Discovery of 1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-ones based novel, potent and PI3Kδ selective inhibitors

Article abstract of DOI:10.1016/j.bmcl.2019.04.007

PI3Kδ is implicated in various inflammatory and autoimmune diseases. For the effective treatment of chronic immunological disorders such as rheumatoid arthritis, it is essential to develop isoform selective PI3Kδ inhibitors. Structure guided optimization of an imidazo-quinolinones based pan-PI3K/m-TOR inhibitor (Dactolisib) led to the discovery of a potent and orally bioavailable PI3Kδ isoform selective inhibitor (10h), with an improved efficacy in the animal models.

Full text of DOI:10.1016/j.bmcl.2019.04.007

Accepted Manuscript
Discovery of 1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-ones based novel, po-
tent and PI3Kδ selective inhibitors
Rajesh Bahekar, Bhushan Dave, Shubhangi Soman, Dipam Patel, Rajendra
Chopade, Radhika Funde, Jeevan Kumar, S. Sachchidanand, Poonam Giri,
Abhijit Chatterjee, Jogeswar Mahapatra, Purvi Vyas, Krishnarup
Ghoshdastidar, Debdutta Bandyopadhyay, Ranjit C. Desai
PII:
S0960-894X(19)30216-1
https://doi.org/10.1016/j.bmcl.2019.04.007
BMCL 26374
DOI:
Reference:
To appear in:
Bioorganic & Medicinal Chemistry Letters
Received Date:
Revised Date:
Accepted Date:
24 December 2018
19 March 2019
3 April 2019
Please cite this article as: Bahekar, R., Dave, B., Soman, S., Patel, D., Chopade, R., Funde, R., Kumar, J.,
Sachchidanand, S., Giri, P., Chatterjee, A., Mahapatra, J., Vyas, P., Ghoshdastidar, K., Bandyopadhyay, D., Desai,
R.C., Discovery of 1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-ones based novel, potent and PI3Kδ selective
inhibitors, Bioorganic & Medicinal Chemistry Letters (2019), doi: https://doi.org/10.1016/j.bmcl.2019.04.007
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Discovery of 1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-ones based novel, potent and PI3K
#
selective inhibitors
a*
a,b
b
a
a
Rajesh Bahekar , Bhushan Dave , Shubhangi Soman , Dipam Patel , Rajendra Chopade ,
a
c
c
d
d
Radhika Funde , Jeevan Kumar , Sachchidanand S , Poonam Giri Abhijit Chatterjee ,
,
d
e
e
e
Jogeswar Mahapatra , Purvi Vyas , Krishnarup Ghoshdastidar , Debdutta Bandyopadhyay
and Ranjit C. Desai
a
a
Department of Medicinal Chemistry, Zydus Research Centre, Sarkhej-Bavla, N.H. 8A Moraiya,
Ahmedabad 382210, India.
Department of Chemistry, Faculty of Science, M.S. University of Baroda, Vadodara 390002,
b
India.
c
Department of Bioinformatics, Zydus Research Centre, Sarkhej-Bavla, N.H. 8A Moraiya,
Ahmedabad 382210, India
d
Department of Pharmacology, Zydus Research Centre, Sarkhej-Bavla, N.H. 8A Moraiya,
Ahmedabad 382210, India.
e
Department of Cell Biology, Zydus Research Centre, Sarkhej-Bavla, N.H. 8A Moraiya,
Ahmedabad 382210, India.
ABSTRACT:
PI3K is implicated in various inflammatory and autoimmune diseases. For the effective
treatment of chronic immunological disorders such as rheumatoid arthritis, it is essential to
develop isoform selective PI3K inhibitors. Structure guided optimization of an imidazo-
quinolinones based pan-PI3K/m-TOR inhibitor (Dactolisib) led to the discovery of a potent and
orally bioavailable PI3Kδ isoform selective inhibitor (10h), with an improved efficacy in the
animal models.
_______________________________________________________________________
#
*
ZRC communication No: 587 (Part of PhD thesis work of Mr. B. Dave).
Corresponding author: Rajesh Bahekar: Tel.: +91-2717-665555; Fax: +91-2717-665355
E-mail: rajeshbahekar@zyduscadila.com (Rajesh Bahekar)
1

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by synovitis and joint
destruction. Treatment with biologic agents such as tumor necrosis factor (TNF) inhibitors has
improved outcomes, but in general, biologics are expensive, injectable and many patients have
inadequate responses. Thus, orally bioavailable small molecule inhibitors that target signal
transduction and regulate innate and adaptive immune responses in RA have emerged as
1
potential alternatives to expensive biologics.
Phosphoinositide-3-kinases (PI3Ks) constitute central signaling hub that mediates diverse and
2
,3
crucial cell functions, including cell growth, proliferation, differentiation and survival. PI3Ks
have been classified into three classes (I, II and III) based on substrate specificity, sequence
homology and regulatory subunits. The class I PI3Ks consists of four kinases (PI3K-α, β, δ and
γ) and further grouped into two sub-classes: class IA and class IB. The class IA comprises three
4
closely related kinases, PI3K-α, β and δ, while the class IB contains only one member PI3K-γ.
The PI3K and  are expressed in a wide variety of tissues and organs. PI3K is found mainly in
leukocytes, while expression of PI3K is restricted to spleen, thymus, hematopoietic cells and
5
peripheral blood leukocytes. PI3K and PI3K are mainly expressed in rheumatoid arthritis
6
(RA) synovium and regulate innate and adaptive immune responses.
Inhibition of PI3Ks is considered as one of the most interesting targets. Earlier attempts were
mainly focused on developing the broad-spectrum (pan) inhibitors of the PI3K (α, β, γ and δ)
7
,8,9
isoforms, as potential oncology therapeutics.
Knowing the potential side effects associated
with PI3Kα and β isoforms inhibition (due to universal expression), recently, efforts are directed
towards the development of PI3Kδ selective inhibitors, for the effective treatment of
1
0,11,12
hematological malignancy and inflammatory disorders.
Over the past decades, several structurally diverse PI3K inhibitors were identified containing
13,14
quinolines and imidazoquinolinones as promising scaffold (Figure 1). The Omipalisib
and
1
4
Dactolisib , discovered by GlaxoSmithKline and Novartis respectively, as dual PI3K and
15
®
mTOR inhibitors are under clinical trials. PI3K selective inhibitors, Idelalisib (ZYDELIG ,
Gilead Sciences, in 2014) is available for the treatment of hematologic malignancies. Recently,
16,17
®
US-FDA approved Duvelisib
(COPIKTRA , Verastem, Inc) for the treatment of chronic
lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). There is still requirement
to develop safe and highly potent PI3Kδ selective inhibitors, for the effective management of
2

chronic inflammatory and autoimmune disorders, such as rheumatoid arthritis (RA) and
hematological malignancy.
Figure 1. The structures of quinoline and imidazoquinolinone-based PI3K inhibitors.
We aim to discover novel, potent and orally bioavailable PI3Kδ selective inhibitors, mainly by
favoring the suitable accommodation of designed molecules, in the specificity pocket, to achieve
1
8
PI3Kselectivity. Considering imidazoquinolinone moiety as a starting point, appropriate
structural modifications were carried out in the Dactolisib (pan-PI3K/mTOR inhibitor), to
improve PI3K selectivity. Two set of compounds were designed (as listed in Table 1 and 2).
Initial modifications on imidazole ring (of Dactolisib), involves positional changes of methyl
(N1 to N3) and phenyl (N3 to N1) groups and introduction of a carbon spacer (phenyl to benzyl)
at N3 position. Further modifications were carried out at the p-position of benzyl ring (Set-1,
Table 1) to obtain the single digit nM potency (9c). Compound 9c was found to be potent but
showed moderate isoform selectivity (Table 3). In the second set (Set-2, Table 2), changes were
th
carried out on the 8 position of 9c to improve isoform selectivity and in vivo efficacy.
Herein, we report, design, synthesis and biological evaluation of novel 1,3-dihydro-2H-
imidazo[4,5-c]quinolin-2-ones based PI3Kδ selective inhibitors. Test compounds were screened
in vitro for PI3K inhibitory activity and most potent compounds from each set were tested for in
vitro PI3K isoform selectivity (,  & ) and mTOR inhibitory activity. Based on the in vitro
results, highly potent and selective compound 10h was selected for in vivo PK and PD
(anticancer and anti-inflammatory activities) studies.
Synthesis of 1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one derivatives (9a-g and 10a-m) was
2
0
carried out as depicted in Scheme 1, following the modified literature procedure. Treatment of
3

bromo anthranilic acid (1) with nitro methane gives nitro vinyl anthranilic acid (2), which was
cyclized using potassium acetate in acetic anhydride to get the bromo nitro quinolinol (3).
Compound 3 was converted to reactive chloro derivate (4) using POCl , followed by
3
nucleophilic substitution with methylamine to get the compound 5. Nitro group of 5 was
reduced, using SnCl to get the compound 6, which was cyclized using diphosgene in the
2
presence of base, to obtain the imidazoquinoline (7). Alkylation of 7 using strong base and aryl
halides furnished compounds 8a-g, which were converted to 9a-g and 10a-m, using
PdCl (PPh ) , potassium bicarbonate and aryl or heteroaryl boronic acids.
2
3 2
Overall, 20 compounds (9a-g and 10a-m) were prepared in good yield (60 to 80%), under the
mild reaction condition. Spectral data of compounds were found to be in conformity with the
structures assigned, which ensure the formation of the compounds 9a-g and 10a-m (see
supporting information for analytical and spectral data).
For in vitro PI3K inhibitory activities, Idelalisib and Dactolisib were used as a positive control.
In Set-1 (Table 1), 4-substituted-(benzyl)-8-quinolinyl-imidazo[4,5-c]quinolinone (9a-g)
analogues displayed varying degree of PI3K inhibitory activities at 100 nM concentration.
Compound 9a (2-methyl-propanenitrile substitution on a benzyl ring) showed moderate PI3K
inhibitory activity (56% PI3K inhibition at 100 nM), while replacement of the nitrile group
(
Compound 9b: 73% inhibition) exhibited enhanced PI3K inhibitory activity (IC : 28.3 nM).
5
0
Replacement of isopropyl (9b) with methoxy (9c, IC : 9.5 nM) and methyl (9d, IC : 18.4 nM)
5
0
50
demonstrated higher PI3K inhibitory activity, whereas replacement with an electron
withdrawing NO (9e, 62% inhibition), electronegative F (9f: 51% inhibition) and the
2
unsubstituted compound 9g (22% inhibition) displayed weak PI3K activity.
Scheme 1: Synthesis of compounds 9a-g and 10a-l.
4

o
o
Reagents and conditions: i) conc. HCl, water, 26 C,6 h, then nitro methane, NaOH, water, Conc. HCl, 26 C,16 h, 95%; ii)
o
o
o
KOAc, acetic anhydride, 120-125 C,4h, 60%; iii) POCl , 120 C, 4h, 80%; iv) Me-NH , TEA, DCM, 26 C, 12h, 94%; v)
SnCl .2(H O) , EtOAc, 26 C , 60%; vi) Diphosgene, TEA, DCM, 0-26 C, 65%; vii) R -Ar-CH -X (Cl or Br), NaH, THF, 0-26 C, 65 – 75
; viii) R -B(OH) ,PdCl (PPh ) , KHCO , DMF, H O, 90-95 C, 1.5 h, 60 - 80%.
3
2
o
o
o
2
2
2
1
2
o
%
2 2 2 3 2 3 2
5

In Set-1, compound 9c (methoxy) showed most potent PI3K inhibitory activity, which was
found to be similar to Dactolisib (IC : 8 nM; Table 1) and 4.5 fold less potent compared to
5
0
Idelalisib (IC : 2.1 nM). Thus, in the Set-1, positional changes of methyl (N1 to N3) and phenyl
5
0
(
N3 to N1) groups and introduction of a carbon spacer (phenyl to benzyl) at N3 position,
followed by substitution on p-position of benzyl ring led to the single digit nM potent compound
9c) with moderate isoform selectivity (Table 3).
(
Table 1: PI3Kδ inhibitory activity of 4-substituted-(benzyl)-8-quinolinyl-imidazo[4,5-c]quinolinone (9a-g)
1
Comp.
R
PI3Kδ
inhibition (%)
PI3K IC50
a,b
c
(nM)
9
9
a
56
73
ND
b
28.3
9
9
c
98
80
9.5
d
-CH
3
18.4
9
9
9
e
f
g
-NO
-F
-H
-
2
62
51
22
92
96
ND
ND
ND
8
Dactolisib
Idelalisib
-
2.1
a
b
All the data are shown as the mean for at least two experiments. PI3K inhibition at the concentration of 100 nM using PI3K
c
Kinase Activity/Inhibitor assay Kit from Millipore. The IC values for PI3K inhibition.ND: not detected.
5
0
To improve PI3K isoform selectivity, modifications were carried out in 9c as a primary lead. In
the second set (Table 2), we found that the PI3Kδ inhibitory activity was retained by doing
th
modifications at 8 position of quinoline in 9c. As listed in Table 2 (Compounds 10a-m),
replacement of quinoline moiety in 9c with benzothiazole (10a and 10b (acylated 10a)) showed
5
0% PI3K inhibition at 100 nM. Phenyl derivative (10c) was found to be less potent (PI3Kδ
IC : 29.4 nM) compared to 9c, while Pyridyl derivatives (10d) showed some improvement in
5
0
the potency (IC : 20 nM). Introduction of methoxy (10e) and 3-methyl-2-methoxy substituents
5
0
6

(
10f) were found to be equipotent (IC : ~11 nM). Triazole motif (10g) showed less activity
50
compared to 9c, while m-methanesulfonamide derivative (10h) was found to be the most potent
IC : 1.9 nM) among all. Replacement of methyl group in 10h, with iso-propyl (10i) and cyclo-
(
5
0
propyl (10j) showed three fold less activity compared to 10h.
Table 2: Influence of modification of C8 position of Quinoline moiety on PI3Kδ isoform selectivity and
mTOR selectivity.
2
PI3Kδ inhibition PI3K
2
PI3Kδ inhibition PI3K IC50
a,b
c
Comp.
R
a,b
Comp.
10h
R
c
(
%)
IC50 (nM)
(%)
(nM)
1
1
0a
0b
52
58
ND
99
1.9
ND
10i
10j
91
93
6.2
5.9
1
0c
72
29.4
1
1
1
1
0d
0e
0f
81
87
88
62
20
10k
98
60
56
96
4.1
ND
ND
2.1
11.4
11.1
ND
10l
10m
0g
Idelalisib
a
b
All the data are shown as the mean for at least two experiments. PI3K inhibition at the concentration of 100 nM using PI3K
c
Kinase Activity/Inhibitor assay Kit from Millipore. The IC values for PI3K inhibition.ND: not detected.
5
0
7

Compound 10K, a regioisomer of 10h, wherein benzyl and methyl groups are interchanged on
imidazole ring showed two fold less active compared to 10h. Similarly, racemic compound 10l,
and 10m (one carbon homologs at N3 with respect to 10h) were found to be less active.
Most potent compounds (9c, 10h and 10k) were evaluated for their selectivity against PI3K
isoforms (,  and  and mTOR. As shown in the Table 3, initial hits (9c and 10k) showed
moderate selectivity against PI3K isoforms and mTOR over PI3K. Compound 10h (IC : 1.9
5
0
nM) demonstrated 469, 310, and 59-fold selectivity over PI3K,  and  respectively. Moreover,
it was noted that selectivity of 10h against all the three isoforms was higher than standard
compounds. In general, it was observed that the potency and selectivity of imidazoquinolinone-
1
2
based PI3Kδ inhibitors can be modulated using suitable substituents at R and R positions.
Table 3: Isoform selectivity of compounds against PI3K (,,, and ) and mTOR activities.
a
Biochemical IC50 [nM]
b
Comp.
b
b
b
b
mTOR
(
PI3Kα
PI3Kβ
PI3Kγ
PI3Kδ
p70S6K)
9
1
1
c
421
342
38
9.5
676
0h
0k
891
289
5
589
241
79
112
42
6
1.9
4.1
8
>1000
580
14
Dactolisib
Idelalisib
8
31
571
92
2.1
>1000
a
b
The IC values are shown as the mean for at least two experiments. PI3K inhibitory activity assay Kit (Millipore) was
50
used to screen the test compounds.
In vitro kinase profiling study of 10h was carried out @ 1M concentration, against 140 kinases
and % inhibition was found to be < 20% at 1M concentration. Compound 10h was tested for its
2
1
anti-proliferative activities against TMD-8 cell lines with Idelalisib as a reference compound. In
anti-proliferative in vitro assay, 10h and Idelalisib exhibited potent anti-proliferative activity
with an IC value of 340 and 795 nM respectively. Additional profiling studies of compound
5
0
2
2
1
0h was carried out and it was found to be devoid of CYP (<10% CYP inhibition at 10 M
8

concentration, for CYP1A2, CYP2C8, CYP2C9, CYP2D6, CYP2C19 and CYP3A4) and hERG
23
liabilities (IC : > 30 M), while Idelalisib showed moderate CYP3A4 inhibition.
5
0
A comparative single dose (3 mg/kg, po and 1 mg/kg, iv) PK profile of compounds 9h, 10h and
Dactolisib was evaluated in male C57BL/6J mice (n =6) and the various PK parameters (Tmax,
Cmax, t , Cl, AUC and %F) were recorded (Table 4). In PK study, 9c showed moderate AUC
1
/2
and clearance, which resulted into overall low bioavailability (~15%). Compound 10h showed
rapid Tmax, higher AUC (~5 fold, compared to standard), extended t (~3.5 hr) and good oral
1
/2
bioavailability (%F ~69 over standard, 38%). Compound 10h showed extended t1/2 and higher
AUC, which could be due to its low clearance compared to standard (8.24 vs 72.5 ml/min/kg,
iv).
a
Table 4: Pharmacokinetic study parameters of 9c, 10h and Dactolisib in C57 mice
Compd
Tmax (h) Cmax (g/ml) t1/2 (h)
Cl (ml/min/kg), iv AUC (0-) h g/ml
%F*
9
1
c
0.38
0.25
127.61
1278.49
273.83
2.31
3.48
1.88
22.9
8.24
72.5
329.08
3831.48
243.64
14.77
68.91
37.82
0h
Dactolisib 0.21
a
In male C57BL/6J mice (n=6), compounds were administered orally (p.o) at 3 mg/kg dose and plasma concentration was analyzed by
LC-MS, values indicate Mean ± SD.
*
7
Oral bioavailability (%F) was calculated wrt to iv AUC. Compounds 9c, 10h and Dactolisib administered at 1 mg/kg dose, iv AUC:
42.56, 1852.95 and 215.14 respectively.
Considering low bioavailability of 9c, in PD models, only 10h was evaluated. Collagen Induced
1
7
Arthritis (CIA) mice model was used to check anti-arthritic efficacy of test compounds.
Arthritis was developed in male DBA1j mice, using collagen mixture and mice were recruited
for the study once clinical signs were visible. Eight animals were assigned in each of the four
groups [vehicle, positive control (Dactolisib, 60 mg/kg dose was selected considering low oral
bioavailability, compared to 10h) and two doses of test compound 10h (10 and 30 mg/kg) was
selected considering 89% plasma protein binding and t of ~3.5 h]. Treatment was continued for
1
/2
four weeks and percentage inhibition in clinical score was recorded.
9

Figure 2a: Effect of Compound 10h and Dactolisib in CIA mice model.
Figure 2b: In vivo anti-tumor activity of Compound 10h in SCID mice xenograft model.
1
0

As shown in the Figure 2a, standard and 10h showed good reduction in the arthritic score,
compared to vehicle control (untreated group). Two fold higher dose of a standard compound
was used, considering two fold difference in the mice oral bioavailability. At 30 mg/kg dose,
compound 10h showed superior activity compared to standard compound (dose 60 mg/kg). Body
weights of the animals were also recorded 3 times a week as a measure of treatment related side
effect and 10h showed no significant reduction in the body weight, even at 30 mg/kg dose, while
Dactolisib exhibited reduction in body weight.
Additionally, in vivo anti-tumor activity of 10h was checked in male SCID mice xenograft
model (inoculated with TMD-8 cells). Inhibition of tumor volume compared to vehicle control
(untreated group) was considered as efficacy end point. As shown in Figure 2b, three doses (3,
1
0 and 30 mg/kg/day, orally) of 10h were administered and it showed dose dependent reduction
in the tumor volume. At 30 mg/kg dose, 10h showed complete inhibition of tumor volume
compared to vehicle control. Body weights of the animals were also recorded and 10h showed no
significant reduction in the body weight, even at 30 mg/kg dose. Thus improved PK of 10h
justifies its potent in vivo activity in both the animal models.
1
8
The structure of mPI3K co-crystallised with Idelalisib (PDB ID: 4XE0) was prepared using
protein preparation wizard of Schrodinger Suite 2018 at pH 7.4, which was used for generating
the docking grid. The Glide docking was performed using Glide SP with default parameters.
Ligand molecules (Idelalisib, Dactolisib, 9c, 10h and 10k) were prepared using LigPrep module
2
4
of Schrodinger Suite 2018.
The results of docking has been summarized in Figure 3 where it is clear from the docking poses
of the docked ligands that specificity pocket was fully occupied by 10h and 10k, however in case
of Dactolisib and 9c, the specificity pocket was not occupied and this explains why 10h and 10k
were more selective towards PI3K



1
1

A
Dactolisib
Compound 9c
Compound 10h
Compound 10k
Figure 3: The Glide docking studies of Compounds 9c, 10h, 10k and Dactolisib into the site of PI3K (PDB ID: 4XE0).
Compounds are shown as sticks. Hydrogen bonds are shown as yellow dashed lines.
1
2

In conclusion, we have synthesized and evaluated two sets of novel series of 1,3-dihydro-2H-
imidazo[4,5-c]quinolin-2-one derivatives as selective PI3K inhibitors. In first set, appropriate
modifications were carried out in the imidazoquinoline ring, which led to an identification of a
single digit nM potent PI3K inhibitor (9c), with moderate isoform selectivity. In set 2, further
th
structure-activity relationship (SAR) studies on the 8 position of 9c resulted in to the discovery
of N-(2-methoxy-5-(3-(4-methoxybenzyl)-1-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-
c]quinolin-8-yl)pyridin-3-yl)methanesulfonamide (10h) that showed improved isoform
selectivity, PK profile and good efficacy in a CIA and xenograft animal models. The results of
docking study showed that specificity pocket was fully occupied by 10h, which explains its more
selective towards PI3K. Overall pre-clinical data suggest that the development of a potent and
selective PI3K inhibitor could be viable therapeutic option for the effective management of
rheumatoid arthritis.
Acknowledgments:
Authors thank the management of Zydus Research Centre, Cadila Healthcare Ltd. for support
and encouragement and the analytical department for providing analytical data.
Corresponding Author: Rajesh Bahekar
E-mail: rajeshbahekar@zyduscadila.com
Notes
The authors declare no competing financial interest.
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