Charting the chemical space around the (iso)indoline scaffold, a comprehensive approach towards multitarget directed ligands

Article abstract of DOI:10.1016/j.bmcl.2016.07.055

Within the framework of orthosteric G protein coupled receptor (GPCR) polypharmacology herein we report the systematic elaboration and thorough evaluation of a data matrix generated by sampling the chemical space around a common 5,6-fused bicyclic heteroaromatic template applying characteristic pharmacophore elements of central nervous system (CNS) relevant aminergic GPCR ligands.

Full text of DOI:10.1016/j.bmcl.2016.07.055

Accepted Manuscript
Charting the chemical space around the (iso)indoline scaffold, a comprehensive
approach towards multitarget directed ligands
Olivér Éliás, Zoltán Kovács, Gábor Wágner, Zsolt Némethy, Ákos Tarcsay,
István Greiner
PII:
S0960-894X(16)30783-1
DOI:
Reference:
http://dx.doi.org/10.1016/j.bmcl.2016.07.055
BMCL 24099
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
1 June 2016
20 July 2016
22 July 2016
Please cite this article as: Éliás, O., Kovács, Z., Wágner, G., Némethy, Z., Tarcsay, A., Greiner, I., Charting the
chemical space around the (iso)indoline scaffold, a comprehensive approach towards multitarget directed ligands,
Bioorganic & Medicinal Chemistry Letters (2016), doi: http://dx.doi.org/10.1016/j.bmcl.2016.07.055
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Charting the chemical space around the (iso)indoline scaffold, a
comprehensive approach towards multitarget directed ligands
Olivér Éliás*, Zoltán Kovács, Gábor Wágner, Zsolt Némethy, Ákos Tarcsay, István
Greiner
Gedeon Richter Plc, Budapest 10, PO Box 27, H-1475, Hungary
Authors dedicate this paper to György Domány who has been their constant source of inspiration.
This is where the receipt/accepted dates will go; Received Month XX, 2000; Accepted Month XX, 2000 [BMCL RECEIPT]
Abstract—Within the framework of orthosteric G protein coupled receptor (GPCR) polypharmacology herein we report the systematic
elaboration and thorough evaluation of a data matrix generated by sampling the chemical space around a common 5,6-fused bicyclic
heteroaromatic template applying characteristic pharmacophore elements of central nervous system (CNS) relevant aminergic GPCR
ligands. [BMCL ABSTRACT] ©2000 Elsevier Science Ltd. All rights reserved.
Neuropsychiatric symptoms (NPS) associated with dementia, also known as behavioural and psychological symptoms
of dementia (BPSD), refers to the potentially distressing non-cognitive symptoms of dementia. In the affected
population, the significant co-occurrence of psychotic episodes and disruptive nocturnal behaviour can be even more
troubling than the cognitive impairment itself, imposing a substantial impact on both patients and caregivers. The
effective management of psychiatric disturbances linked to mental decay is now receiving increased attention. Hence,
the pharmacological treatment of this symptom cluster has become more pronounced over time.1
Multitarget directed ligands2 (MDL’s) as a part of tailored interventions may help handle unmet medical needs by
alleviating patients’ symptoms via interacting synergistic cascade systems involved in the pathomechanism of
psychotic behaviour or sleep disturbances.
Since clinically used antipsychotics mediate their therapeutic efficacy via the modulation of dopamine D2/D3 receptor
functions, and it is thought that D3 receptor blockade may have a beneficial influence on cognitive function, the
scientific rationale for incorporating D2/D3 modulation into a multitarget ligand is strongly supported.3 Moreover, the
engagement of serotonin 5-HT6 receptors in learning and memory processes is well substantiated also.4 Additionally,
presynaptic histamine H3 receptors are proven to play an important role in the regulation of the release of other
neurotransmitters involved in the maintenance of the sleep-wake cycle.5 Thus, 5-HT6 serotonin, D2/D3 dopamine and
H3 histamine receptors are considered to be relevant targets for the pursuance of a novel multiple acting ligand for
dementia.
Small molecular weight ligands composed of an aromatic moiety and a positively charged side chain are often
considered to be inherently promiscuous under physiological conditions due to the higher chance of
complementarities within the binding pocket of target macromolecules, especially GPCRs.6 Besides the long-range
electrostatic interactions representing a notable fraction of the total binding energy, a well-positioned additional
hydrogen bond acceptor and phenyl ring can complement the binding pocket to achieve the desired potency gain.
Additionally, gradually increasing hydrophobic properties can have an immense effect on ligand – protein interactions
through altering the water arrangement around the interacting partners.7 We assume that these interactions could
effectively govern target selectivity.
Owing to their advantageous and diverse functionalisation potential, the (iso)indoline bicycle has been regarded as an
appropriate core to reach the maximum chemical space coverage possible. Although the medicinal chemistry
literature is widely documented with phenylsulfonyl containing derivatives, this structural motif is mostly prevalent
among 5-HT6 ligands.8 However, a limited number of published phenylsulfonyl ligands display affinity towards H3 or

D2/D3 receptors.9 On the other hand, (alkyl)piperidine and (alkyl)piperazine rings bearing a basic nitrogen atom are
common elements of D2/D3, H3 and 5-HT6 ligands. Accordingly, the introduction of these pharmacophore elements
into an (iso)indoline core enables us to exploit a considerable proportion of the potential chemical space for D2/D3, H3
and 5-HT6 receptor ligands.
Applying a paradigm shift to our MDL programs we decided to conduct a discovery research initiative whereby a
distinct set of (alkyl)piperidinyl and (alkyl)piperazinyl isoindolines and indolines possessing the phenylsulfonyl
pharmacophore were screened on receptors relevant to our therapeutic objectives. Therefore, with the aim of
investigating whether promiscuity is attainable in this chemical space, 1-4 isoindolines and 5-10 indolines have been
prepared and assayed in vitro. The scope of the present analysis focuses on probing the binding free energy
landscapes on multiple targets and a detailed pharmacological characterisation is beyond the scope of this study. In
view of the above, addressing the binding selectivity issue was our main goal.
BOC
N
Br
( )n
( )n
NH
( )m
Br
O
(i)
(ii)
S
N
O
( )n
X
O
( )m
Ph
N
S
O
( )m
Ph
isoindoline (n=1, m=1):
11: 4-Br; 12: 5-Br
isoindoline (n=1, m=1):
: 4-Br; : 5-Br
16 17
4-yl isoindoline (n=1, m=1): : X=C; : X=N
21 22
indoline (n=2, m=0):
indoline (n=2, m=0):
5-yl isoindoline (n=1, m=1): : X=C; : X=N
23 24
: 4-Br; : 5-Br; : 6-Br
14 15
13
18: 4-Br; 19: 5-Br; 20: 6-Br
4-yl indoline (n=2, m=0): 25: X=C; 26: X=N
5-yl indoline (n=2, m=0): 27: X=C; 28: X=N
6-yl indoline (n=2, m=0): 29: X=C; 30: X=N
R
N
H
N
( )n
X
( )n
X
O
(iii)
(iv)
O
S
O
N
S
O
N
( )m
( )m
Ph
Ph
4-yl isoindoline (n=1, m=1): : X=C; : X=N
1a 2a
4-yl isoindoline (n=1, m=1): - : X=C; - : X=N
1b e 2b e
5-yl isoindoline (n=1, m=1): 3a: X=C; 4a: X=N
4-yl indoline (n=2, m=0): 5a: X=C; 6a: X=N
5-yl isoindoline (n=1, m=1): 3b-e: X=C; 4b-e: X=N
4-yl indoline (n=2, m=0): 5b-e: X=C; 6b-e: X=N
5-yl indoline (n=2, m=0): : X=C; : X=N
5-yl indoline (n=2, m=0): - : X=C;
7b e
- : X=N
8b e
7a
8a
6-yl indoline (n=2, m=0): : X=C;
: X=N
6-yl indoline (n=2, m=0): - : X=C;
9b e
- : X=N
10b e
9a
10a
Scheme 1. Reagents and conditions: (i) benzenesulfonyl chloride, triethylamine, dichloromethane, ambient temperature, 24h; (ii) to 21, 23, 25, 27 and 29:
I.: (1-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)boronic acid pinacol ester, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex
with dichloromethane, potassium carbonate, dioxane-water 4:1, 90 °C, 4h; II: hydrogenation on palladium hydroxide on carbon, methanol, rt, 6h; to 22, 24,
26, 28 and 30: tert-butyl piperazine-1-carboxylate, tris(dibenzylideneacetone)dipalladium(0), 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene, sodium tert-
butoxide, rfx, 6h; (iii) hydrogen chloride solution in ethyl acetate, 0 °C, 4h; (iv) to compounds were R=Me: 37% formaldehyde solution, dichloromethane-
acetonitrile 1:5, sodium triacetoxyborohydride, rt, 24h; to other alkylated compounds: corresponding oxo-compound, dichloromethane, sodium
triacetoxyborohydride, rt, 24h.
A straightforward synthetic strategy was employed to elaborate compounds 1-10. Key intermediates 21, 23, 25, 27
and 29 tert-butoxycarbonyl protected piperidines were prepared from the corresponding bromoisoindoline (11 and 12)
or bromoindoline (13-15) derivatives combining sulfonamide formation and Suzuki-Miayura coupling followed by
catalytic reduction of the alkene intermediate. Analogous 22, 24, 26, 28 and 30 tert-butoxycarbonyl protected
piperazines were obtained from the same starting material by a similar reaction sequence applying sulfonamide
formation and subsequent Buchwald-Hartwig amination. Removal of the protecting groups furnished the secondary
amines 1a, 2a, 3a, 4a, 5a, 6a, 7a, 8a, 9a and 10a. Finally, tertiary amines 1b-e, 2b-e, 3b-e, 4b-e, 5b-e, 6b-e, 7b-e, 8b-
e, 9b-e and 10b-e were prepared by reductive alkylation of the corresponding secondary amine. (Scheme 1)
With respect to 5-HT6 affinity, the spatial arrangement of the two pharmacophore elements in pos1 is definitely best

for high affinity and the order of preference is as follows: pos1 > pos5 > pos3 > pos4 > pos2 (Table 1, Supporting
Information Table 2, Supporting Information Table 3 and Supporting Information Figure 1). Furthermore, in almost
all cases, alkyl substitution of the basic nitrogen atom results in affinity loss (Supporting Information Table 1).
Growing the compounds along this vector has a detrimental effect on affinity: H > Me > Et > Pr > cBu. By contrast,
switching from piperidine to piperazine has no dramatic influence on 5-HT6 affinity. Accordingly, 4-(piperidin-4-
yl)isoindoline 1a and 4-(piperazin-1-yl)isoindoline 2a derivatives are the best 5-HT6 binders with a Ki value of 0.4
nM and 1.9 nM, respectively (101% and 98% inhibition at 1 μM, respectively). Since piperazine substitution gives
rise to promiscuity, the most selective 5-HT6 binders are piperidines 1a and 1b (Ki value for 1b is 9 nM, 94%
inhibition at 1 μM). These two compounds displayed >100 binding selectivity over the investigated targets. Some
elements of the SAR detailed above have been reported in the literature.10
Table 1. Percentage displacement values at 1 μMa for compounds 1-10.
R
N
R
N
N
R
H
1a
101
16
17
4
Me
1b
94
14
14
14
3b
56
34
19
41
5b
87
13
35
10
7b
86
48
14
59
9b
93
75
34
3
Et
1c
98
53
27
3
Pr
1d
92
55
40
4
cBu
1e
91
-5
H
2a
98
61
29
11
4a
46
37
14
7
Me
2b
100
85
43
19
4b
29
41
11
21
6b
96
77
67
17
8b
84
85
18
35
10b
92
72
52
-7
Et
2c
98
92
55
17
4c
-7
Pr
2d
98
97
64
12
4d
-11
85
29
38
6d
78
97
87
27
8d
38
98
59
39
10d
82
99
80
16
cBu
2e
98
72
47
16
4e
1
pos1
cpd
5-HT6
D3
NSO2Ph
49
13
3e
-10
24
25
28
5e
1
D2
H3
cpd
pos2
3a
54
3
3c
4
3d
26
48
16
27
5d
45
56
38
-5
5-HT6
D3
32
18
48
5c
59
58
25
50
7c
40
72
17
54
9c
95
86
39
11
61
22
60
6c
89
91
80
50
8c
53
94
50
65
10c
86
95
77
20
34
1
NSO2Ph
9
D2
3
74
6e
51
60
60
59
8e
28
68
24
36
10e
60
78
50
36
H3
pos3
cpd
5-HT6
D3
5a
83
6
6a
97
40
22
-3
9
10
-5
48
82
7e
-9
D2
NSO2Ph
H3
pos4
cpd
5-HT6
D3
7a
74
20
13
2
7d
39
79
35
22
9d
81
98
59
14
8a
90
75
18
4
48
22
11
9e
62
59
29
1
D2
NSO2Ph
H3
cpd
pos5
9a
91
49
27
-6
10a
95
58
32
4
5-HT6
D3
D2
NSO2Ph
H3
a
Values are means of three independent experiments; assay details are given in the Supporting Information. Target-based grouping of this table and the
statistical details are available as Supporting Information Table 3 and Table 5, respectively.
In the case of D3, the affinity decreases in the order: pos5 > pos4 > pos1 = pos3 > pos2 (Supporting Information Fig 1,
Supporting Information Table 2, 4). Moreover, inverted ranking was observed in the case of alkyl substituents: Pr > Et
> Me > cBu > H compared to 5-HT6. Only cBu is a less preferable substituent for both receptors. Concerning D3
binding, piperazine unequivocally outranks piperidine. Thus, 6-(4-propylpiperazin-1-yl)indoline derivative 10d is the
best D3 binder with a Ki value of 5.7 nM (99% inhibition at 1 μM). Not surprisingly, due to the high binding site
similarity among this compound collection, D3 and D2 binding properties follow quite similar patterns. The order of
priority for the D2 binding affinity is: pos3 = pos5 > pos1 = pos4 > pos2. Interestingly, pos1 and pos3 fall into line
with pos4 and pos5, respectively, suggesting the possibility of dissociating D2 affinity from D3 affinity. High D2
affinity requires alkylation on the basic nitrogen atom (Pr > Et > cBu > Me > H) and the piperazine ring is also
favourable as in the case of D3 receptors. Thus, besides compound 6d, with a D2 Ki value of 42 nM (87% inhibition at
1 μM), and compound 6c, with a D2 Ki value of 84 nM (80% inhibition at 1 μM), their pos5 analogue 10d has a Ki
value of 95 nM (80% inhibition at 1 μM). It is worth underscoring that pos3 piperazines 6b-d display around 1.5 fold
D3/D2 selectivity, whereas among pos5 compounds typically at least 10 fold D3/D2 selectivity can be observed.

Interestingly, 4d is the mostly selective D3 compound with 103 nM affinity and less than 40% inhibition at 1 μM for
additional targets.
Differing mostly in position preference, H3 binding is also sensitive to the nature of the alkyl substituent. In this case
pos2 and pos4 were equally the best positions whereas pos5 was the least tolerable (pos2 = pos4 > pos3 > pos1 >
pos5). With alkyl substitution on the basic nitrogen atom there was an Et and cBu preference and no active
compounds could be identified among unsubstituted derivatives (Et = cBu > Me = Pr > H). Although piperazine
substitution seems to be statistically better (paired t-test, p<0.01) than piperidine, the best H3 binder compound 5e (H3
Ki value of 214 nM, 82% inhibition at 1 μM) and the highest selective compound 3c (H3 Ki value of 302 nM, 48%
inhibition at 1 μM) contain the piperidine ring. Interestingly, piperazine 4e also exhibits high selectivity against H3
receptors (H3 Ki value of 395 nM, 74% inhibition at 1 μM).
This comprehensive set of analogues has enabled us to evaluate the impact of positional subtitution, switching
between nitrogen and carbon in the ring (piperidine, piperazine) and R-group substitutions with molecular match pair
analysis (MMPA) that is presented as Supporting Information Table 4. Systematic discussion of the observed trends is
beyond the scope of this letter, so only some of the more interesting observations are highlighted herein. Changing the
arrangement around the core from Pos1 to Pos5 was found to have a positive effect for dopamine receptors, but in
contrast the 5-HT6 affinity decreased in 70% of the cases. The unique role of Pos1 on 5-HT6 affinity can also be
identified by analysis of corresponding pairs: the detrimental effect is unequivocal (Supporting Information Table
4/M, N, O). Changing the piperidine ring to piperazine resulted in higher affinity in general (Supporting Information
Table 4/A). The highest effect can be observed for D3 affinity change, where improvement was achieved in 92% of
the cases. Changing Pos3 to Pos4 (Supporting Information Table 4/S) provided an intricate case, since the D2 and D3
affinity change showed opposite trends. In terms of D2 the affinity dropped in 70% of the examples, while for D3 there
was an affinity gain in 80% of the examples.
Figure 1. Compound promiscuity (magenta bar: displacement > 40%, black triangle: displacement > 65%, cyan bar: displacement > 90%).
By making individual pair-wise comparisons, decoupling of D2 affinity from that of D3 was also observed in the
course of replacing the ethyl group with cyclobutyl in the Pos1 piperidine series, see compounds 1c and 1e in Table 1.
Furthermore, in the case of compound 2e D3 affinity was considerably improved by introducing a piperazine ring,
while 5-HT6 and D2 affinities remained in the same range as that for compound 1e. Thus, the mentioned sequence of
modifications turned the dual acting 5-HT6-D3 compound 1c through the dual acting 5-HT6-D2 compound 1e into the
triple acting 5-HT6-D2-D3 compound 2e. Another triple acting compound was attainable from the dual acting 9c. In
this case the piperidine to piperazine change yielded compound 10c in which D2 affinity increased markedly close to
that of the 5-HT6 and D3 affinities. In addition, the strong D3 binder 4d became a prominent H3 binder upon propyl to
cyclobutyl transformation, see compound 4e. Moving the cyclobutylpiperidine moiety from Pos1 to Pos3 (from
compound 1e to 5e) was also manifested in dramatic affinity changes. In this case a strong 5-HT6 binder evolved into

an H3 binder retaining the interesting D2/D3 pattern. Notably, among the triple acting compounds, exemplified by the
7b-7c pair, adding a methylene to the side chain transferred the emphasis from 5-HT6 affinity to D3 while preserving
low D2 and moderate H3 affinities.
The collected dataset has been analysed from a different viewpoint to identify the structure-activity relationship
(SAR) patterns responsible for the multi-target nature of the investigated compound set. To do this, compound
promiscuity was plotted using three different threshold values in terms of the binding percentages: >40%, >65% and
>90% (Figure 1). This chart represents the SAR from an exceptional perspective, since it shows that this limited
chemical space is able to cover a wide range of promiscuity: from totally inactive, through single, dual, triple to fully
active ligands. The desirable impact on affinity - thus higher promiscuity - of the piperazine ring compared to
piperidine ring is also unequivocal from Figure 1. Promiscuity increases by growing the R substituents through Me-
Et-Pr at pos1, see 1b, 1c and 1d in Figure 1. A similar trend can be recognized in compound groups 6, 7, 8 and 10.
The highest multi-target effect was realized in compound group 6. In order to facilitate understanding of the cross
target effects, all pair-wise comparisons are available as Supporting Information Figure 2. As expected, the activities
on the different targets are independent, with the exception of D2-D3 pairing which shows binding site similarity.
In order to challenge the quality of the binding interactions, ligand efficiency11 (LE) values were calculated for all the
cases where Ki had been determined. In the case of 5-HT6 all the ligands could be characterized with high (LE>0.3)
LE (Supporting information Figure 3). Moreover, plotting LE versus pKi revealed that the investigated compound
collection shows a strong inverse correlation (R=0.92). Thus, the smaller the ligand the higher the LE, which might
suggest that the key pharmacophore features of the scaffold are exposed optimally and thus the quality of the binding
interactions should not be enhanced by further hydrophobic enlargement or solvation-mediated effects (the maximal
LE was 0.52, compound 1a). In the case of the LE values calculated from the D3 Ki a similar trend can be observed,
albeit with a weaker correlation and smaller slope (Supporting Information Figure 3). For the D2 and H3 targets the LE
values are also in the desirable range, although the small number of examples does not permit a deeper analysis. For
the 5-HT6-D3 pairings (the group with the largest number of measured Ki values) lipophilic ligand efficiency12 (LLE)
values were also calculated (Supporting Information Figure 4). This analysis showed that dual-acting ligands with
desirable lipophilic ligand efficiency (LLE>4) on both targets could be identified (mainly piperazines).
Having observed that the affinity change from H to the bulkier Pr group is different for 5-HT6 compared to D3 and D2,
we were curious to analyse this phenomenon in terms of the lipophilicity versus the affinity change (Supporting
Information Figure 5). Interestingly, in the case of 5-HT6 a weak inverse correlation was found between the two that
further underpins the previous observations as discussed above. This evaluation suggests that the systematic SAR
exploration of well-known pharmacophore elements is a fruitful approach to identify compounds with desirable
physicochemical and binding parameters on multiple targets.
Providing a different angle on the conceptual approach to selectivity design, the present study supplies evidence that
altering only the given spatial arrangement of relevant functionalities together with adjusting hydrophobic properties
around hot spot interacting key moieties, can have a substantial influence on a compounds’ binding profile even in the
intrinsically limited chemical space characterised by low molecular weight. Herein, we demonstrate that in addition to
high affinity selective ligands (e.g. 1a, 1b, 5a and 5b for 5-HT6; 4e for H3; 4d for D3), potent dual- (e.g. 8a and 8b for
5-HT6 and D3; 1e for 5-HT6 and D2; 4c for D3 and H3; 5e for D2 and H3) and triple- (e.g. 6d and 10d for 5-HT6, D3
and D2; 5c, 7b and 7c for 5-HT6, D3 and H3) acting agents could also be identified among this set of compounds,
implying the opportunity of MDL design. In conclusion, our detailed research offers a new insight into drug
promiscuity and has served as a starting point for various MDL programs that have strongly supported the validity of
the strategy presented. Further optimisation from selected multiple acting starting points revealed by this study and
the transfer of SAR to other core structures will be published under different cover.
Acknowledgement
We profoundly appreciate Derek Buckle for his contribution in the preparation of the manuscript. O. É. is deeply
indebted to N. Bús for preparative assistance. Contributions of Katalin Kovács, Éva Schmidt, Ferenc Horti, Károly
Fazekas and Sándor Kolok to the in vitro pharmacological measurements are gratefully acknowledged. Authors thank
Márta Sípos and Zoltán Szakács for their valuable help in the purity assessment and compound characterisation.
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