Multitarget Compounds for Bipolar Disorder: From Rational Design to Preliminary Pharmacokinetic Evaluation

Article abstract of DOI:10.1002/cmdc.202000210

Due to the complex and multifactorial nature of bipolar disorder (BD), single-target drugs have traditionally provided limited relief with no disease-modifying effects. In line with the polypharmacology paradigm, we attempted to overcome these limitations by devising two series of multitarget-directed ligands endowed with both a partial agonist profile at dopamine receptor D3 (D3R) and inhibitory activity against glycogen synthase kinase 3 beta (GSK-3β). These are two structurally unrelated targets that play independent, yet connected, roles in cognition and mood regulation. Two compounds (7 and 10) emerged as promising D3R/GSK-3β multitarget-directed ligands with nanomolar activity at D3R and low-micromolar inhibition of GSK-3β, thereby confirming, albeit preliminarily, the feasibility of our strategy. Furthermore, 7 showed promising drug-like properties in stability and pharmacokinetic studies.

Full text of DOI:10.1002/cmdc.202000210

Accepted Article
Title: Multitarget compounds for bipolar disorder: from rational design
to preliminary pharmacokinetic evaluation
Authors: Rita Maria Concetta Di Martino, Giovanni Bottegoni,
Francesca Seghetti, Debora Russo, Ilaria Penna, Alessio De
Simone, Giuliana Ottonello, Sine Mandrup Bertozzi, Andrea
Armirotti, Tiziano Bandiera, Federica Belluti, and Andrea
Cavalli
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: ChemMedChem 10.1002/cmdc.202000210
Link to VoR: https://doi.org/10.1002/cmdc.202000210
01/2020

10.1002/cmdc.202000210
ChemMedChem
COMMUNICATION
Multitarget compounds for bipolar disorder: from rational design
to preliminary pharmacokinetic evaluation
Rita Maria Concetta Di Martino,§[a] Giovanni Bottegoni,§[f] Francesca Seghetti,[b] Debora Russo,[c] Ilaria
Penna,[c] Alessio De Simone,[e] Giuliana Ottonello,[d] Sine Mandrup Bertozzi,[d] Andrea Armirotti,[d] Tiziano
Bandiera,[c] Federica Belluti*[b] and Andrea Cavalli*[a, b]
[a]
[b]
Prof. A. Cavalli, Dr. R. M. C. Di Martino
Computational & Chemical Biology
Italian Institute of Technology
Via Morego 30, 16163, Genoa, Italy
E-mail: andrea.cavalli@iit.it.
Prof. A. Cavalli, Prof. F. Belluti, Dr. F. Seghetti
Department of Pharmacy and Biotechnology
University of Bologna
Via Belmeloro 6, 40126, Bologna, Italy
E-mail: federica.belluti@unibo.it
[c]
[d]
Dr. T. Bandiera, Dr. D. Russo, Dr. I. Penna
D3 PharmaChemistry
Italian Institure of Technology
Via Morego 30, 16163, Genova, Italy
Dr. A. Armirotti, Dr. S. Mandrup Bertozzi, Dr. G. Ottonello
Analytical Chemistry Lab
Italian Institute of Technology
Via Morego 30, 16163, Genoa, Italy
[e]
[f]
Dr. A. De Simone
Sygnature Discovery
BioCity, Pennyfoot St, Nottingham NG1 1GR, United Kingdom
Dr. G. Bottegoni
School of Pharmacy
University of Birmingham
Sir Robert Aitken Institute for Clinical Research
Edgbaston, B15 2TT, United Kingdom
§
*
These authors contributed equally to this work
These authors contributed equally to this work
Supporting information for this article is given via a link at the end of the document.
Abstract: Due to the complex and multifactorial nature of bipolar
disorder (BD), single target drugs have traditionally provided limited
relief with no disease modifying effects. In line with the
polypharmacology paradigm, we attempt to overcome these
limitations devising two series of multitarget-directed ligands endowed
with both a partial agonist profile at dopamine receptor D3 (D3R) and
inhibitory activity against glycogen synthase kinase 3 beta (GSK-3β).
These are two structurally unrelated targets that play independent yet
connected roles in cognition and mood regulation. Two compounds (7
and 10) emerged as promising D3R/GSK-3β multitarget-directed
ligands with nanomolar activity at D3R and low micromolar inhibition
of GSK-3β, confirming, albeit preliminarily, the feasibility of our
strategy. Furthermore, 7 showed promising drug-like properties in
stability and pharmacokinetic studies.
estimated worldwide prevalence up to 4%, BD is one of the
leading causes of disability. While molecular details of BD
etiopathology remain rather controversial, it has been shown that
an increased level of striatal dopamine (DA) D2/3 receptors
(D2/3Rs) leads to hyperdopaminergia and in turn to mania; in
parallel, elevated levels of striatal DA transporter induce hypo-
dopaminergia, which leads to depression. Additionally, faulty
homoeostatic mechanisms of DA are likely to play a role in cyclical
and marked changes of DA tone, which are at the basis of the
bipolar nature of the disorder.[1] Depending on the specific phase,
DA antagonists or partial agonists have been employed for the
treatment of BD. Some D2/D3Rs partial agonists, namely
cariprazine and aripiprazole (Figure 1), have been approved as
monotherapy for BD.[2] However, the therapeutic outcome of this
regimen is hampered by severe side effects caused by
Bipolar disorder (BD) is a severe neuropsychiatric condition in
which episodes of mania alternate with depression. With an
1
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10.1002/cmdc.202000210
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antagonism at D2R. D3R-selective agents could represent a
better option.[3] Recently, several selective and potent D3R partial
agonists have been reported (e.g. BP-897, Figure 1).[4]
systems directed to the D3R specificity binding pocket (SBP) and
GSK-3β hinge region. In detail, compounds 5-7 (series I) bear a
2-oxo-2,3-dihydro-1H-benzimidazole and 8-10 (series II) a 1H-
pyrazol-5-amino framework. These heterocyclic cores have
previously been exploited for GSK-3β inhibition (compounds 2, 3
and 4, Figure 2).[11] For the unsubstituted analogues 5 and 8,
bound conformations at both targets were predicted by docking
simulations (Figure 3). Based on these outcomes, the role of the
substituents able to establish additional interactions (van der
Waals or H-bond) with the targets was investigated; thus, series I
and II scaffolds were decorated with a phenyl or a 3-pyridine
moiety, to obtain analogues 6, 9 and 7, 10 (Figure 2). For series
I, to separate the contributions of the 2-oxo-benzimidazole
framework and the arylpiperazine function to the affinity for GSK-
3β, fragments 11-13 were prepared (Figure 2, Scheme S3 of SI).
Figure 1. Chemical structures of the D2/D3R partial agonists, the selective D3R
partial agonist, and the dual D3R/FAAH modulator mentioned in this study.
In response to persistently elevated extracellular DA levels, the
D2-like receptors, through a cAMP-independent mechanism,
negatively regulate the Akt/GSK-3β (glycogen synthase kinase 3
beta) intracellular pathway, resulting in GSK-3β activation.[5] This
cascade is considered a signal integrator that ensues a fine-
tuning of the DA system and that affects several pathways
involved in mood regulation, i.e. circadian clock, glutamatergic
and serotonergic neurotransmission.[5a] The clinical effects of
lithium (Li), a mood stabilizer widely used in BD treatment, could
be mediated by either a direct or an indirect GSK-3β inhibition.
Given the multifactorial nature of BD, can we exploit for
therapeutic purposes the independent yet connected roles of D3R
and GSK-3β in cognition and mood regulation? Multitarget-
directed ligands (MTDLs)[6] matching both the pharmacophoric
traits of D3R selective partial agonists[7] and the signature H-bond
forming pattern of protein kinases inhibitors[8] would be able to
concurrently modulate the DA signalling network at two key
nodes.
Here, applying a rational multitarget design strategy already
employed in the discovery of dual D3R/FAAH modulators (e.g.
compound 1, Figure 1),[9] we disclose the first series of D3R
partial agonist/GSK-3β inhibitors MTDLs (Figure 2). These dual
Figure 2. Design strategy for series I and II of dual D3R/GSK-3β modulators
and GSK-3β fragments.
modulators display the following features:
a
2,3-di-
chlorophenylpiperazine function, widely recognised as a G
protein-coupled receptor (GPCR) privileged fragment, able to
target ASP110 (conserved position 3.32, according to the
Ballesteros–Weinstein numeration[10]) in the orthosteric binding
pocket (OBP); a four-methylene aliphatic linker; two different
ureido/amido-functionalised heterocyclic cores, as dual H-bond
The synthetic strategies to prepare derivatives 5-10 are reported
in Schemes 1 (5-7) and 2 (8-10). In Scheme 1, route A, acylation
of 14 with trichloromethyl chloroformate afforded 17, that, reacting
with the amine 18, gave derivative 5. In route B, reaction of 15
and 16 with the isocyanate 19 yielded the N-Boc-protected 2-oxo-
2
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10.1002/cmdc.202000210
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COMMUNICATION
benzimidazoles 20 and 21, respectively. Analogue 20 underwent
HCl treatment to remove the protecting group and gave 6 by basic
work-up. Compound 7 was obtained from 21 by TFA treatment,
conversion into the free base 22, and final transformation into HCl
salt (Schemes S1 and S2 for intermediates synthesis).
Scheme 2. Synthesis of compounds 8-10. Reagents and conditions: a) HATU,
DIPEA, dry DMF, rt, 5 h, yield: 80-87%; b) TEA, dry 1,4-dioxane, rt, Ar, 48 h,
yield: 28%; c) oxalyl chloride, dry DMF, dry CH2CH2, 0 °C to rt, 1 h, yield:
assumed 100%; d) TFA, dry CH2Cl2, 0 °C to rt, 2-18 h, (work-up with saturated
aq NaHCO3 solution), yield: 64-88%.
Scheme 1. Synthesis of compounds 5-7. Reagents and conditions: a)
trichloromethyl chloroformate, charcoal, dry THF, trap with aq NH4OH solution
(30%), 100 °C, Ar, 30 h, yield: 53%; b) dry CH2Cl2/DMF (9:1), rt, Ar, 72 h, yield:
51%; c) dry CH2Cl2, rt, Ar, 3 h and 30 min-20 h, yield: 37-50%; d) HCl in 1,4-
dioxane (4 M), 1,4-dioxane/CH3OH (1.5:1), 0 °C to rt, 24 h, (work-up with
saturated aq NaHCO3 solution), yield: 66%; e) TFA, dry DCM, 0 °C to rt, 2 h and
30 min, (work-up with saturated aq NaHCO3 solution), yield: 93%; f) HCl in 1,4-
dioxane (4 M), 1,4-dioxane, rt, 1 h, yield: 83%.
Peptide & Europium-anti-phospho-Glycogen Synthase (Ser641)
Antibody, SI for details]. Efficacy at D3R, expressed as a fraction
of the effect elicited by 300 nM DA, was also determined. The
results obtained are reported in Tables 1 and 2 for series I and II,
respectively. Regarding series I, (Table 1) compound 5, with an
unsubstituted 2-oxo-benzimidazole core, was a potent D3R
modulator with an EC50 value of 7.9 nM; molecular modelling
studies showed as it simultaneously engaged both the OBP and
the SBP (Figure 3A), in line with previously reported
simulations.[9b, 12] At GSK-3β, 5 showed an IC50 value of 20.1 µM;
the 2-oxo-benzimidazole moiety engaged the hinge region of the
enzyme, forming the typical H-bond pattern of kinase inhibitors,
while the arylpiperazine group projected outside the pocket
(Figure 3B). A D3R activity similar to that of 5 was observed for
analogue 7 (EC50 = 10.1 nM), bearing a 3-pyridine group, that
possibly engaged the extracellular loop 2 with an additional H-
bond (Figure S1A). An increased GSK-3β activity up to an IC50 of
0.56 µM was also obtained; this effect could be due to the
formation of an H-bond between the pyridine nitrogen and LYS85
In Scheme 2, route A, an HATU-mediated amide coupling
reaction between the key intermediate 26 and the 1H-THP-
protected-pyrazoles (23 and 24) gave 28 and 29, respectively. In
route B, 27, obtained by oxalyl chloride treatment of 26, was
reacted with 25, to afford 30. Treatment of 28-30 with TFA, to
remove the protecting group, followed by mild basic work-up,
allowed obtaining the final compounds 8-10 (Schemes S4 and S5
for intermediates synthesis).
The biological activities of the newly synthesized compounds 7-
10 were studied in a HTRF-cAMP functional assay on stably
transfected human-D3R expressing CHO-K1 cells and a GSK-3β
kinase assay [ULight™-Glycogen Synthase (Ser641/pSer657)
3
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COMMUNICATION
Table 2. Biological results of series II compounds (8-10).
(Figure S1B). The interactions provided by this substituent were
of crucial importance, since for 6, with a phenyl function, a marked
decrease in D3R activity (EC50 = 42.4 nM) along with no GSK-3β
inhibition (up to 5 µM concentration) were observed. This last
effect was likely due to poor solubility in buffer (AlogP 5.72).
In series II (Table 2), compound 8, characterized by a methyl
group on the pyrazole scaffold, turned out to be a potent D3R
modulator (EC50 = 8.0 nM), as supported by its proposed binding
mode (Figure 3C) consistent with that of 5. When tested on GSK-
3β, this derivative showed an IC50 of 10.1 µM; its bound
conformation confirmed the possibility to form relevant H-bond
with the enzyme hinge region while accommodating the
arylpiperazine toward the solvent (Figure 3D). Interestingly, the
presence of a 3-pyridine instead of the methyl moiety improved
activities on both targets as derivative 10 exhibited activities of 2.9
nM and 2.6 µM on D3R and GSK-3β, respectively. Binding studies
demonstrated that this substituent was likely lodged in the D3R
subpocket formed between transmembrane helices 1 and 2
(Figure S1C), while for GSK-3β the 3-pyridine ring was
favourably lodged toward the conserved salt bridge without,
however, directly contacting LYS85 (Figure S1D). These data
reinforced the importance of this heterocycle for an optimal
modulation of both targets. Indeed, its substitution with a phenyl
ring (compound 9) slightly decreased D3R activity (EC50 = 14.1
nM) while no GSK-3β inhibition was observed up to 100 µM.
Moreover, series I and II displayed a classical partial agonist
profile (efficacies between 21.5% and 56.3%).
Cpd
R1
AlogP
D3R[a]
GSK-3β[a]
LELP
EC50
(nM)
IC50
Efficacy %
(µM)
8
9
CH3
Ph
2.17
3.84
8.0±1.8
47.0±7.5
56.3±7.6
10.1±2.9
n.i.
8.40
14.1±2.5
3-
10
2.69
2.9±0.6
43.4±11.1
2.6±0.2
11.00
pyr
[a] EC50 and IC50 values are reported as a mean value of three determinations.
n.i.= no inhibition up to the concentration of 100 µM (the highest dose tested).
GSK-3 activity of fragments 11-13 was also investigated and
reported in Table S1. Consistently with series I, introducing a
phenyl ring (12) was detrimental for activity, while a 3-pyridine
substituent (13) greatly increased the activity (IC50 = 37.8 nM).
Interestingly, 5 and 11 displayed the same potency and 13 was
more potent than its counterpart 7. In line with the results of our
docking studies, this behaviour suggested that the 2,3-dichloro-
substituted arylpiperazine does not contribute to binding and it is
either tolerated or actually detrimental for activity. This is clearly
captured by the variation in the ligand efficiency lipophilic price
(LELP), which steeply decreases from 19.79 in 5 to 5.45 in 11 and
from 19.32 in 7 to 5.53 in 13. The role of the substituents was
further investigated by means of a molecular interaction field
(MIF) analysis.[15] As reported in Figure 4, the vector projecting
from position 6 of the 2-oxo-benzimidazole core points toward a
strongly hydrophobic region (green mesh in Figure 4A). The 3-
pyridine could fit in the hydrophobic region, likely capturing an
additional H-bond with LYS85, while causing an only moderate
increase in logP (Figure 4B). In line with the obtained biological
activities on both selected targets, we chose 7 (EC50 = 10.1 nM
towards D3R and IC50 = 561 nM towards GSK-3β) as a dual
modulator prototype for generating preliminary pharmacokinetic
(PK) data (Table S2) and establishing a baseline for further
optimisation. This compound displayed stability in mouse plasma
(over 2 hours). Stability was limited (18 minutes) in mouse liver
microsomes but increased to over 1 hour in human liver
microsomes (Table S2). PK analysis revealed moderate blood
clearance, a low volume of distribution and a t1/2 of 0.182 h after
intravenous administration (IV) at 2.0 mg/kg. After oral
administration (PO) at 10 mg/kg, peak plasma concentration of 7
was observed after 30 minutes (Cmax 482 ng/ml). The compound
was detectable up to 8 h post dosing, and systemic exposure
Table 1. Biological results of series I compounds (5-7).
HCl
salt
LELP
[14]
Cpd
R
AlogP[13]
D3R[a]
GSK-3β[a]
IC50
EC50 (nM)
Efficacy %
(µM)
5
6
H
no
no
4.20
5.72
7.9±1.8
43.4±11.9
21.5±6.8
20.1±1.4
n.i.
19.79
37.79
Ph
42.4±11.9
3-
yes
7
4.57
10.1±0.4
26.3±2.4
0.6±0.04
19.32
pyr
(y=3)
[a] EC50 and IC50 values are reported as a mean value of three determinations.
n.i.= no inhibition up to the concentration of 5 µM (the highest dose tested due
to poor solubility of compound 6 in the assay buffer).
4
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A
B
C
D
Figure 3. Predicted bound conformations of 5 and 8. The protein structure is reported in grey ribbons. The binding pocket is highlighted by a transparent grey mesh.
Amino acids interacting with the ligand are reported in grey sticks and labelled explicitly. Bound conformation of 5 (green carbon atoms) at A) D3R and B) GSK-3β.
Bound conformation of 8 (pink carbon atoms) at C) D3R and D) GSK-3β.
A
B
Figure 4. Predicted bound conformations of 11 (A) and 13 (B) at the ATP binding pocket of GSK-3β. MIFs are reported as: C1= probe, transparent green mesh -
2.5 kcal/mol isocontour indicating a lipophilic region, and CH3 probe, transparent grey at -1 kcal/mol, defining the pocket shape.
(AUClast) was 488 h*ng/ml. Oral bioavailability was estimated at
16.1%. Central nervous system (CNS) penetration of 7 was also
evaluated by quantifying the compound brain concentrations up
to 8 h after PO (Table S2). Low brain exposure was observed with
a maximal brain concentration of 23.1 ng/g and AUClast value of
45.7 h*ng/g. A 17-fold increase in brain penetration was reported
after co-administration with P-glycoprotein 1 (P-gp) and breast
cancer resistance protein (BCRP) inhibitor Elacridar,[16]
suggesting an interaction of 7 with these ATP-dependent efflux
transporters. We later confirmed this hypothesis by testing 7 in a
P-gp human transporter cell-based antagonist assay.[17] In MDR1-
MDCKII cells, the compound inhibited P-gp-mediated
acetoxymethyl calcein (calcein-AM) efflux by 47.9% and 69.8% at
1 and 10 µM, respectively (SI for details). Notably, our PK studies
were performed on male C57BL/6J mice. While a fully validated
in vivo model for BD capable of emulating both manic and
depressive episodes is still missing, recent models have been
generated introducing on the C57BL/6J strain genetic alterations
5
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COMMUNICATION
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are usually considered safer than potent ones,[19] since they do
not interfere with the physiological activity of the peripheral
enzyme. The outcomes of these efforts will be reported in due
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6
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COMMUNICATION
Table of Contents
This study describes multitarget-directed ligands combining partial agonist activity at Dopamine Receptor D3 and inhibitory activity at
glycogen synthase kinase 3 beta (GSK-3β). Thanks to a seamless integration of key pharmacophore features, these compounds could
originate a new wave of therapeutic agents for the treatment of bipolar disorder, endowed with a disease-modifying effect while devoid
of severe side effects.
7
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