,
serum triglycerides and insulin.3 In vitro and preclinical in vivo studies have demonstrated
PPARγ activation to be directly linked to these benefits.4-6 More recently, the partial PPARγ
agonist properties of Telmisartan was explained by an unique binding mode in PPARγ ligand
binding domain.7
The identification of essential structural components of Telmisartan for PPARγ receptor
activation has already been disclosed.8 These reports highlighted the importance of the alkyl
side chain at position 2 of the benzimidazole ring9 and the influence of the lipophilic moiety
at position 5 and 610 on potency, efficacy and co-factor recruitment.11
Telmisartan analogues have been designed and reported as dual angiotensin II type 1 receptor
antagonists and partial PPARγ agonists.12−14 More recently, Casimiro-Garcia et al. showed
that modification of the central scaffold could lead to compounds with dual in vitro activity
(imidazo[4,5-c]pyridin-4-one series)15 and in vivo pharmacological effects (imidazo[4,5-
b]pyridine series)16 in two different rodent models (Spontaneously Hypertensive Rats (SHR)
and Zucker fa/fa rats).
In a previous report,17 our group confirmed that the replacement of the methylbenzimidazole
moiety of Telmisartan with a carboxamide at the 6-position of the benzimidazole central core
(compound 2) (Fig.1), increased the affinity for PPARγ while maintaining an acceptable AT1

receptor antagonist activity. Analogue compound substituted at the 5-position (compound 1)
was a less potent PPARγ agonist.
FIGURE 1
Having established that PPARγ activity of Telmisartan could be enhanced while retaining
some AT1 receptor inhibiting activity, we explored novel related scaffolds in order to increase
potency at both PPARγ and AT1 receptors.
In our previous report,17 we demonstrated that the replacement of Telmisartan’s
benzimidazole central core by indole central scaffold (compound 3, Fig. 1) revealed a very
potent PPARγ partial agonist. The crystal structure of compound 3 displayed a novel binding
mode in PPARγ ligand binding domain. This compound demonstrated a similar
pharmacological effect compare to a full PPARγ agonist GW192918 albeit with fewer side
effects as assessed by in vivo experiments in the Zucker fa/fa rat. Unfortunately, compound 3
was totally inactive on AT1 receptor.
Cruciani et al.19 have thoroughly discussed the SAR for AT1 receptor inhibition, emphasizing
the importance of the nitrogen at position 3 on the benzimidazole as a H-bond acceptor key
for AT1 receptor pharmacophore. We therefore focused our efforts on chemical scaffolds that
allow the crucial H-bonding interaction lacking in the indole series.
New ligands where a nitrogen atom is acting as H-bond acceptor (Fig. 2) were design with the
aim to maintain PPARγ agonist activity while restoring AT1 receptor antagonism.
FIGURE 2
The synthetic route of reverse indole series is depicted in Scheme 1. Methyl-4-methyl-3-
nitrobenzoate 4a and methyl-3-methyl-4-nitrobenzoate 4b were submitted to Batcho-

Leimgruber conditions, then sequentially acylated and alkylated to give the corresponding
ketones 6a-b. Reductive cyclization using Pd/C followed by alkylation with methyl iodide led
to compound 9b while zinc-mediated reduction in acetic acid followed by alkylation or tert-
butylcarbamate protection gave compounds 7a and 8a. Saponification, acylation and
deprotection steps afforded compounds 13a, 14a, 15b and 16b.
SCHEME 1
Reverse indoles substituted in position 6 (13a, 14a) act as potent partial PPARγ agonists
(Table 1). Compounds substituted in position 5 (15b, 16b) were more potent PPARγ agonists
than benzimidazole derivative 2. Despite its ability to act as an H-bond acceptor, indole 15b
showed no AT1 receptor activity. Not surprisingly, indoles 14a and 16b which nitrogens are
H-bond donors were inactive on AT1 receptor.
TABLE 1
The synthesis of pyrazolopyridine (compounds 22, 26 and 27) is described in Scheme 2.
Compound 18 was synthesized in two steps from 4-bromobenzoic acid 17 using Weinreb
methodology. Intermediate 18 underwent a 1,3-dipolar cycloaddition reaction with compound
19 to give expected pyrazolopyridine ring 20. Methyl ester was saponified using lithium
hydroxide to afford compound 21. On one hand, a Suzuki reaction followed by a standard
peptide coupling procedure, saponification of the methyl ester using lithium hydroxide and
carbonyl function reduction followed by deshydroxylation under acidic conditions led to
compound 22. On the other hand, compound 23 was prepared by carbonyl function reduction
and deshydroxylation followed by acylation and dehydratation using Eaton reagent.
Introduction of appropriate substituted benzeneboronic acid by Suzuki coupling and
conversion to the corresponding carboxylic acid and tetrazole led respectively to compounds
26 and 27.

SCHEME 2
The modification of central scaffold from reverse indole to pyrazolopyridine ring led to a
similar PPARγ activity (compound 16b vs. 22). However, nitrogen atom acting as H-bond
acceptor in the desired region restored AT1 receptor antagonist activity. Modification of the
left hand side moiety (22 vs. 26) showed a 20-fold improvement on AT1 receptor with similar
potency and efficacy on PPARγ. The replacement of the carboxylic acid 26 to the tetrazole
bioisostere 27 not only improved both AT1 receptor and PPARγ activities, but also led to the
loss of partial agonism.
TABLE 2
The hypothesis to restore AT1 receptor activity proved to be accurate. Thus, we decided to
continue our efforts to discover a molecule with a more attractive dual profile. We decided to
change the central scaffold from pyrazolopyridine to 2H-indazole ring (Fig. 2).
SCHEME 3
The synthetic route of 2H-indazole series is illustrated in Scheme 3. The indazole ring was
prepared via diazotation and cyclization from methyl 4-amino-3-methylbenzoate 28 and
converted to compound 29 by iodination. The compound 29 was then transformed using
iodine-magnesium exchange and the resulting magnesiated species was trapped with tert-
butyl-4'-formyl-2-biphenylcarboxylate A to afford compound 30.21-22 The compound obtained
was then saponified and subjected to peptide-coupling conditions to introduce the lipophilic
left hand side group. Finally, the use of triethylsilane and trifluoroacetic acid in
dichloromethane allowed dehydroxylation and deprotection leading to compound 31.

Compound 35 (R1 = tetrazole) was prepared using an analogous general methodology. For
compounds 37 and 38, the carboxamide moiety was replaced by a butyl-benzimidazole
substituent.
TABLE 3
The replacement of the pyrazolopyridine by an indazole led to a more attractive dual profile
(22 vs. 31). Compound 31 was a more potent AT1 receptor antagonist and an attractive partial
PPARγ agonist. The replacement of carboxylic acid to tetrazole (31 vs. 35) confirmed the
improvement in AT1 receptor antagonist activity (10-fold more potent).
The replacement of carboxamide by butylbenzimidazole (35 vs. 38) led to a very interesting
dual compound (nanomolar range on AT1 receptor and a partial PPARγ agonist activity
compared to Telmisartan).
Compound 38 was also screened on murine PPARα and PPARδ receptors and was found
selective (>10 µM) in a transactivation assay over these two receptor subtypes.
Compound 38, a very interesting dual AT1 receptor and partial PPARγ agonist was then
administered to Zucker fa/fa rats by oral and intravenous routes to determine its
pharmacokinetic profile (Table 4).
TABLE 4
Compound 38 showed a good oral bioavailability (78%) and exhibited a moderate in vivo
clearance (11 mL/min/kg). The pharmacokinetic properties illustrate that compound 38 was
suitable for chronic oral administration allowing it was thus progressed into Zucker fa/fa and
SHR models.

Compound 38 was chronically administrated per os daily for 12 days at 10 mg/kg in SHR
(Fig. 3). During the treatment phase, the systolic and diastolic blood pressure significantly
decreased compared to baseline value and vehicle-treated animals. At the end of the treatment
phase, a wash out period showed that blood pressure in compound 38-treated group was
similar to the vehicle-treated control group, thus confirming in vivo efficacy of compound 38
on blood pressure through AT1 receptor antagonism.
FIGURE 3 / FIGURE 4
Compound 38 was administrated per os to Zucker fa/fa rats for 5 days at 75 mg/kg once daily
and compared to a PPARγ full agonist GW192918 dosed at 1 and 10 mg/kg in the same study
(Fig. 4). The dose chosen for this experiment was deliberately high in order to check that
compound 38 was really acting as a partial PPARγ agonist and to demonstrate potential side
effects.
Compound 38 (75 mg/kg) substantially lowered plasma levels of free fatty acids, insulin and
triglycerides, indicating significant insulin sensitizing activity compared to vehicle-treated
group. The pharmacological effect of compound 38 was found similar when comparing to the
full PPARγ agonist GW1929 administered at 1 mg/kg. However, compound 38 did not
change body weight gain during the study when compared to vehicle group, while a
significant increase in body weight gain was observed in the group treated with the full
PPARγ agonist GW1929 (Fig. 4).
In summary, compound 38 was identified as a potent and selective dual AT1 receptor
antagonist and partial PPARγ agonist. It was found active at 10 mg/kg on blood pressure in
the SHR model. At the dose of 75 mg/kg, compound 38 demonstrated similar effects on
insulin, NEFA and triglycerides compared to a full PPARγ agonist but with no weight gain as
assessed
by
in
vivo
experiments
in
the
Zucker
fa/fa
rats.

Reference and notes
1. Miranda, P. J.; DeFronzo, R. A.; Califf, R. M.; Guyton, J. R. Am. Heart J. 2005, 149, 33.
2. Grundy, S. M. Nat. Rev. Drug Disc. 2006, 5, 295.
3. Kurtz, T.W. Acta Diabetol. 2005, 42, S9-S16.
4. Kurtz, T.W.; Pravenec, M. J. Hypertens. 2004, 22, 2253.
5. Schupp, M.; Janke, J.; Clasen, R.; Unger, T.; Kintscher, U. Circulation 2004, 109, 2054.
6. Benson, S. C.; Pershadsingh, H. A.; Ho, C. I.; Chittiboyina, A.; Desai, P.; Pravenec, M.; Qi,
N; Wang, J.; Avery, M. A.; Kurtz, T.W. Hypertension 2004, 43, 993.
7. Amano, Y.; Yamaguchi, T.; Ohno, K.; Niimi, T.; Orita, M.; Sakashita, H.; Takeuchi, M.
Hypertens. Res. 2012, 35, 719
8. Goebel M.; Clemenz M.; Staels B.; Unger T.; Kintscher U. and Gust R. Chem. Med. Chem.
2009, 4, 445.
9. Goebel, M.; Staels, B.; Unger, T.; Kintscher, U.; Gust R. Chem. Med. Chem. 2009, 4, 1136.
10. Goebel, M.; Wolber, G.; Markt, P.; Staels, B.; Unger, T.; Kintscher, U.; Gust, R. Bioorg.
Med. Chem. 2010, 18, 5885.
11. Herbst, L.; Goebel, Bandholtz, S.; M.; Gust R.; Kintscher, U. Chem. Med. Chem. 2012, 7,
1935.
12. Mizuno, C. S.; Chittiboyina, A. G.; Patny, A.; Kurtz, T. W.; Pershadsingh, H. A.; Speth,
R. C.; Karamyan, V. T.; Avery, M. A. Med. Chem. Res. 2009, 18, 611.
13. Mizuno, C. S.; Chittiboyina, A. G.; Patny, A.; Kurtz, T. W.; Pershadsingh, H. A.; Speth,
R. C.; Karamyan, V. T.; Avery, M. A. Med. Chem. Res. 2009, 18, 611.
14. Mizuno, C. S.; Chittiboyina, A. G.; Shah, F. H.; Patny, A.; Kurtz,T. W.; Pershadsingh, H.
A.; Speth, R. C.; Karamyan, V. T.; Carvalho,P. B.; Avery, M. A. J. Med.Chem. 2010, 53,
1076.
15. Casimiro-Garcia, A.; Heemstra, R. J.; Bigge, C. F.; Chen, J.; Ciske, F. A.; Davis, J. A.;
Ellis, T.; Esmaeil, N.; Flynn, D.; Han, S.; Mehran, J.; Ohren, J. F.; Powell, N. A. Bioorg.
Med. Chem. Lett. 2013, 23, 767.

16. Casimiro-Garcia, A.; Filzen, G. F.; Flynn, D.; Bigge, C. F.; Chen, J.; Davis, J. A.; Dudley,
D. A.; Edmunds, J. J.; Esmaeil, N.; Geyer, A.; Heemstra, R. J.; Jalaie, M.; Ohren, J. F.;
Ostroski, R.; Padalino, T.; Schaum, R. P.; Stoner, C. J. Med. Chem. 2011, 54, 4219.
17. Lamotte, Y.; Martres, P.; Faucher, N.; Laroze, A.; Grillot, D.; Ancellin, N.; Saintillan, Y.;
Beneton, V.; Gampe, R. T. Jr. Bioorg. Med. Chem. Lett. 2010, 20, 1399.
18. Brown, K., K.; Henke, B., R.; Blanchard, S., G.; Cobb, J., E.; Mook, R.; Kaldor, I.;
Kliewer, S., A.; Lehmann, J., M.; Lenhard, J., M.; Harrington, W., W.; Novak, P., J.; Faison,
W., Binz, J., G.; Hashim, M., A.; Oliver, W., O.; Brown, H., R.; Parks, D., J.; Plunket,, K., D.;
Tong, W-Q.; Menius, J., A.; Adkison, K.; Noble, S., A.; Willson, T., M. Diabetes 1999, 48,
1415.
19. Berellini, G.; Cruciani, G. and Mannhold R. J. Med. Chem. 2005, 48, 4389.
20. 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.; Szewczyk, J. R.; Willson,
T. M. J. Med. Chem. 1998, 41, 5020.
21. Despotopoulou, C.; Gignoux, C.; McConnell, D.; Knochel, P. Synthesis 2009, 21, 3661.
22. Knochel, P.; Dohle, P.; Gommermann, N.; Kneisel, F. F.; Kopp, F.; Korn, T.; Sapountzis,
I.; Vu, V. A. Angew. Chem. Int. Ed. 2003, 42, 4302.

Figure 1. Starting from Telmisartan, a very potent PPARγ modulator was previously identified.

Figure 2. Design of new central scaffolds to restore AT1 receptor antagonist activity.

Figure 3. Effect of Compound 38 at 10 mg/kg/day or Vehicle on systolic and diastolic blood pressures
in SHR.

Figure 4. Effect of Compound 38 (75 mg/kg per os – once daily) and GW1929 on triglycerides, insulin,
NEFA and weight gain in male Zucker fa/fa rats after a 5 day oral dosing. (* p < 0.05; ** p < 0.001; ***
p < 0.0001)

Scheme 1. Reagents and conditions: (i) DMF-DMA, DMF, 130°C; (ii) Butyryl chloride, pyridine, DCM,
RT; (iii) NaH, KI, 0°C then 5, reflux; (iv) H2, Pd/C, EtOH/THF, RT; (v) Zn, AcOH, 80°C; (vi) NaH, MeI,
DMF, 0°C to RT; (vii) Boc2O, DMAP, THF, RT; (viii) NaOH, dioxane, 80°C or reflux; (ix) 1-phenylpropan-
1-amine, HATU, Et3N, DCM, RT; (x) HCl(g), EtOAc, RT; (xi) H2, Pd/C, MeOH, RT.

Scheme 2. Reagents and conditions: (i) N,O-Dimethylhydroxylamine hydrochloride, EDCI, HOBt, Et3N,
DMF, RT; (ii) Pent-1-yne, n-BuLi, THF, -78°C to RT; (iii) K2CO3, DMF, 0°C to RT; (iv) LiOH 1N,
THF/MeOH, 70°C; (v) NaBH4, THF/MeOH, RT; (vi) TFA, Et3SiH, DCM, RT; (vii) boronic acid A or B,
Pd(PPh3)4, Cs2CO3 or Na2CO3 or CsF, DME, 110°C; (viii) 1-phenylpropan-1-amine, EDCI, HOBt, Et3N,
DMF, RT; (ix) LiOH, THF/MeOH, reflux; (x) 1,2-benzenediamine, HATU, Et3N, DMF, RT; (xi) Eaton
reagent, RT to 120°C; (xii) n-PrI, Cs CO DMF, 70°C; (xiii) Azidotributyltin, 165°C.
,
3
2

Scheme 3. Reagents and conditions: (i) a) NH4BF4, HCl 37%, NaNO2, H2O, 0°C to RT; b) KOAc, 18-
Crown-6, CHCl3, RT ; (ii) PrI, K2CO3, DMF, 60°C; (iii) NIS, AcOH, 80°C; (iv) iPrMgCl, 40°C to -20°C,
THF/NMP (10/1), then aldehyde A-C to RT; (v) NaOH 1N , dioxane, 80°C; (vi) 1-Phenylpropan-1-
amine, HATU, Et3N, DMF, RT ; (vii) TFA, Et3SiH, DCM, reflux; (viii) EDCI, tBuOH, reflux; (ix)
Azidotributyltin, 165°C; (x) N1-butylbenzene-1,2-diamine, HATU, Et3N, THF, RT; (xi) Acetic acid, 80°C;
(xii) NaOH 1N, MeOH, reflux ; (xiii) Ammonium chloride, HATU, Et3N, DCM/DMF, RT; (xiv) 2,2,2-
Trichloroacetyl chloride, Et3N, DCM, 0°C.

Table 1. Reverse indole series: In vitro evaluation on human (h) and murine (m) PPARγa and AT1
receptors.
EC50 (µM)
EC50 (µM)
Substituent
position
lC50 AT1
R1
h PPARγ
(%activation)b
0.002 (52)
m PPARγ
(%activation)b
0.003 (42)
Compound
(µM)
Me
H
6
6
5
5
>10
>10
>10
>10
13a
0.006 (47)
0.09 (29)
0.35 (39)
0.009 (36)
0.20 (17)
0.51 (24)
14a
15b
OMe
H
16b
a Data generated using cell based transient transfection assays.19 PPAR EC50 values are means of 2 independent
experiments. AT1 IC50 values were assessed once.
Compound 13a and 14a displayed respectively EC50 of 0.17 µM (90%) and 0.79 µM (71%) on murine PPARα
isoform. Compounds 15b and 16b were found inactive (>10 µM) on murine PPARα. Compounds 13a, 14a and
16b were not evaluated on murine PPARδ isoforms. Compounds 15b was found inactive (>10 µM) on murine
PPARδ.
b
% of maximal activation for all compounds was compared to the reference compound rosiglitazone
normalized to 100%.

Table 2. Pyrazolopyridine series: In vitro evaluation on human (h) and murine (m) PPARγa and AT1
receptors.
R1
EC50 (µM)
h PPARγ
EC50 (µM)
m PPARγ
lC50 AT1
Structure
Cpd
(µM)
number
(%activation)b
(%activation)b
-COOH
0.39 (37)
1.02 (32)
1.69
22
-COOH
26
0.28 (43)
0.08 (81)
0.38 (27)
0.13 (60)
0.085
0.023
N
N N
N
R1
-Tetrazole
27
a Data generated using cell based transient transfection assays.19 PPAR EC50 values are means of 2 independent
experiments. AT1 IC50 values were assessed once.
All compounds were found inactive (>10 µM) on murine PPARα and PPARδ isoforms.
b
% of maximal activation for all compounds was compared to the reference compound rosiglitazone
normalized to 100%.

Table 3. Indazole series: In vitro evaluation on human (h) and murine (m) PPARγa and AT1 receptors.
EC50 (µM)
EC50 (µM)
R1
IC50 AT1
Structure
h PPARγ
m PPARγ
Cpd number
(µM)
(%activation)b
(%activation)b
-COOH
31
0.13 (24)
0.18 (21)
0.64 (40)
0.25 (40)
0.25 (19)
0.25 (9)
1.0
-Tetrazole
35
0.097
0.06
-COOH
37
1.39 (37)
0.27 (18)
N
N
N
N
R1
-Tetrazole
38
0.006
a Data generated using cell based transient transfection assays.19 PPAR EC50 values are means of 2 independent
experiments. AT1 IC50 values were assessed once.
All compounds were found inactive (>10 µM) on murine PPARα and PPARδ isoforms.
b
% of maximal activation for all compounds was compared to the reference compound rosiglitazone
normalized to 100%.

Table 4. Pharmacokinetic parameters of 38 in ZDF rata
Dose
AUCpo
Route
T1/2 (h)
14.00
Vdss (L/kg) Cl (mL/min/kg) F (%)
(ng.h/mL)
(mg/kg)
5.2
IV
8011
7.8
11
PO
30
36325
78
a IV: DMSO/Hydroxypropyl-β-Cyclodextrin 20% in phosphate buffer 60MM pH 7; PO: HPMC K100 0.5%/TWEEN
80 0.1% IN PHOSPHATE BUFFER 60MM PH 7.