Fragment-assisted hit investigation involving integrated HTS and fragment screening: Application to the identification of phosphodiesterase 10A (PDE10A) inhibitors

Article abstract of DOI:10.1016/j.bmcl.2015.10.100

Fragment-based drug design (FBDD) relies on direct elaboration of fragment hits and typically requires high resolution structural information to guide optimization. In fragment-assisted drug discovery (FADD), fragments provide information to guide selecti

Full text of DOI:10.1016/j.bmcl.2015.10.100

Bioorganic & Medicinal Chemistry Letters 26 (2016) 197–202
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Fragment-assisted hit investigation involving integrated HTS
and fragment screening: Application to the identification
of phosphodiesterase 10A (PDE10A) inhibitors
a,
⇑
b
a
a
a
Jeffrey G. Varnes , Stefan Geschwindner , Christopher R. Holmquist , Janet Forst , Xia Wang ,
b
a
a
a
a,
⇑
Niek Dekker , Clay W. Scott , Gaochao Tian , Michael W. Wood , Jeffrey S. Albert
a
CNS Discovery Research, AstraZeneca Pharmaceuticals, 1800 Concord Pike, PO Box 15437, Wilmington, DE 19850-5437, USA
Discovery Sciences, AstraZeneca R&D, SE-431 83 Mölndal, Sweden
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Fragment-based drug design (FBDD) relies on direct elaboration of fragment hits and typically requires
high resolution structural information to guide optimization. In fragment-assisted drug discovery
Received 4 September 2015
Revised 26 October 2015
Accepted 30 October 2015
Available online 11 November 2015
(FADD), fragments provide information to guide selection and design but do not serve as starting points
for elaboration. We describe FADD and high-throughput screening (HTS) campaign strategies conducted
in parallel against PDE10A where fragment hit co-crystallography was not available. The fragment screen
led to prioritized fragment hits (IC50’s ꢀ500
l
M), which were used to generate a hypothetical core
Keywords:
PDE10A
Fragment-based drug discovery
Fragment-assisted drug discovery
Phosphodiesterase inhibitor
Schizophrenia
scaffold. Application of this scaffold as a filter to HTS output afforded a 4
l
M hit, which, after preparation
of a small number of analogs, was elaborated into a 16 nM lead. This approach highlights the strength of
FADD, as fragment methods were applied despite the absence of co-crystallographical information to
efficiently identify a lead compound for further optimization.
Ó 2015 Elsevier Ltd. All rights reserved.
The cyclic nucleoside monophosphates cAMP and cGMP serve
as critical intracellular signaling agents. Signal termination is reg-
ulated by hydrolytic cleavage of cAMP and cGMP by members of
the phosphodiesterase (PDE) family of enzymes. Among the 11
PDE families, PDE10A has received significant attention as a target
for new antipsychotic drugs.1 PDE10A has a restricted expression
pattern within the body, with high levels found only in the
MSN output pathways, inhibitors of this enzyme offer a novel
therapeutic mechanism with a potentially different clinical profile
to existing therapy.
Several classes of structurally diverse PDE10A inhibitors from
1
1
12
preclinical studies and clinical trials have been described in
the literature (Fig. 1). These compounds have resulted from the
1
b
natural product papavarine (1),
structure-based drug design (2–5),
random screening and/or
2
–4
11–13
14
brain.
Specifically, PDE10A protein is localized to the cell bodies
and fragment screening.
and dendrites of the striatal medium spiny neurons (MSN) where it
modulates excitability and striatal output.5 These neurons can be
separated into two distinct output pathways with different
dopamine receptor expression profiles: a D1-expressing ‘direct’
pathway and a D2-expressing ‘indirect’ pathway.7
Clinically validated antipsychotics contain D2 antagonist or
partial agonist activity and principally modulate the MSN indirect
pathway. However, these medicines do not treat all schizophrenia
symptoms (especially negative symptoms and cognitive deficits)
and a significant patient population discontinues treatment due
to lack of efficacy or the occurrence of adverse effects, indicating
significant unmet need.10 Since PDE10A is expressed in both
Our strategy to identify novel PDE10A inhibitors was to use alter-
native screening approaches. We considered using fragment-based
drug discovery (FBDD), which is now widely used to identify novel
,6
1
5–22
chemotypes,
however, fragment co-crystallography was not
–9
available despite the existence of published and in-house crystallo-
graphic data for PDE10A. Instead we chose to use fragment screen-
ing information to influence more traditional screening methods,
such as high-throughput screening (HTS). This strategy, which is
illustrated in Figure 2, is referred to as fragment-assisted drug dis-
covery (FADD) to differentiate it from FBDD, where the fragments
1
8
themselves serve directly as starting points.
An HTS analysis of our corporate compound collection for
PDE10A inhibitors afforded more than 11,000 initial hits (>75%
PDE10A inhibition, see Supplemental; hit rate: 5%). We eliminated
compounds that were structurally related to known PDE inhibitors
and those compounds that were of potential risk due to off-target
⇑
Corresponding authors. Tel.: +1 781 839 4944 (J.G.V.), +1 786 529 1730 (J.S.A.).
E-mail addresses: jeffrey.varnes@astrazeneca.com (J.G. Varnes), jeffrey.albert@
intellisynrd.com (J.S. Albert).
http://dx.doi.org/10.1016/j.bmcl.2015.10.100
0
960-894X/Ó 2015 Elsevier Ltd. All rights reserved.

1
98
J. G. Varnes et al. / Bioorg. Med. Chem. Lett. 26 (2016) 197–202
Figure 1. Representative examples of PDE10A inhibitors. Data are reported PDE10A IC50’s according to citations within the text.
Figure 2. Fragment-assisted drug discovery strategy used to reveal, prioritize, and
progress novel PDE10A inhibitors.
pharmacology, low predicted physical properties, or core
pharmacophore features with potentially undesirable metabolic
or reactivity profiles. The resulting set of 5328 compounds was
tested for multi-dose IC50 determination against PDE10A.
Additionally, compounds were also analyzed for their activity
against PDE2A as an early indication of selectivity. PDE2A was cho-
sen for selectivity profiling among the various isoforms because of
its high similarity to PDE10A in the catalytic region, which includes
a proximal tyrosine that is analogous to PDE10A’s Tyr693.
Figure 3. PDE10A inhibition (IC50
)
versus ligand efficiency23 (LE). Red:
PDE2A-preferring (PDE2A activity >3-fold stronger than PDE10A), yellow:
PDE10A-nonselective (PDE2A activity within 3-fold relative to PDE10A), green:
PDE10A-preferring (>3-fold stronger than PDE2A activity). The yellow circle
indicates the point corresponding to compound 8 according to the original HTS data.
molecular weight (150–250 g/mol and cLogP À0.8 to 3.0). Frag-
ments were screened at a concentration of 100 lM using OWG
(
optical waveguide grating) as the detection method to identify
The results of HTS profiling are shown graphically in Figure 3
where PDE10A IC50 (enzyme inhibition assay) is plotted against
hits (>20% PDE10A inhibition) in the 10 lM to 10 mM binding
2
3
24,25
range.
As with the HTS, the hit rate was quite high (14%) and
ligand efficiency (LE) and colored according to PDE2A/PDE10A
selectivity ratio. Hits covered a potency range (IC50’s) of 5 nM to
many compounds (414) had excellent LE (0.30–0.55). Fragment
hits (not shown) with the highest LE tended to share certain struc-
tural features: they typically were composed of 2 or 3 fused aro-
1
00 lM and were structurally very diverse. In addition, a substan-
tial fraction of compounds had quite high LE; more than 1500 com-
pounds had LE >0.3 and a favorable PDE10A selectivity profile (vs
PDE2A).
As part of our alternative screening approach, a fragment screen
was conducted in parallel to the HTS on 3000 compounds with low
1
3
matic heterocycles and were reminiscent of 2. While these
were viable starting points, such structures tend to be associated
with higher lipophilicity, lower solubility, and possibly reduced
2
6
druggability.

J. G. Varnes et al. / Bioorg. Med. Chem. Lett. 26 (2016) 197–202
199
Figure 5. Hypothetical PDE10A scaffold derived from fragment hits 6 and 7 and
docking studies where a core five-membered heterocycle is connected to a second
heterocycle on one side and an aromatic or hydrophobic group on the other.
Figure 4. Exemplar biaryl fragment hits with PDE10A activity.
A second group of fragment hits, exemplified by heterocycles 6
and 7 (Fig. 4), were fewer in number but had quite different struc-
tural features. These compounds had PDE10A binding affinities
the evaluation of a set of 2,3-bis-substituted benzamides and led
to identification of 11 (IC50 = 0.10
lM), which showed high selec-
tivity with respect to PDE2A (IC50 >100
l
M). Despite this apparent
(
IC50’s) of 851
lM and 324
lM, respectively, as measured using a
selectivity and high LE (0.38), liabilities included low solubility and
surface plasmon resonance (SPR) binding affinity assay (see
Supplemental). Interestingly, since this work was conducted, Hoff-
man-La Roche has reported several series of PDE10A inhibitors, one
of which also contains pyridine–thiazole and pyridine–pyrazole
increased lipophilicity.
To investigate the role of H-bond donors, we prepared 12,
where the benzimidazole nitrogen was capped by methylation
and the pyrazole NH was eliminated by replacing that heterocycle
with thiazole. Gratifyingly, 12 showed the highest potency
1
1g
scaffolds.
Other reported scaffolds with similar functionality
1
2a
include Takeda’s pyridazinone–pyrazoles (e.g., TAK-063)
and
(IC50 = 0.016 lM, LE = 0.41) and lowest polar surface area
Janssen’s imidazopyrazine–pyrazoles.1
1a
(PSA = 54). Substituents on the aromatic ring of the amide were
also revisited in an attempt to decrease lipophilicity. This led to
identification of 13 which retained substantial potency
To differentiate the potential binding modes of fragment screen
hits resembling 2 and those more structurally similar to fragments
6
and 7, we used computational docking studies (see Supplemen-
(IC50 = 0.11
lM, LE = 0.38, cLogP = 3.3). Subsequent methylation
tal) based on the extensive SAR and structural work discussed by
the Pfizer group and others for the class of compounds related to
afforded 14, which was equipotent (IC50 = 0.12
l
M, LE = 0.36).
We reasoned that since the benzimidazole of 13 could be
methylated without potency loss, one of the benzimidazole
nitrogens functioned as an acceptor and the other nitrogen had
no key interactions with the protein and was likely oriented
toward solvent. To test this hypothesis we prepared 15 where
the benzimidazole NH was used as a tethering point to add an ami-
noethyl group as a hydrophilic substituent. This moderately
1
1,12
3.
Thus fragment hit 2 was predicted to bind to PDE10A in
the region near the catalytic pocket, while 6 and 7 were suggested
to bind between the selectivity and catalytic pockets. Unfortu-
nately, because we did not have a co-crystal structure for 6 or 7,
both the true position and the orientation of these fragment hits
were unknown.
At this stage our objective was to assess how we could use frag-
ment screening results with the previously executed HTS to rapidly
identify structurally differentiated lead compounds. Our approach
was to select fragments that we considered to be distinct from
known PDE10A inhibitors to use as substructure core filters of
the extensive HTS hit set. We illustrate this strategy with frag-
ments 6 and 7, where the absence of a co-crystal structure did
not preclude progression since we were looking for novel scaffolds.
We formulated the hypothesis that key structural features of
this fragment subset included a core five-membered heterocycle
connected to a second heterocycle on one side and an aromatic
or hydrophobic group on the other (Fig. 5). We next conducted a
bond-connectivity matching analysis of the corporate collection
and found that 6000 compounds fit the proposed scaffold; cross-
referencing this set with HTS actives led to a 14 compound subset.
Of those 14 compounds, 13 were eliminated upon follow-up anal-
ysis either because they were false positives or because they con-
tained unattractive functionality. The final compound was
benzimidazole 8 (Table 1), which had moderate potency (IC50
reduced potency and LE (IC50 = 0.49
lM, LE = 0.31) but did improve
solubility (13 M) and lipophilicity (cLogP 2.5). Such improve-
l
ments in solubility increase the likelihood of generating co-crystal
structures and further evolving this chemotype.
The co-crystal structure of 3 with PDE10A as reported by Pfizer
1
2c
is shown in Figure 6.
Two key interactions between 3 (green
scaffold) and PDE10A are (1) between the pyrazolopyridine region
and the catalytic pocket and (2) between the quinoline and what is
termed the selectivity pocket because it is most apparent in
PDE10A (and is smaller or absent in other PDE isoforms). This same
enzyme structure was used for docking studies with our com-
pounds, and the most favored docked pose for 11 (magenta) is
shown overlayed with 3. According to this model, the benzimida-
zole nitrogen acts as a hydrogen bond accepter with Tyr693 and
thus as a surrogate for the quinoline nitrogen of 3. This orientation
of 11 therefore directs the second benzimidazole nitrogen toward
solvent, which is consistent with the observation that there are
no significant differences in potency between NH compound 13
(IC50 0.11
consistent with the observation that the large aminoethyl
replacement in 15 (IC50 0.49 M) is tolerated, although with
lM) and its N-methyl analog 14 (IC50 0.12 lM). It is also
3.8 lM) and reasonable LE (0.32). Prompted by this finding we
re-screened available close analogs in order to provide some assur-
ance that 8 was not a singleton. Such analogs typically showed
weak but detectable activity. For example, 9 showed 23% inhibition
l
reduced potency relative to 13 and 14. Furthermore, the central
pyrazole appears to serve mostly as a spacer and does not
contribute any selective binding interactions. Finally, the
benzamide aryl group likely participates in a stacking interaction
with Phe729.
of PDE10A activity at 30
lM, which was too weak to establish an
IC50 (>30 M). Thus, this small family of weak hits was unremark-
l
able in terms of potency or physical properties. However, we
judged that if the compounds did represent elaborated forms of
fragment hits 6 and 7 then we might be able to use that knowledge
to evolve the chemotype in a more optimal manner.
Starting with 8 as a reference, we explored analogs containing
the same benzimidazole–pyrazole left side region and varied the
right side amide substituent. A small set of analogs was prepared
containing various five- and six-membered aromatic groups. The
The synthesis of substituted pyrazoles 8–11 is shown Scheme 1,
and further details for abbreviations and procedures can be found
2
8
in Supplemental information. Thus, acid 16 was coupled with
1,2-phenylenediamine using PyClop to afford 17. Acid-mediated
cyclization of this material gave 18. The nitro group was reduced
by catalytic hydrogenation, and the resulting crude amine (19)
was coupled with an appropriate carboxylic acid prior to
deprotection under acidic conditions to afford 8–11.
most potent in the group was 10 (IC50 = 0.28 lM). This prompted

2
00
J. G. Varnes et al. / Bioorg. Med. Chem. Lett. 26 (2016) 197–202
Table 1
Enzymatic activity and properties of biaryl pyrazoles and analogs
#
Structure
PDE10A IC50a
(
lM)
LEb
Solc
2
(lM)
cLogP
PSAd
107
N
H
N
O
N
8
3.8
0.32
1.7
N
O
N
H
N
H
H
N
N
S
9
>30
—
nd
<1
2.1
3.9
121
84
N
O
O
O
N
H
N
H
H
N
N
1
0
0.28
0.36
N
O
Cl
N
H
N
H
H
N
N
Cl
0.10e,f
1
1
2
0.38
0.41
<1
<1
4.4
4.6
84
54
N
O
N
H
N
H
H
N
N
N
S
0.016e,f
1
Cl
N
O
H
N
N
S
CN
CN
0.11e,f
0.12
13
14
15
0.38
0.36
0.31
1
3.3
3.3
2.5
86
72
N
N
O
O
N
H
H
N
N
N
S
<1
13
NH2
S
H
N
N
N
0.49
100
CN
N
O
a
b
c
d
e
f
Results are the average of at least two determinations and reproducibility is <0.3log units based on replicate determinations.
23
Ligand efficiency.
Equilibrium solubility at pH 7.4 in phosphate buffer.
27
Polar surface area.
PDE2A IC50 >100 nM.
PDE2A IC50 determinations were sometimes made at drug concentrations (in assay buffer) that were higher than the measured equilibrium solubility (at pH 7.4 in
phosphate buffer). Test samples were confirmed not to have any visible precipitate, but the drug solubility under the exact assay conditions is unknown and this results in
unavoidable uncertainty in assessing PDE2A selectivity.
Compounds 12–14 (Scheme 2) were prepared by reacting either
5
-(1H-benzo[d]imidazol-2-yl)thiazol-2-amine (22a; prepared from
commercial 21a) or 5-(1-methyl-1H-benzo[d]imidazol-2-yl)thia-
2
9
zol-2-amine (22b; prepared from commercial 21b) with an
appropriate benzoic acid and coupling reagent such as TBTU or
HATU. Thiazole 15 was prepared from known carbamate 2330 fol-
lowing Raney nickel catalyzed hydrogenation to afford 24, which
was cyclized with 2-aminothiazole-5-carbaldehyde to yield 22c.
Acylation of 22c with 3-cyanobenzyolchloride provided 25, and
deprotection under acidic conditions then gave 15.
In summary, we employed a high-concentration fragment
screen using a biophysical assay. The resulting fragment hits were
prioritized based on ligand efficiency, potency, and physical prop-
erties. Docking studies suggested that prioritized fragment hits
exemplified by 6 and 7 adopted a different binding pose relative
to fragments resembling 2, however, we were unable to co-crystal-
lize the former with the target. While this work was ongoing, we
carried out a traditional HTS screen using an enzymatic assay. As
expected based on the known high druggability of the target, we
observed a high hit rate and, consequently, were left with a large
collection of possible starting points.
Figure 6. Overlay of the crystallographically determined orientation12c of 3 (green)
with the computationally derived preferred binding mode of 11 (magenta).
Potential hydrogen bond interactions with Tyr693 are shown as dotted lines.

J. G. Varnes et al. / Bioorg. Med. Chem. Lett. 26 (2016) 197–202
201
Scheme 1. Reagents and conditions: (a) 1,2-phenylenediamine, PyClop, DIPEA, DCE, 60 °C, 1.5 h, 41%; (b) HOAc, 70 °C, 40 min, 85%; (c) 10% Pd/C, H
2
, THF/MeOH, 50 °C, 4 h,
9
2
9%; (d) RCO H, PyClop, DIPEA, DCE, 60 °C, 4–18 h, 38–85%; (e) TFA, 75 °C, 5 min, 49–86%.
Scheme 2. Reagents and conditions: (a) 2-aminothiazole-5-carbaldehyde, DMSO, 120 °C, 30 h, 63%; (b) 2-aminothiazole-5-carbaldehyde, PEG-400, 110–125 °C, 4 h, 14–64%;
c) Raney Ni, hydrazine, rt, 2 h, 80%; (d) 3-chloro-2-methyl- or 3-cyano-benzoic acid, TBTU, HOBT, DIPEA, DMF, rt, 25–34%; (e) 3-cyanobenzoic acid, HATU,
N-methylmorpholine, DMF, 60 °C, 18 h, 94%; (f) 3-cyanobenzoyl chloride, DIPEA, DCM, rt, 18 h, 36%; (g) 3 M methanolic HCl, rt, 2 h, 96%.
(
As an alternative to using fragment hits directly (FBDD), we
opted to start with the knowledge derived from our fragment
screen (FADD) and hypothesized the key scaffold shown in Figure 5.
This scaffold was used to filter our HTS hits, resulting in identifica-
Instead, FADD enabled us to apply the benefits of fragment based
methods in the absence of fragment co-crystallography to an
analysis of an HTS screen and afforded a lead series of PDE10A
inhibitors.
tion of pyrazole 8 (IC50 3.8
IC50 0.28 M), and efforts to reduce the polar surface area (desired
PSA: <80) and explore contributions from hydrogen bond donors
led to 12 (IC50 0.016 M), all while retaining good LE. Further
exploration led to compounds 14 and 15 which had weaker affinity
but modestly better solubility and/or lower cLogP.
It is unlikely that benzimidazole 8 would have been exploited
by HTS data alone simply because of the number of alternative
hits and limited resources. This is supported by an assessment
of Figure 3, where many hit compounds had stronger potency
and higher LE than 8. Similarly, fragment approaches alone would
not have enabled progression of hits 6 and 7 because of their
unknown mode of binding and lack of co-crystallization data.
lM). Rapid SAR exploration led to 10
(
l
Acknowledgements
l
We gratefully acknowledge the contributions of Helen Feng for
the original syntheses of compounds 8–11. We also acknowledge
Camil Joubran and Nancy Degrace for confirming the structures
of 17 and 18.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2015.10.
100.

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J. G. Varnes et al. / Bioorg. Med. Chem. Lett. 26 (2016) 197–202
Cueva, M.; Talreja, S.; Kornecook, T.; Chen, H.; Porter, A.; Hungate, R.; Treanor,
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2
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(
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