Discovery of GSK1997132B a novel centrally penetrant benzimidazole PPARγ partial agonist

Article abstract of DOI:10.1016/j.bmcl.2011.06.088

The peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated nuclear receptor, thought to play a role in energy metabolism, glucose homeostasis and microglia-mediated neuroinflammation. A novel benzimidazole series of centrally penetrant PPARγ partial agonists has been identified. The optimization of PPARγ activity and in vivo pharmacokinetics leading to the identification of GSK1997132B a potent, metabolically stable and centrally penetrant PPARγ partial agonist, is described.

Full text of DOI:10.1016/j.bmcl.2011.06.088

Bioorganic & Medicinal Chemistry Letters 21 (2011) 5568–5572
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of GSK1997132B a novel centrally penetrant benzimidazole
PPARc partial agonist
Mairi Sime a, , Amanda C. Allan a, Paul Chapman a, Charlotte Fieldhouse a, Gerard M. P. Giblin a,
Mark P. Healy a, Millard H. Lambert b, Lisa M. Leesnitzer c, Ann Lewis a, Raymond V. Merrihew c,
Richard A. Rutter a, Rosemary Sasse a, Barry G. Shearer d, Timothy M. Wilson d, Robert X. Xu b, David J. Virley a
⇑
a Neurosciences Centre for Excellence in Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Harlow, Essex, CM19 5AW, United Kingdom
b Computational and Structural Chemistry, Molecular Discovery Research, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709, USA
c Screening and Compound Profiling, Molecular Discovery Research, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709, USA
d Metabolic Disease Centre of Excellence in Drug Discovery, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The peroxisome proliferator-activated receptor
c (PPARc) is a ligand-activated nuclear receptor, thought
Received 10 March 2011
Revised 17 June 2011
Accepted 18 June 2011
Available online 29 June 2011
to play a role in energy metabolism, glucose homeostasis and microglia-mediated neuroinflammation. A
novel benzimidazole series of centrally penetrant PPAR partial agonists has been identified. The optimi-
zation of PPAR activity and in vivo pharmacokinetics leading to the identification of GSK1997132B a
potent, metabolically stable and centrally penetrant PPAR
c
c
c
partial agonist, is described.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
PPAR
c
Peroxisome proliferator-activated receptor
Alzheimer’s disease
Benzimidazoles
The peroxisome proliferator-activated receptors (PPARs) are li-
gand-activated nuclear receptors that act as lipid sensors, and reg-
ulators, of energy metabolism and glucose homeostasis.1 Three
subtypes of PPAR have been identified, PPARa, d and c. As a result
of their role in glucose homeostasis the PPARs have proven to be
that activation of PPARc plays a role in microglia-mediated neuro-
inflammation.2–5 In fact, both rosiglitazone and pioglitazone have
been shown to be active in preclinical models of AD,6,7 as well as
small AD clinical trials, where stratification to ApoE genotype,8,9
or insulin-resistant status/presence of type II diabetes mellitus,10,11
have been shown to reveal improvements with these agents on
memory and cognitive function. However, more recently rosiglit-
azone-XR (extended release formulation) has failed to meet pri-
mary end-points in three large phase III trials in AD.12,13
Although the reason for this failure is presently unclear, a more
rewarding drug targets for the treatment of a variety of metabolic
diseases. In particular, synthetic PPARc ligands, rosiglitazone 1
(Avandia) and pioglitazone 2 (Actos), examples of thiazolidinedi-
ones (TZDs), are currently marketed for the treatment of type II
diabetes mellitus, Figure 1.
An additional role for PPAR
heimer’s disease (AD) has been suggested from the observation
c
agonists in the treatment of Alz-
centrally penetrant PPAR
advantages regarding efficacy, through improved access to and di-
rect activation of the CNS PPAR target receptor.
We were interested in identifying a centrally penetrant PPAR
agonist to further investigate the role of PPAR in the CNS, and
c agonist approach may offer significant
c
O
NH
c
O
NH
c
S
N
its relevance to the treatment of AD. Additionally, we were also
keen that the compounds identified should show partial agonist
S
O
N
O
O
N
O
activity (max. response 30–70% in a hPPAR
gene assay)14 since preclinically partial agonists have been shown
to avoid side effects known to occur with full agonists of PPAR , for
c luciferase reporter
1, Rosiglitazone
Figure 1. Marketed PPAR
2, Pioglitazone
c
example, weight gain, edema, fluid retention and cardiovascular
c
agonists.
effects.15,16
Recently, PPAR
c partial agonists and modulators have been re-
⇑
Corresponding author.
E-mail address: m.sime@beatson.gla.ac.uk (M. Sime).
ported in the literature.15–19 However, these templates generally
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.06.088

M. Sime et al. / Bioorg. Med. Chem. Lett. 21 (2011) 5568–5572
5569
O
O
O
O
NO2
R1
NO2
F
R1
NH2
NH
a
b,c
HO
clogP 6.3, PSA 47Å, MW 452
PPARγ pEC50 7.3, % activation 64%
PPARα pEC50 < 5.0, PPARδ pEC50 < 5.0
N
N
N
N
H
H
H
F
N
4
9
Ar
Cl
10
3
Cl
O
d
R1
Figure 2. Benzimidazole lead compound.
N
N
H
N
Ar
contain an acidic moiety, for example, carboxylic acid, sulfon-
amide, characteristic which is associated with poor brain
a
11
penetration. We were pleased therefore when benzimidazole 3,
Figure 2, was identified as an attractive non-acidic starting point
Scheme 2. Reagents and conditions: (a) R1NH2, EDAC, DCM/THF, 21 h, 0 °C to rt; (b)
ArCH2NH2, DIPEA, THF, 17 h, reflux; (c) SnCl2Á2H2O, EtOAc, 2 h, reflux; (d) HCOOH,
1 h, 110 °C.
for a centrally penetrant PPAR
452, 1 HBD). Preliminary profiling of 3 revealed it to be a partial
PPAR agonist (pEC50 7.3, % activation 64%, profiled in a hPPAR
luciferase reporter gene assay10), with excellent selectivity for
the other PPARs (PPAR pEC50 <5.0, PPARd pEC50 <5.0). In fact, all
compounds prepared during the course of this work showed little
or no activity at PPAR or PPARd.
c partial agonist (PSA 47 Å, MW
c
c
following cyclisation, gave benzimidazoles 7 in good yield. Finally,
hydrolysis of ester 7 provided the intermediate carboxylic acid
which was used to prepare amide 8.22
Alternatively, the amide could be introduced in the initial stages
of the synthesis, Scheme 2. Starting from acid 4, amide 9 was pre-
pared using standard coupling conditions.23 SNAr reaction of 9 with
the appropriate benzylamine, followed by reduction of the nitro
group, gave diamine 10. Treatment of 10 with formic acid gave
benzimidazoles 11 in good yield.22
a
a
Benzimidazole 3 was profiled further to determine the likely
pharmacokinetic profile of the series. We were disappointed to find
that despite benzimidazole 3 showing encouraging in vitro clear-
ance in liver microsomes across species (mouse CLi 1.75 mL/min/
g, rat CLi 2.5 mL/min/g, human CLi 0.5 mL/min/g),20 the compound
exhibited high blood clearance when progressed to in vivo phar-
macokinetic studies (mouse CLb 736 mL/min/kg).21 Keen to im-
prove the activity and to optimise the apparently poor
pharmacokinetic properties of the benzimidazole template, we de-
vised a plan of work aiming to establish the structure–activity rela-
tionships (SAR) of the series and to block potential sites of
metabolism. We elected to concentrate on the SAR of three main
areas of the benzimidazole template namely the benzylamide,
the N-benzyl group and the 2-substituent of the benzimidazole.
The binding mode of the benzimidazole series was determined
by co-crystallisation of an example from the series with the PPAR
c
ligand binding domain (LBD), with the structure of benzimidazole
13 solved at 2.55 Å (R = 22.4%, Rfree = 28.4%, PDB code 3S9S). As
shown in Figure 3, 13 binds to PPARc in a similar fashion to rosig-
litazone, with the benzylamide occupying the same pocket as the
thiazolidinedione of rosiglitazone. However, unlike rosiglitazone,
the benzimidazole makes no H-bonding interactions with the
Tyr473, His323 and His449 triad, and instead makes H-bonds only
with Ser289 and Tyr327. We propose that the lack of H-bonding
interactions in this area, particularly with Tyr473 positioned on
the AF-2 helix, is potentially responsible for the partial agonist
character of the series, in a similar manner to that reported for
Our efforts to optimise the PPARc activity and metabolic stability
of the benzimidazole series are described herein.
The benzimidazoles were routinely prepared in seven synthetic
steps from commercially available starting materials, Scheme 1.
Starting from benzoic acid 4, esterification and subsequent dis-
placement of fluorine with an appropriate benzylamine gave inter-
mediate 5. Reduction of the nitro group 5 to aniline 6 was achieved
using tin (II) chloride in ethyl acetate. The aniline 6 was subse-
quently acylated using the appropriate acid chloride which,
INT131, a selective PPARc
modulator.16 The disubstituted benzyl
O
O
O
NO2
F
NO2
NH
NH2
NH
c
a, b
HO
MeO
MeO
4
Ar
Ar
5
6
O
O
d, e
R1
f, g
MeO
N
N
N
H
R2
N
R2
N
Ar
Ar
7
8
Scheme 1. Reagents and conditions: (a) SOCl2, MeOH, 24 h, reflux; (b) ArCH2NH2,
DIPEA, THF, 17 h, reflux; (c) SnCl2Á2H2O, EtOAc, 2 h, reflux; (d) R2COCl, DIPEA,
30 min, 0 °C to rt; (e) AcOH, 18 h, reflux; (f) (i) LiOH, THF/water, 18 h, reflux; (ii)
HCl; (g) R1NH2, HATU, DIPEA, DMF, 18 h, rt.
Figure 3. X-ray crystal structures of benzimidazole 13 (pink) and rosiglitazone
(blue) with PPAR LBD.
c

5570
M. Sime et al. / Bioorg. Med. Chem. Lett. 21 (2011) 5568–5572
Table 1
Table 3
Effect of variation of the
a
-alkyl substituent
SAR of benzyl group
O
O
R1
N
N
N
N
H
H
N
R2
N
Cl
R3
Cl
a,b
a,b
Compd
R2
R3
PPAR
c
pEC50
% activation
Compd
R1
PPAR
c
pEC50
% activation
83
23
24
25
26
27
28
29
30
31
32
33
34
35
36
Me
Me
Me
Me
Me
Me
H
H
H
H
H
2-Cl
3-Cl
4-Cl
4-F
4-SO2Me
4-CONH2
2-F
2-OMe
2-SO2Me
4-Cl
4-F,3-Cl
2-F,4-F
2-Cl,4-Cl
2-F,4-Cl
7.3 (10)
7.1 (11)
7.5 (13)
6.8 (5)
5.3 (3)
5.0 (1)
8.1 (6)
8.3 (5)
6.4 (5)
8.5 (6)
8.2 (2)
8.8 (4)
9.3 (5)
9.1 (6)
80
76
66
74
48
17
80
75
73
74
85
73
77
74
12
6.4 (5)
7.4 (8)
13
14
75
21
6.6 (1)
H
H
H
15
16
7.3 (8)
6.2 (1)
77
50
a
Value quoted is mean, number in parentheses represents number of
determinations.
b
As determined in a hPPARc luciferase reporter gene assay.
a
Value quoted is mean, number in parentheses represents number of
determinations.
b
As determined in a hPPARc luciferase reporter gene assay.
of the 2-methyl led to a significant increase in PPAR
c activity,
example 17. It was hypothesised that removal of the methyl allows
water molecules to approach Arg288 more closely, bridging the
gap between Arg288 and the carbonyl oxygen of Leu340. Replace-
ment of the methyl group with other small alkyls 18–20 led only to
group of the benzimidazole fills the same deep pocket as the amino
pyridine of rosiglitazone.
We began our SAR analysis by investigating the influence of the
a-ethyl group on activity of the benzimidazole template, Table 1.
a decrease in PPAR
sition retained moderate PPAR
Variation of the benzyl substituent highlighted the potential to
increase PPAR activity, Table 3. In particular, 2-substituted and 4-
substituted benzyls were optimal for PPAR activity, for example,
c
activity. A ketone substituent 22 in the 2-po-
We found that removal of the ethyl group 12 led to a marked de-
crease in activity. There was also a clear difference in activity be-
tween enantiomers, with the (R) enantiomer routinely showing
c
activity.
c
increased PPARc activity in comparison to the (S) enantiomer.
c
From the X-ray crystallography of benzimidazole 13, Figure 3, we
rationalised that the (S) isomer leads to an unfavourable steric
interaction of the alkyl group with His449 thus leading to the low-
23 and 25. Suitable substituents appeared to be limited to
er PPAR
c
activity observed. The ethyl group of 13 can be replaced
activity.
Table 4
SAR of pyridyl analogues
with a methyl group 15 whilst retaining PPAR
c
We next turned our attention to the role of the 2-substituent of
O
the benzimidazole, Table 2. We were pleased to find that removal
N
N
H
N
Table 2
R4
SAR of the 2-substituent
a,b
Compd
R4
PPAR
c
pEC50
% activation
O
37
38
39
2-Pyridyl
3-Pyridyl
4-Pyridyl
6.9 (4)
6.3 (4)
6.1 (3)
59
74
63
N
N
H
R2
Cl
N
N
40
41
42
43
7.8 (4)
7.4 (4)
9.3 (3)
8.0 (2)
81
80
76
68
Cl
Cl
N
a,b
Compd
R2
PPAR
c
pEC50
% activation
Cl
17
18
19
20
21
H
Et
iPr
cyPr
CF3
O
8.6 (9)
6.7 (6)
6.4 (6)
6.9 (7)
6.6 (4)
71
65
42
58
60
N
Cl
N
Cl
22
7.1 (10)
75
F
F
a
a
Value quoted is mean, number in parentheses represents number of
Value quoted is mean, number in parentheses represents number of
determinations.
determinations.
b
b
As determined in a hPPARc luciferase reporter gene assay.
As determined in a hPPARc luciferase reporter gene assay.

M. Sime et al. / Bioorg. Med. Chem. Lett. 21 (2011) 5568–5572
5571
M)
Table 5
In vitro and in vivo clearance
Compd
Rat CLia (mL/min/g)
Human CLia (mL/min/g)
Rat S9 CLi (mL/min/g)
Rat CLbb (mL/min/kg)
Br:Blb
[Br]b
(l
15
17
34
37
43
1.4
3.3
3.7
nt
0.5
0.6
0.5
nt
8.3
10.0
nt
nt
1.6
75c
84
107
78
0.29:1d
0.71:1
0.59:1
0.20:1
0.22:1
0.012d
0.655
0.455
0.228
0.446
1.2
0.5
30
a
b
c
Liver microsomes, see Ref. 20.
iv steady state infusion, 2 mg/kg/h targeted dose (2% (v/v) DMSO/10%(w/v) HPB in 0.9% (w/v) saline).
iv infusion, 1 mg/kg targeted dose (2% (v/v) DMSO/10%(w/v) HPB in 0.9% (w/v) saline).
po, 3 mg/kg targeted dose (1% (w/v) methylcellulose).
d
lipophilic groups such as chloro, since more polar examples such as
sulfones 27 and 31 led to a significant drop in activity. Similarly,
Table 6
Summary of data for benzimidazole 43
primary amide 28 was not tolerated and abolished PPAR
c activity.
O
By combination of substituents at the 2- and 4-position of the ben-
43
N
N
H
GSK1997132B
zyl group, a number of very active PPAR
identified.
c agonists 34–36 were
N
F
N
In an attempt to lower the c log P of the series and block poten-
tially metabolically labile sites we investigated substituted pyridyl
analogues, Table 4. We were pleased to find that 2-pyridyl 37 re-
F
PPAR
c
activity
pEC50 (%act.)
8.0 0.1 (68)
tained moderate PPARc activity whereas 3- and 4-pyridyl ana-
aMetabolic stability
Rat CLi (mL/min/g liver)
Human CLi (mL/min/g liver)
1.2
0.5
logues 38 and 39, on the other hand, showed reduced activity
and were therefore not investigated further. Re-introduction of
substituents to the pyridyl ring 42 and 43 improved PPARc activity
markedly, but of the two, only the 3,5-difluoro analogue 43 re-
Solubility (0.5 h)
Water (
l
g/mL)
330
>1000
80
SGF ( g/mL)
l
FaSSIF (
FeSSIF (
l
l
g/mL)
g/mL)
tained partial agonist character (max. response 30-70% in a
220
hPPARc
luciferase reporter gene assay).14
bPermeability
Pexact
Efflux ratio
1215 nm/s
1.6
A number of examples were progressed to in vitro and in vivo
pharmacokinetic studies to investigate the metabolic profile and
the previously identified discrepancy between intrinsic clearance
and blood clearance, Table 5. It became apparent that the rat
in vitro clearance was not predictive of the rat in vivo clearance
for the benzimidazole series, compounds which showed low
intrinsic clearance in vitro were routinely showing high in vivo
blood clearance (compound 15 showed rat CLi 1.4 mL/min/g but
when profiled in vivo demonstrated high blood clearance in rat
CLb 75 mL/min/kg). To further explore this discrepancy, a number
of examples were tested in rat S9 fraction to account for phase II
metabolic pathways. The intrinsic clearance determined using
the S9 fraction was found to be more indicative of the blood clear-
ance observed in rat (compound 15 showed S9 CLi 8.3 mL/min/g cf
rat CLb 75 mL/min/kg). As a result, the S9 assay was used thereaf-
ter to identify examples with potential to exhibit low in vivo blood
clearance in rat.
Using this approach, we were pleased to discover benzimid-
azole 43, GSK1997132B, the first metabolically stable example
(rat CLb 30 mL/min/kg) from the benzimidazole series. Interest-
ingly, both the inclusion of the 2,4-difluoro substitution and the
pyridyl nitrogen are important for the metabolic stability, since
neither of these components in isolation led to improved metabolic
stability, examples 34 and 37.
Protein binding
Fraction unbound Bl
Fraction unbound Br
17.5%
11.5%
cRat pharmacokinetics
CLb (mL/min/kg)
Br:Bl
[Br] lM
30
0.22:1
0.446
a
b
c
Liver microsomes, see Ref. 20.
MDCKII-MDR1 Pgp assay.
iv steady state infusion, 2 mg/kg/h targeted dose (2% (v/v) DMSO/10%(w/v) HPB
in 0.9% (w/v) saline).
for PGP (MDCKII-MDR1 Pgp assay; Pexact AP/BL = 1215 nm/s, ef-
flux ratio = 1.6). Benzimidazole 43 was subsequently used as a tool
compound in biomarker studies where it was observed that upon
chronic dosing of 43, adiponectin was up-regulated in the periph-
ery, indicative of activation of peripheral PPAR
tify a CNS biomarker of PPAR
course.
In summary, we have described the identification and subse-
quent optimisation of a novel benzimidazole series of PPAR ago-
nists. Optimisation of PPAR activity and in vivo metabolic
stability led to the identification of benzimidazole 43, a centrally
penetrant PPAR partial agonist.
c.
26 Studies to iden-
c activation will be described in due
c
c
c
Upon further profiling, benzimidazole 43 was found to have a
high fraction unbound in both blood (17.5% unbound) and brain
(11.5% unbound), Table 6.24 We were pleased to observe that de-
spite its apparently low brain penetration (Br:Bl 0.22:1), the free
brain concentration for 43 was 51 nM (following a 1 mg/kg iv
dose), fivefold above the EC50 for benzimidazole 43 (EC50 = 10 nM).
The compound was also found to have low potential for CYP450
Acknowledgements
We thank Jean-Baptiste Blanc for first synthesis of compound 3,
and we thank Lisa Shewchuk for refining the crystal structure.
References and notes
inhibition (CYP1A2 IC50 14
42 M, CYP2D6 IC50 65 M, CYP3A4 (DEF) IC50 45
(7BQ) IC50 >100 M) and showed moderate to good solubility in
a variety of media (all data measured at 0.5 h; H2O 330 g/mL,
SGF >1000 g/mL, FeSSIF 220 g/mL, FaSSIF 80
g/mL).25 Example
43 showed excellent permeability and demonstrated low affinity
lM, CYP2C19 IC50 87
lM, CYP2C9 IC50
l
l
lM, CYP3A4
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