Design, synthesis, and evaluation of imidazo[4,5-c]pyridin-4-one derivatives with dual activity at angiotensin II type 1 receptor and peroxisome proliferator-activated receptor-γ

Article abstract of DOI:10.1016/j.bmcl.2012.11.088

Identification of a series of imidazo[4,5-c]pyridin-4-one derivatives that act as dual angiotensin II type 1 (AT1) receptor antagonists and peroxisome proliferator-activated receptor-γ (PPARγ) partial agonists is described. Starting from a known AT1 antagonist template, conformational restriction was introduced by incorporation of an indane ring that when combined with appropriate substitution at the imidazo[4,5-c]pyridin-4-one provided novel series 5 possessing the desired dual activity. The mode of interaction of this series with PPARγ was corroborated through the X-ray crystal structure of 12b bound to the human PPARγ ligand binding domain. Modulation of activity at both receptors through substitution at the pyridone nitrogen led to the identification of potent dual AT1 antagonists/PPARγ partial agonists. Among them, 21b was identified possessing potent dual pharmacology (AT1 IC ₅₀ = 7 nM; PPARγ EC₅₀ = 295 nM, 27% max) and good ADME properties.

Full text of DOI:10.1016/j.bmcl.2012.11.088

Bioorganic & Medicinal Chemistry Letters 23 (2013) 767–772
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design, synthesis, and evaluation of imidazo[4,5-c]pyridin-4-one
derivatives with dual activity at angiotensin II type 1 receptor
and peroxisome proliferator-activated receptor-
c
Agustin Casimiro-Garcia a, , Ronald J. Heemstra b, Christopher F. Bigge b, Jing Chen b, Fred A. Ciske b,
Jo Ann Davis c, Teresa Ellis b, Nadia Esmaeil b, Declan Flynn b, Seungil Han b, Mehran Jalaie c,
Jeffrey F. Ohren b, Noel A. Powell b
⇑
a Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development, 200 Cambridgepark Drive, Cambridge, MA 02140, USA
b Pfizer Worldwide Research and Development, Eastern Point Rd, Groton, CT 06340, USA
c Pfizer Worldwide Research and Development,10770 Science Center Drive, San Diego, CA 92121, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Identification of a series of imidazo[4,5-c]pyridin-4-one derivatives that act as dual angiotensin II type 1
Received 9 October 2012
Revised 15 November 2012
Accepted 20 November 2012
Available online 1 December 2012
(AT1) receptor antagonists and peroxisome proliferator-activated receptor-c (PPARc) partial agonists is
described. Starting from a known AT1 antagonist template, conformational restriction was introduced
by incorporation of an indane ring that when combined with appropriate substitution at the imi-
dazo[4,5-c]pyridin-4-one provided novel series 5 possessing the desired dual activity. The mode of inter-
action of this series with PPAR
human PPAR ligand binding domain. Modulation of activity at both receptors through substitution at
the pyridone nitrogen led to the identification of potent dual AT1 antagonists/PPAR partial agonists.
c was corroborated through the X-ray crystal structure of 12b bound to the
Keywords:
Angiotensin
Peroxisome proliferator-activated receptor
c
c
Among them, 21b was identified possessing potent dual pharmacology (AT1 IC50 = 7 nM; PPAR
c
PPAR
c
EC50 = 295 nM, 27% max) and good ADME properties.
Hypertension
Ó 2012 Elsevier Ltd. All rights reserved.
Metabolic syndrome
Hypertension is commonly associated with an array of other
factors including abdominal obesity, insulin resistance, elevated
plasma glucose, and dyslipidemia that collectively are often re-
ferred to as the metabolic syndrome.1,2 Currently, there are no ap-
proved drugs that can reduce all of the risk factors associated with
the metabolic syndrome. Therefore, there is a growing interest in
therapeutic approaches that simultaneously target multiple factors
with a single therapy. Angiotensin II type 1 (AT1) receptor blockers
(ARBs) are clinically effective, well tolerated agents for the treatment
of hypertension. Among them, telmisartan (1, Fig. 1), is not only a
potent and selective AT1 receptor antagonist, but also, it was re-
ported with partial activity at the nuclear hormone receptor perox-
PPAR
c
. More recently, telmisartan was shown to be more effective
than valsartan, an ARB without PPAR
c activity, in reducing body
weight and providing better renal protection in a rodent model of
the metabolic syndrome.8 These effects of telmisartan have also been
attributed to its partial PPAR
possessing the dual pharmacology of AT1 receptor antagonism and
partial PPAR agonism could potentially treat several recognized
cardiovascular risk factors including hypertension, insulin resistance
and hypertriglyceridemia in patients with metabolic syndrome. Our
group recently reported a series of imidazo[4,5-b]pyridines 2 pos-
sessing this dual pharmacology.10–12 This series is exemplified with
3 that was identified as a potent angiotensin II type I receptor block-
c
activity.8,9 A pharmaceutical agent
c
isome proliferator-activated receptor-
c
(PPAR
c
).3,4 Telmisartan has a
er (IC50 = 1.6 nM) with partial PPARc agonism (EC50 = 212 nM, 31%
well documented efficacy in blood pressure (BP) reduction,5 and has
also demonstrated improvements in glucose and lipid metabolism in
small clinical trials.6,7 The improvements observed in patients taking
telmisartan could be reasonably attributed to its partial activity at
max) and oral bioavailability in rat.11 The dual pharmacology of 3
was demonstrated in animal models of hypertension (spontaneously
hypertensive rat - SHR) and insulin resistance (Zucker diabetic fatty
rat - ZDF). The potent selective antagonism of the AT1 receptor
translated into highly effective BP lowering in the SHR. A single dose
of 10 mg/kg produced BP lowering for a full 24 h equivalent to the
effect observed with telmisartan. The potent, partial activation of
⇑
Corresponding author.
E-mail address: agustin.casimiro-garcia@pfizer.com (A. Casimiro-Garcia).
Abbreviations: ARB, angiotensin receptor blocker; AT1, angiotensin II type
receptor; BP, blood pressure; BW, body weight; CV, cardiovascular; LBD, ligand
binding domain; PPAR , peroxisome proliferator-activated receptor- ; SHR, sponta-
neously hypertensive rat; ZDF, Zucker diabetic fatty rat.
1
the PPAR
c receptor translated into dose dependent efficacy in the
male ZDF rat with glycemic improvements equivalent to that of
pioglitazone with a significantly reduced incidence of weight gain.
c
c
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.11.088

768
A. Casimiro-Garcia et al. / Bioorg. Med. Chem. Lett. 23 (2013) 767–772
R3
R2
R1
N
N
N
N
N
R4
N
N
N
N
N
N
N
O
N
N
HN
HN
N
N
OH
Telmisartan (1)
2
3
Figure 1. Chemical structures of telmisartan (1), imidazo[4,5-b]pyridines series 2, and 3.
More interestingly, plasma concentrations achieving significant effi-
cacy were within three-fold in the SHR and ZDF models for 3 dem-
onstrating the potential utility of this compound in treating
multiple risk factors at a single dose level.
A complementary series possessing the desired dual pharma-
cology of AT1 antagonism and partial PPARc agonism was desired.
From a strategic point of view, we were interested in the identifi-
cation of a second series possessing a relatively similar dual activ-
ity profile to that obtained with 3. This profile was already shown
to provide significant efficacy in animal models of both hyperten-
sion and insulin resistance at a single dose level. During the course
of our research with the imidazo[4,5-b]pyridines series 2, it was
demonstrated that conformational restriction derived from the in-
and triphenylphosphine in THF provided the desired N-indanylim-
idazopyridone 8, albeit in low and irreproducible yields. The prob-
lem with this transformation was likely derived from the low
solubility of the imidazopyridone 6 in the reaction mixture. Efforts
to improve the yield of this step were unsuccessful. The regio-
chemistry of substitution in 8 was established through 2-D NMR
studies. X-ray crystallography studies described later in this report
further supported the structural assignment. Suzuki cross-coupling
of bromide 8 with boronic acid 1016 in the presence of catalytic
palladium acetate, triphenylphosphine, and potassium carbonate
in DME-water gave 11a (R = H). Removal of the trityl group under
the conditions of 3 M HCl in acetone afforded tetrazole 12a (R = H).
Benzylation of 8 to provide bromide 9b (R = benzyl), followed by
Suzuki cross-coupling of this bromide with boronic acid 10, and re-
moval of the trityl protecting group provided 12b (R = benzyl). The
synthetic route utilized for the preparation of 12a and 12b was not
adequate to support efforts to further explore modifications in this
series and led us to investigate an alternative route. Selective pro-
tection of the imidazole NH group in 6 using Boc anhydride and
catalytic DMAP gave 13. The position of the Boc group in 13 was
confirmed through 2-D NMR studies. Alkylation of 13 with appro-
priate alkyl-, or benzyl halides utilizing potassium tert-butoxide in
dry THF provided 14. Boc group removal under the conditions of
TFA in DCM gave 15. The Mitsunobu reaction of 15 with (R)-5-bro-
mo-1-indanol (7) was then investigated. Optimal conditions con-
sisted in performing this reaction in the presence of di-tert-butyl
azodicarboxylate and trimethylphoshine in THF to give the desired
N-indanylimidazopyridones 9 (R = substituted benzyl or alkyl) in
satisfactory and reproducible yields. Interestingly, the solubility
of the N-substituted imidazopyridones 15 was noticeably better
than for the unsubstituted 6 under these conditions. The remaining
of the synthesis followed the same steps as previously described
for bromide 9b. In this manner, additional tetrazoles 12 incorporat-
ing substituted benzyl or alkyl groups at the pyridone nitrogen
were obtained. The modified conditions were also applied for the
Mitsunobu reaction between 15 and the more elaborated and pre-
viously reported indanol 1611 to provide in a single step trityl-pro-
tected tetrazoles 11 in acceptable yields that could be converted
into the desired tetrazoles 12 (R = substituted benzyl or alkyl) after
trityl group removal.
dane ring is required for PPAR
R1 in scaffold 2 (Fig. 1) was identified as an optimal position to
modulate activity at both AT1 and PPAR receptors. Examination
c activity. In addition, substitution at
c
of known ARBs revealed a number of scaffolds that might be used
to build the dual activity.13 Among them, a series of imidazo[4,5-
c]pyridin-4-one derivatives 4 (Fig. 2) reported as potent AT1 recep-
tor antagonists appeared as potential starting points.14 It was envi-
sioned that conformational restriction obtained by introduction of
an indane ring, and appropriate substitution at the imidazopyri-
done ring could provide novel series 5 possessing the desired dual
activity of AT1 antagonism and partial PPARc agonism. Based on
our previous work with series 2,11 only compounds with the S con-
figuration at the indane asymmetric center were planned in the
new series 5. In this Letter, the design, synthesis, and in vitro bio-
logical evaluation of this novel series of imidazo[4,5-c]pyridin-4-
ones 5 are described.15
The synthesis of imidazo[4,5-c]pyridin-4-one analogs incorpo-
rating an indane ring is depicted in Scheme 1. The heterocyclic
head group 6 was prepared as previously described,14 while (R)-
5-bromo-1-indanol (7) was obtained via catalytic enantioselective
reduction of 5-bromo-1-indanone using conditions previously
reported by our group.11 Mitsunobu reaction of indanol 7 with imi-
dazopyridone 6 utilizing the conditions of diethyl azodicarboxylate
R3
Selected analogs with a methyl group at the C-7 position of the
imidazo[4,5-c]pyridin-4-one were prepared according to Scheme 2.
Heating a mixture of diaminopyridine 1717 with propionic acid in
the presence of polyphosphoric acid provided imidazopyridine
18. After purification, 18 was treated with 96% formic acid and
the mixture heated under reflux to provide imidazopyridone 19.
Mitsunobu reaction of 19 with indanol 7 was accomplished by run-
ning this reaction in the presence of di-tert-butyl azodicarboxylate
and trimethylphoshine in THF to give 20 in satisfactory yields. To
complete the synthesis, N-benzylation, followed by Suzuki cross-
coupling and removal of the trityl group as described above pro-
vided tetrazoles 21.
N
N
N
N
R2
R2
N
N
R1
R1
O
O
N
N
N
N
HN
HN
N
N
4
5
Figure 2. Chemical structure of known series of imidazo[4,5-c]pyridin-4-one AT1
antagonists 4 and new series 5.

A. Casimiro-Garcia et al. / Bioorg. Med. Chem. Lett. 23 (2013) 767–772
769
OH
Tr
N
N
N
10
N
N
N
N
R
Br
B(OH)2
N
N
7
N
HN
O
N
N
H
R
a
c
O
O
6
N
Br
11
N
8
9
N
N
R = H
b
Tr
R = benzyl or alkyl
e
OH
h
d
g
Boc
N
N
N
N
N
N
f
N
N
N
N
N
R
R
N
R
H
N
Tr
O
O
O
13 R = H
16
15
b
14 R = benzyl or alkyl
N
12
N
HN
N
Scheme 1. Synthesis of imidazo[4,5-c]pyridin-4-one analogs. Reagents and conditions: (a) 7, DEAD, Ph3P, THF, 0–25 °C, 6–10%; (b) RBr, KOtBu, THF, 40–50%; (c) 10, Pd(OAc)2,
PPh3, K2CO3, DME–H2O, 80 °C, 75–85%; (d) 3 M HCl, acetone, 75–95%; (e) Boc2O, DMAP, Et3N, THF, 49%; (f) TFA, DCM; (g) 7, DtBAD, Me3P, THF, ꢀ78 to 25 °C, 70–80%, 2 steps;
(h) 16, DtBAD, Me3P, THF, ꢀ78 to 25 °C, 40–50%.
Table 1
NH2
N
N
AT1 and PPARc transactivation activity of imidazo[4,5-c]pyridin-4-one derivatives
12a–g and reference compounds
a
b
N
N
HN
NH2
17
N
H
N
H
Cl
Cl
O
O
N
N
N
18
19
c
N
N
N
R
O
N
N
N
N
NH
R
N
N
N
N
d
N
O
HN
HN
N
N
Br
3
12a-g
N
21
20
N
Compound
R
AT1 IC50 (nM)
h-PPARc
HN
N
EC50 (nM)a(% max)b
Scheme 2. Synthesis of C-7 methyl imidazo[4,5-c]pyridin-4-one analogs. Reagents
and conditions: (a) propionic acid, PPA, 80 °C, 76%; (b) 96% formic acid, reflux, 92%;
(c) 7, DtBAD, Me3P, THF, ꢀ78 to 25 °C, 29%; (d) (i): RBr, KOtBu, THF, rt; (ii): 10,
Pd(OAc)2, PPh3, K2CO3, DME–H2O, 80 °C; iii: 3 M HCl, acetone, 66%, 3 steps.
Telmisartan
Pioglitazone
3
12a
12b
12c
12d
12e
12f
12g
0.49
—
1.6
593
12.7
24.4
19.8
348
19.4
41
1520 (33)
1280 (80)
212 (31)
>100,000
292 (25)
>100,000
1250 (27)
>100,000
1710 (23)
942 (26)
H
CH2Ph
CH2CON(CH3)2
CH2COOCH2Ph
CH2COOH
CH2CH(CH3)2
CH2c-hexyl
The new compounds were evaluated for affinity for the AT1
receptor utilizing human recombinant AT1 receptors in a competi-
tion radioligand binding assay with [125I]Tyr4-Sar1,Ile8-Angiotensin
II. The IC50 values of the imidazo[4,5-c]pyridin-4-one analogs are
a
TA (transactivation assay). Mean value of at least two determinations.
The maximal efficacy of darglitazone in the PPARc activation assay was defined
b
displayed in Tables 1 and 2. Activation of human PPAR
c was deter-
as 100%. All compounds were prepared as the (S)-enantiomer.
mined using a chimeric receptor (PPAR Ligand Binding Domain
c
(LBD)/ Gal4 DNA Binding Domain) transactivation assay. The EC50
values and the percent of maximal activation with darglitazone18
as a reference full agonist (defined as 100% effect) are also pre-
sented in Tables 1 and 2. Telmisartan, pioglitazone, and 3 are in-
cluded as reference compounds.
Our initial efforts were directed at determining the impact of
the indane ring on the AT1 activity of the new scaffold, and to
investigate if PPARc activity could be obtained. Imidazopyridones
12a and 12c were synthesized early and compared with previously
reported AT1 receptor antagonists.14 While results obtained with
12a suggested loss of AT1 activity with introduction of the indane
ring, substitution on the pyridone nitrogen in 12c demonstrated
that this activity could be recovered with appropriate substitution
compounds. Efforts were focused to investigate additional substit-
uents at the pyridone nitrogen, including both lipophilic and polar
groups. These modifications led not only to improve AT1 activity,
but also to achieve the desired dual activity as several of the new
derivatives demonstrated PPAR
pounds, benzyl analog 12b represented the most potent analog
(AT1 IC50 = 12.7 nM, PPAR EC50 = 292 nM, 25% max) and provided
an interesting lead for further investigation. Benzyl analog 12b was
tested in PPAR and PPARb screens and showed no activity for
these receptors (EC50 >50,000 nM) thus confirming the selectivity
of this scaffold for PPAR . We have observed similar selectivity re-
sults with our previously reported 3.11 The difference in AT1 and
c activity. Among this set of com-
c
a
c
(Table 1). However, no PPARc activity was observed with these two

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A. Casimiro-Garcia et al. / Bioorg. Med. Chem. Lett. 23 (2013) 767–772
Table 2
AT1 and PPARc transactivation activity of imidazo[4,5-c]pyridin-4-one derivatives 12b–s and 21a–b
N
N
N
N
N
N
N
N
N
O
O
O
R
R
R
N
N
N
N
N
N
HN
HN
HN
N
N
N
12p-s
12b-o
21a-b
Compound
R
AT1 IC50 (nM)
h-PPARca
EC50 (nM) (% max)b
12b
12h
12i
H
2-F
2-CH3
12.7
37.7
5.1
292 (25)
103 (22)
97 (20)
12j
12k
12l
2-CN
2-CF3
2-OCF3
3-F
3-CH3
13.5
94.1
29.3
67.4
36.9
81.6
63.8
45.2
250
63.4
6.8
685 (24)
187 (25)
20 (30)
12m
12n
12o
12p
12q
12r
12s
21a
21b
159 (20)
108 (21)
449 (19)
3580 (15)
3640 (32)
>25,000
4470 (14)
42 (32)
3-CF3
2-Pyridyl
3-Pyridyl
4-Pyridyl
3,5-Dimethyl-4-isoxazolyl
2-CH3
2-CN
7
295 (27)
a
TA (transactivation assay). Mean value of at least two determinations.
The maximal efficacy of darglitazone in the PPARc activation assay was defined as 100%. All compounds were prepared as the (S)-enantiomer.
b
PPAR
c
activity observed when comparing 12a with 12b is quite
2 and differed from that observed with full PPARc
agonists.19,20 The
drastic. It was known from the previous work reported on this class
of AT1 antagonists that a benzyl group at the pyridone nitrogen
had comparable AT1 activity to that of an unsubstituted pyridone
analog.14 Thus, it appears that a benzyl, or other lipophilic substi-
tuent is required in the indane-based scaffold to achieve better
affinity for the AT1 receptor. Based on the assumption that the
lipophilic benzyl group is projected into the AF-2 domain pocket of
the receptor and interacts with the charge clamp residues and
other residues in this region through non-polar, van der Waals
interactions. The crystal structure also revealed that the acidic tet-
razole motif is buried into the hydrophobic anterior of the receptor
and makes an H-bond interaction between the N-1 of the tetrazole
0
new imidazo[4,5-c]pyridin-4-one scaffold would bind to PPAR
in a similar mode to that of our previously reported series 2, incor-
poration of lipophilic groups on the pyridone nitrogen of 12a was
expected to provide an improvement on PPARc activity. In our pre-
c
ring and the backbone NH of Ser342 (2.9 ÅA distance). An H-bond
between N-2 of the tetrazole ring and Arg288 was observed with
series 2. This H-bond is absent in the structure of the complex of
12b as this residue appears to be flexible and is positioned away
from the ligand.
The crystallography results obtained with 12b provided guid-
ance for the selection and position of substituents incorporated
on the phenyl ring of the benzyl group to improve interaction with
vious work with series 2, it was observed that larger and more lipo-
philic R1 substituents in 2 (Fig. 1) generally led to more potent
PPARc agonists. The improved PPARc activity was likely derived
from additional interactions with hydrophobic residues that sur-
round this region of the molecule. The results obtained with 12b,
12d, 12f, and 12g showed this approach works in this scaffold to
PPARc. The C-2 position on the phenyl ring appeared optimal as a
pocket in the receptor was identified surrounding this region of the
ligand. Analogs incorporating small groups like CH3, F, and CN on
the benzyl ring were expected to be well tolerated. Analogs with
substitution at other positions, as well as compounds with hetero-
aryl groups replacing the benzyl moiety were also planned. The re-
sults obtained with 12h–12l containing small C-2 substituents
showed that indeed this position can provide enhancements in
improve PPARc activity, as this set of compounds exhibited PPARc
activity in an acceptable potency range.
The benzyl analog 12b was the most potent compound in the
initial set and an interesting lead for further investigation. Our ap-
proach to take advantage of this interesting compound was two-
fold. First, taking advantage of our experience in X-ray
crystallography of PPAR
getting a crystal structure of 12b bound to the PPAR
c
agonists,11,19,20 efforts were directed at
ligand bind-
PPAR
PPAR
c
c
potency (Table 2). This set of compounds showed potent
activity, with 12l (R = 2-OCF3; EC50 = 20 nM, 30% max) as
c
ing domain (LBD) that could be used to guide design. Second, a
number of analogs incorporating modifications on the benzyl ring,
as well as replacements of the benzyl group with heteroaryl rings
were planned to gain a better knowledge of structural require-
the most potent analog in this set that represents >14-fold increase
in PPAR potency over 12b. Although only a limited set of hetero-
c
aryl rings were explored, the results obtained with 12p–12s (Ta-
ble 2) suggested a limited opportunity to replace the benzyl
moiety with an heteroaryl group, as these compounds exhibited
ments for both AT1 and PPAR
c
activity. The structure of the com-
LBD was determined by X-
plex of 12b bound to the human PPAR
c
>10-fold drop in PPARc potency when compared to 12b. The
ray crystallography at 2.02 Å resolution and is displayed in Fig. 3
(see Supplementary data S-Table 1 for X-ray data collection and
structure refinement statistics).21 The mode of binding of 12b
resembled the mode of binding observed with our previous series
apparently limited toleration for the more polar heteroaryl rings
was not expected, as the region surrounding the benzyl group of
12b is not entirely lined with hydrophobic residues. There are sev-
eral polar residues in PPARc near the benzyl group of 12b that

A. Casimiro-Garcia et al. / Bioorg. Med. Chem. Lett. 23 (2013) 767–772
771
Tyr327
Ser342
His323
Tyr473
His449
Figure 3. Three-dimensional representation of 12b (gold) bound in the ligand binding pocket of human PPARc (blue ribbons and b-sheets with magenta residues). The
compound wraps around helix 3 that lies in the middle. The benzyl group interacts through a number of hydrophobic interactions with the charge clamp residues and other
0
residues in this region. Formation of an H-bond between N-1 of the tetrazole ring and the backbone NH of Ser342 (2.9 ÅA distance) was observed.
Table 3
In vitro ADME and physicochemical properties of selected analogs.
Compound
LogDa
HLM Clint
(l
L/min/mg)
PAMPAb (ꢁ 10ꢀ6 cm/sec)
Solubilityc
(lM)
DDId (% inhibition)
3A4
2D6
12i
12j
21a
21b
2.6
1.7
2.9
2.5e
32.6
14
37.5
20.7
3.6
10.7
7.0
3.5
11.7
ND
14
31
3.5
0
6
11
4.5
0
19
5.2
a
b
c
Experimental LogD.22
Permeability determined using PAMPA.
Kinetic solubility.23
d
e
Drug–drug interaction.24
Calculated LogD value.
could accommodate heteroaryl groups. Other factors like higher
desolvation penalty of the heteroaryl rings might explain the loss
polar nitrile group in these compounds would confer better prop-
erties. In particular, 21b demonstrated moderate in vitro human li-
ver microsomes intrinsic clearance, high permeability, moderate
kinetic solubility, and low potential for drug-drug interactions for
two major cytochrome P450 isoforms 3A4 and 2D6, while exhibit-
ing potent activity at both receptors.
in PPAR
c
potency observed with these compounds.
activity, improving AT1 activity was
In contrast to the PPAR
c
significantly more challenging. In general most of the substituents
incorporated on the benzyl group, as well as the heteroaryl group
replacements led to a drop in AT1 potency when compared to 12b
(Table 2). Two compounds were identified that provided moderate
In summary, a new series of dual AT1 antagonists and partial
PPARc agonists based on a imidazo[4,5-c]pyridin-4-one scaffold
improvements over 12b. 12i (R = 2-CH3) showed
a
modest
was discovered through modification of a known AT1 antagonist
template. Our approach to build the desired dual activity consisted
in utilizing conformational restriction derived from introduction of
an indane ring and appropriate substitution at the imidazopyri-
done ring. This effort was further guided by the X-ray crystallogra-
improvement in potency at both receptors (AT1 IC50 = 5.1 nM;
EC50 = 97 nM, 20% max). Another interesting analog was 12j
(R = 2-CN) that although it showed similar potency for AT1 and re-
duced potency for PPARc (AT1 IC50 = 13.5 nM; EC50 = 685 nM, 24%
max) than 12b, the presence of the more polar nitrile group at C-2
was interesting as it was predicted to provide advantages in terms
of physicochemical and ADME properties. In an effort to further
improve on these compounds, incorporation of a methyl group at
C-7 of the imidazopyridone scaffold was pursued. This approach
was based on results from our series 2 in which the methyl group
at C-7 of the imidazopyridine ring was observed to enhance AT1
phy structure of 12b bound to PPAR
confirm the mode of binding of this series with PPAR
fered from that observed with full PPAR agonists. It was interest-
ing to observe that modulation of activity at both receptors could
be accomplished through modification at a single position, the
pyridone nitrogen. This work led to the identification of potent
c
LBD that also served to
c
which dif-
c
dual AT1 antagonists/PPAR
c partial agonists represented with
and PPAR
c
potency. Both 21a (AT1 IC50 = 6.8 nM; EC50 = 42 nM,
21b that not only showed a potency profile at both receptors sim-
ilar to some of the best compounds from our previously disclosed
series 2, but it also demonstrated good ADME and physicochemical
properties.
32% max) and 21b (AT1 IC50 = 7 nM; EC50 = 295 nM, 27% max) were
approximately equipotent to their corresponding analogs 12i and
12j. Although the number of compounds is limited, the results
obtained with 21a and 21b suggested a limited opportunity to
achieve a large improvement in potency with the methyl at C-7 po-
sition and demonstrated differences in SAR between the imidazo-
pyridone scaffold and series 2.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2012.
11.088.
Selected physicochemical and in vitro ADME properties of ana-
logs 12i, 12j, 21a and 21b are displayed in Table 3. The measured
properties of 12j and 21b confirmed our expectations that the

772
A. Casimiro-Garcia et al. / Bioorg. Med. Chem. Lett. 23 (2013) 767–772
Tugnait, M. Presented at the 244th American Society National Meeting,
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