Discovery of novel imidazo[4,5- b ]pyridines as potent and selective inhibitors of phosphodiesterase 10A (PDE10A)

Article abstract of DOI:10.1021/ml5000993

We report the discovery of novel imidazo[4,5-b]pyridines as potent and selective inhibitors of PDE10A. The investigation began with our recently disclosed ketobenzimidazole 1, which exhibited single digit nanomolar PDE10A activity but poor oral bioavailab

Full text of DOI:10.1021/ml5000993

Letter
pubs.acs.org/acsmedchemlett
Discovery of Novel Imidazo[4,5‑b]pyridines as Potent and Selective
Inhibitors of Phosphodiesterase 10A (PDE10A)
Essa Hu,*,† Kristin Andrews,‡ Samer Chmait,‡ Xiaoning Zhao,⊥ Carl Davis,§ Silke Miller,∥
Geraldine Hill Della Puppa,∥ Mary Dovlatyan,∥ Hang Chen,∇ Dianna Lester-Zeiner,∇ Jessica Able,∇
Christopher Biorn,∇ Ji Ma,○ Jianxia Shi,○ James Treanor,∥ and Jennifer R. Allen†
†Department of Medicinal Chemistry, ‡Department of Molecular Structure, §Department of Pharmacokinetics and Drug Metabolism,
∥
and Department of Neuroscience, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, California 93012-1799, United States
⊥Department of Molecular Structure and Characterization, ∇Department of Neuroscience, and ○Department of Pharmacokinetics
and Drug Metabolism, Amgen, Inc., 1120 Veterans Boulevard, South San Francisco, California 94080, United States
S
* Supporting Information
ABSTRACT: We report the discovery of novel imidazo[4,5-
b]pyridines as potent and selective inhibitors of PDE10A. The
investigation began with our recently disclosed ketobenzimidazole
1, which exhibited single digit nanomolar PDE10A activity but
poor oral bioavailability. To improve oral bioavailability, we turned
to novel scaffold imidazo[4,5-b]pyridine 2, which not only retained
nanomolar PDE10A activity but was also devoid of the morpholine metabolic liability. Structure−activity relationship studies
were conducted systematically to examine how various regions of the molecule impacted potency. X-ray cocrystal structures of
compounds 7 and 24 in human PDE10A helped to elucidate the key bonding interactions. Five of the most potent and
structurally diverse imidazo[4,5-b]pyridines (4, 7, 12b, 24a, and 24b) with PDE10A IC50 values ranging from 0.8 to 6.7 nM were
advanced into receptor occupancy studies. Four of them (4, 12b, 24a, and 24b) achieved 55−74% RO at 10 mg/kg po.
KEYWORDS: Phosphodiesterase 10A, schizophrenia, receptor occupancy, bioavailability
of dopaminergic pathways and glutamatergic pathways, two
major pathways that have been associated with the pathophysi-
ology of schizophrenia, it has been hypothesized that inhibition
of PDE10A could be used to treat all three main symptoms of
schizophrenia, the positive, the negative, and the cognitive
deficits.7 To date, at least two PDE10A inhibitors have been
advanced into clinical trials to test this hypothesis.8
We recently reported the discovery of ketobenzimidazole 1
as an inhibitor of PDE10A (Figure 1).9 This compound
exhibited single digit nanomolar activity against PDE10A
enzyme (IC50 = 4.5 nM) with moderate in vivo clearance in
hosphodiesterase (PDE) enzymes regulate the intracellular
Psignaling of cyclic adenosine 3′-5′-monophosphate
(cAMP) and cyclic guanosine 3′-5′-monophosphate (cGMP)
by cleaving their phosphodiester bonds and converting them to
AMP and GMP. The PDE isoforms are highly localized,
positioned to modulate the cNMP gradients and signaling in a
specific tissue. Since 10 out of 11 PDE isoforms have splice
variants in the CNS, it has been postulated that having a means
to control the activity of a specific PDE isoform in the CNS
could be beneficial to a range of neuropsychiatric and
neurodegenerative diseases such as psychosis, depression,
Parkinson’s disease, Alzheimer’s disease, etc.1−3
An in depth analysis of the medications prescribed for
treatment of schizophrenia revealed a disease area with
significant unmet medical needs.4 The current standard of
care (SOC) was found to be inadequate, with limited efficacy
and adverse effects on patient quality of life. Since these SOC
shared similar mechanisms of action, the authors concluded
that novel targets should be explored for future drug
development. PDE10A represented such a novel target
opportunity for treatment of schizophrenia.5 The PDE10A
enzyme is highly expressed in the striatum, a brain region
believed to be dysregulated in schizophrenia. In a locomotor
behavioral model, PDE10A knockout mice showed blunted
response when treated with PCP suggesting that a PDE10A
antagonist could have therapeutic benefit.6 Since PDE10A is
positioned to modulate levels of cAMP and cGMP downstream
Figure 1. Structures of compounds 1 and 2.
Received: March 7, 2014
Accepted: March 28, 2014
Published: March 28, 2014
© 2014 American Chemical Society
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Letter
rat (Cl = 0.53 L/h/kg). However, its oral bioavailability was
low (10% F). Poor permeability and metabolic instability have
been found to be two common causes of poor oral
bioavailability.10 Since 1 was highly permeable, we focused
our efforts on reducing its metabolic liability. As disclosed in
our recent report, we found that replacement of the morpholine
ring with metabolically robust heterocycles improved its
pharmacokinetic (PK) profile.9 Meanwhile, we searched for a
novel scaffold devoid of a morpholine to circumvent the PK
issue. One intriguing lead that emerged from this search was
imidazo[4,5-b]pyridine 2, which exhibited comparable PDE10A
inhibitory activity (IC50 = 15.1 nM) to 1. In this letter, we
present our thorough examination of the structure−activity
relationship (SAR) of this novel scaffold and our discovery of
structurally diverse, potent, and selective inhibitors of PDE10A
with improved in vivo profiles.
Table 1. Examination of Linker and Benzimidazole
Replacements on Compound 2
We began with an investigation of linker and benzimidazole
replacements (Table 1). As we had observed with ketobenzi-
midazole 1, replacement of the carbonyl linker with an amine
(3) resulted in a 30-fold boost in potency but a high P-gp efflux
ratio. Amino benzthiazole 4 not only showed a 3-fold increase
in potency (IC50 = 5.7 nM) compared to 2 but also maintained
a low efflux ratio in P-gp assays (1.6 in human; 1.7 in rat) and
acceptable in vitro clearance (65 μL/min/mg in human; 62 μL/
min/mg in rat). Significant erosion of PDE10A potency was
observed with quinoline 5 suggesting the 6−6 fused system
may be too bulky for the binding pocket. Interestingly, while
chloro pyridine 6 experienced a reduction of PDE10A activity,
methylpyridine 7 (IC50 = 4.1 nM) was 10-fold more potent
than 6. Analogue 7 also exhibited low in vitro clearance (34
μL/min/mg in human; 27 μL/min/mg in rat) plus low P-gp
efflux ratios (1.4 in human; 1.9 in rat).
As shown in Figure 2, the methoxy imidazo[4,5-b]pyridine
motif was also found to be necessary for PDE10A inhibitory
activity. Opening the imidazole ring (8) greatly deteriorated the
potency of the compound. Removal of the methoxy substituent
(9) also afforded a much weaker analogue compared to 4. To
understand how the methoxy substituent helped to increase
PDE10A binding affinity, we embarked on a systematic
examination of the methoxy substituent on benzthiazole 4
and pyridine 7 (Table 2). Replacement with a methyl group
(10a and 10b) decreased potency compared to their methoxy
analogues 4 and 7. Extending the substitution to an ethyl group
(11a and 11b) had minimal impact on activity, indicating the
electron withdrawing oxygen atom on the methoxy substituent
had a critical role in the potency of the compounds. To our
surprise, while cyclopropyl benzthiazole 12a showed no change
in potency from its ethyl analogue 11a, cyclopropyl
methylpyridine 12b achieved single digit nanomolar potency
(IC50 = 6.7 nM), 7-fold more potent than its ethyl analogue
11b.
a
Each IC50 value reported was an average of at least two independent
experiments with 22 point dose−response curve in duplicates at each
concentration. In vitro human and rat liver microsomal stability
b
studies were conducted in the presence of NADPH at 37 °C for 30
min at a final compound concentration of 1 μM of compound.
c
Human and rat efflux ratio reported was based on the ratio of the
basolateral to apical permeability over apical to basolateral
permeability of a compound. MDR1-Madin-Darby canine kidney
(MDCK) cells were used to measure the compound’s apparent
permeability in each direction. (h): human. (r): rat. LM: liver
microsomal stability. NT: not tested.
General synthetic routes for compounds 2−12b are shown in
Scheme 1. Route A illustrated the synthesis of compound 2,
which began with protection of benzimidazole 13 and
deprotonation using LHMDS to add to methyl 4-iodobenzoate
14 to afford ketobenzimidazole intermediate 15. Palladium
catalyzed coupling of 3-nitropyridin-2-amine 16 followed by
nitro reduction using molybdenum hexacarbonyl produced (4-
((3-aminopyridin-2-yl)amino)phenyl)(1-(tetrahydro-2H-
pyran-2-yl)-1H-benzo[d]imidazol-2-yl)methanone 17. Acid
promoted synthesis of imidazo[4,5-b]pyridine core and sulfuric
acid deprotection of THP group formed (1H-benzo[d]-
imidazol-2-yl)(4-(2-methoxy-3H-imidazo[4,5-b]pyridin-3-yl)-
Figure 2. Structures of compounds 8 and 9.
phenyl)methanone 2. Route B depicted the general synthetic
scheme for analogues 3−12b. Coupling of N-(4-aminophenyl)-
acetamide 18 with 2-chloro-3-nitropyridine 19 by SNAr
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catalyzed cyclization formed the desired imidazo[4,5-b]pyridine
22.
Table 2. Examination of Methoxy Replacements on
Compounds 4 and 7
We were able to obtain an X-ray cocrystal structure of
imidazo[4,5-b]pyridine 7 in the human PDE10A catalytic
binding domain in order to elucidate the key binding
interactions of this novel scaffold (Figure 3). Two critical
Figure 3. X-ray cocrystal structure of compound 7 in human PDE10A
enzyme.
hydrogen bonding interactions were observed. The first
interaction was between the pyridine nitrogen on imidazo-
[4,5-b]pyridine and the conserved Gln716. The other
interaction was between the pyridine nitrogen on the
methylpyridine and Tyr683. The center phenyl ring did not
appear to be making any binding interactions with the PDE10A
enzyme. Instead, it served as a scaffold that enabled both
imidazo[4,5-b]pyridine and methylpyridine rings to make the
critical hydrogen binding interactions with the PDE10A
enzyme.
a
Each IC50 value reported was an average of at least two independent
experiments with 22 point dose−response curve in duplicates at each
concentration.
displacement reaction followed by removal of acetyl protecting
group gave N-(3-nitro-pyridin-2-yl)-benzene-1,4-diamine (20).
A second SNAr displacement to install the desired R3 ring
followed by reduction of the nitro group using palladium
hydrogenation afforded aniline intermediate 21. Finally, acid
To further explore the role of the middle phenyl ring, we
examined other moieties that could still maintain the linear
orientation between the imidazo[4,5-b]pyridine and the
a
Scheme 1. Syntheses of Compounds 2−12b
a
Reagents and conditions: (1) 3,4-dihydro-2H-pyran, p-toluenesulfonic acid, 130 °C, 88% yield; (2) 14, LHMDS, THF, −78 °C, 33% yield; (3)
Pd2(dba)3, Xantphos, 16, Cs2CO3, DMA, 100 °C, 98% yield; (4) Mo(CO)6, DBU, EtOH, 150 °C, 77% yield; (5) propionic acid, tetramethyl
orthoformate, 100 °C, 50% yield; (6) sulfuric acid, THF, EtOAc, −20 °C, 23% yield; (7) 19, TEA, DMSO, 90 °C, 90% yield; (8) 5 N HCl, 1,4-
dioxane, 70 °C, 90% yield; (9) 2-chloro-5-methyl-pyridine, 180 °C; (10) Pd/C, MeOH, H2; (11) propionic acid, HATU, TEA, DCM, room
temperature; (12) acetic acid, 90 °C; (13) tetramethyl orothocarbonate, propionic acid, 90 °C.
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a
methylpyridine (Table 3). With a cyclohexyl group as the
central ring, 23 experienced a significant reduction in potency.
Scheme 2. Synthesis of Compound 24
Table 3. Examination of Central Phenyl Ring Replacements
a
Reagents and conditions: (1) benzylamine, sodium cyanoborohy-
dride, MeOH, 80% yield; (2) 50% Pd(OH)2/C, MeOH, H2, 95%
yield; (3) 27, DIPEA, NMP, 180 °C, 50% yield; (4) HCl, MeOH; (5)
19, sodium carbonate, DMF, reflux, 70% yield for two steps; (6) 50%
Pd/C, MeOH, H2, 97% yield; (7) propionic acid, tetramethyl
orthocarbonate, 90 °C, 63% yield.
We were able to obtain an X-ray cocrystal structure of cis/
trans mixture 24 in the human PDE10A catalytic domain
(Figure 4). An overlap of both isomers (cis isomer colored
a
Each IC50 value reported was an average of at least two independent
experiments with 22 point dose−response curve in duplicates at each
b
concentration. In vitro human and rat liver microsomal stability
studies were conducted in the presence of NADPH at 37 °C for 30
min at a final compound concentration of 1 μM of compound. (h):
human. (r): rat. LM: liver microsomal stability.
Figure 4. Overlap of X-ray cocrystal structure of cis/trans mixture 24
in human PDE10A enzyme. Cis isomer colored yellow. Trans isomer
colored green.
Presumably, the cyclohexyl ring was too bulky to fit in the
narrow channel between Gln716 and Tyr683. To our surprise,
cis/trans-cyclobuty mixture 24 exhibited single digit nanomolar
activity (IC50 = 2.2 nM) comparable to its phenyl analogue 4.
We separated the mixtures and found the cis-cyclobutyl isomer
(24a) had an IC50 of 3.4 nM against PDE10A and the trans-
cyclobutyl isomer (24b) had an IC50 of 0.8 nM against
PDE10A.
The synthesis of compound 24 was accomplished as depicted
in Scheme 2. Reductive amination of tert-butyl (3-
oxocyclobutyl)carbamate 25 with benzylamine followed by
deprotective hydrogenation afforded tert-butyl (3-
aminocyclobutyl)carbamate 26 as mixture of cis and trans
isomers. Installation of benzthiazole ring via SNAr displacement
using chlorobenzthiazole 27 then acid catalyzed removal of Boc
protecting group gave N1-(benzo[d]thiazol-2-yl)cyclobutane-
1,3-diamine 28. Installation of 3-aminopyridine via first SNAr
displacement with 2-chloro-3-nitropyridine 19 then nitro
reduction by hydrogenation afforded N2-(3-(benzo[d]thiazol-
2-ylamino)cyclobutyl)pyridine-2,3-diamine 29. Acid promoted
cyclization formed the cis/trans-imidazo[4,5-b]pyridine 24.
Separation by chiral chromatography led to the isolation of
cis-cyclobutyl isomer 24a and trans-cyclobutyl isomer 24b.
yellow and trans isomers colored green) illustrated their nearly
identical binding modes. Compared to cocrystal structure of
compound 7 in PDE10A, the benzthiazole portion of both
isomers maintained similar key hydrogen bond interactions
with Tyr683. An extra water molecule was observed between
the pyridine nitrogen on the imidazo[4,5-b]pyridine core and
the conserved Gln716. Since both cis and trans cyclobutane
rings were able to fit in the narrow channel between Gln716
and Tyr683, both cis isomer 24a and trans isomer 24b were
able to achieve single digit nanomolar activity against PDE10A.
For the primary pharmacodynamic (PD) model, we were
reluctant to use the prevalent rodent behavioral models since
they could not discern whether the desired outcome was
achieved as a result of on-target or off-target mechanism. We
wanted a more direct and definitive readout of target
engagement and chose instead to measure receptor occupancy
(RO) as our PD readout. We recently disclosed the
development of PDE10A tracer AMG7980 that provided a
direct, in vivo measurement of PDE10A inhibition.11 To
determine whether the imidazo[4,5-b]pyridines could pass the
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ACS Medicinal Chemistry Letters
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blood−brain barrier (BBB) and block the PDE10A enzymes in
the CNS, all five single digit nanomolar imidazo[4,5-b]pyridine
inhibitors (4, 7, 12b, 24a, and 24b) were dosed into Sprague−
Dawley rats at 10 mg/kg po. The brains of the rodents were
collected 1 h postdosing, and the level of CNS blockage was
assessed by incubating brain slices with [3H]-AMG7980. As
shown in Table 4, four compounds (4, 12b, 24a, and 24b)
PDE10A enzyme, we were able to replace the middle phenyl
ring with cyclobutanes and obtained comparable or greater
potency with either cis-cyclobutane 24a (IC50 = 3.4 nM) or
trans-cyclobutane 24b (IC50 = 0.8 nM). Four imidazo[4,5-
b]pyridines (4, 12b, 24a, and 24b) achieved 55−74% RO at 10
mg/kg po in our PDE10A ex vivo RO study. Compounds 4 and
12b also achieved 71% and 57% RO in the in vivo LC−MS/MS
RO assay, reaching levels superior to the 21% RO shown by
ketobenzimidazole 1. All of the compounds advanced into the
RO assay also exhibited greater than 30 μM activity against
other PDE isoforms. An exhaustive SAR study of the
cyclobutane series and their improved in vivo PK and efficacies
will be reported in a separate publication.
a
Table 4. PDE10A ex Vivo Receptor Occupancy and in Vivo
b
Rat PK of Compounds 4, 7, 12b, 24a, and 24b
cmpd receptor occupancy Cl (L/h/kg) Auc (μM·h) T1/2 (h) % F
4
55%
36%
67%
68%
74%
0.65
1.17
2.05
0.88
0.21
11.9
7.56
3.44
10.7
16.0
3.24
3.78
0.91
2.1
30
28
24
32.5
7
7
12b
24a
24b
ASSOCIATED CONTENT
■
S
* Supporting Information
3.5
Experimental procedures and analytical data, along with
protocols for X-ray cocrystallization and biological assays.
This material is available free of charge via the Internet at
http://pubs.acs.org.
a
In vivo receptor occupancy measurements were taken 1 h post po
b
dosing of compounds at 10 mg/kg. In vivo RO and PK studies were
conducted in male Sprague−Dawley rats. Vehicles used: 100% DMSO
for iv; 1% Tween, 2% HPMC with methanesulfonic acid, pH 2.2 for
po.
Accession Codes
The PDB ID codes for coordinates of 7 and 24 with PDE10A
are 4P1R and 4P0N, respectively.
achieved greater than 50% PDE10A occupancy in the ex vivo
RO assay. Even though benzthiazole 4 and methylpyridine 7
exhibited similar PDE10A potency in the in vitro assay,
compound 7 was only able to reach 36.4% occupancy
compared to 54.5% of compound 4, presumably due to the
higher in vivo clearance of 7. In contrast, compound 12b was
able to achieve 67% receptor occupancy despite its high in vivo
clearance. We were excited to see both cis and trans isomers of
cyclobutyl imidazo[4,5-b]pyridines (24a and 24b) achieved
excellent PDE10A RO (68% and 74%, respectively). Interest-
ingly, these two isomers exhibited different in vivo PK profiles
in rat: cis-cyclobutyl isomer 24a showed modest clearance (Cl =
0.88 L/h/kg) and acceptable oral bioavailability (32.5% F),
while trans-cyclobutyl isomer 24b exhibited low clearance (Cl =
0.21 L/h/kg) but poor oral bioavailability (7% F).
To compare the in vivo efficacies of ketobenzimidazole 1 and
these novel imidazo[4,5-b]pyridines, we advanced imidazo[4,5-
b]pyridines 4 and 12b to an LC−MS/MS RO assay, an in vivo
RO measurement platform we had previously developed.11 In
this study, both the inhibitor and our PDE10A tracer
AMG7980 were dosed in vivo, and then the relative levels of
the compounds in the rat brain were quantified by LC−MS/
MS. We had previously reported that ketobenzimidazole 1
produced 21% RO at 10 mg/kg po in the LC−MS/MS RO
assay.9 In contrast, at the same 10 mg/kg po dose, imidazo[4,5-
b]pyridines 4 and 12b achieved 71% RO and 57% RO,
respectively, suggesting that these imidazo[4,5-b]pyridines were
more efficacious than 1 in vivo.
AUTHOR INFORMATION
■
Corresponding Author
*(E.H.) Phone: 805-313-5300. E-mail: ehu@amgen.com.
Notes
The authors declare no competing financial interest.
ABBREVIATIONS
■
BBB, blood−brain barrier; cAMP, cyclic adenosine 3′-5′-
monophosphate; cGMP, cyclic guanosine 3′-5′-monophos-
phate; ER, efflux ratio; HPMC, hydroxypropylmethylcellulose;
LC−MS/MS, liquid chromatography-tandem mass spectrome-
try; LM, liver microsome; cNMP, cyclic nucleotide mono-
phosphate; PCP, phencyclidine; PD, pharmacodynamic; PDE,
phosphodiesterase; RO, receptor occupancy; SOC, standard of
care
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