Identification of a novel orally bioavailable NLRP3 inflammasome inhibitor

Article abstract of DOI:10.1016/j.bmcl.2020.127571

NLRP3 inflammasome mediated release of interleukin-1β (IL-1β) has been implicated in various diseases, including COVID-19. In this study, rationally designed alkenyl sulfonylurea derivatives were identified as novel, potent and orally bioavailable NLRP3 i

Full text of DOI:10.1016/j.bmcl.2020.127571

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Identification of a Novel Orally Bioavailable NLRP3 Inflammasome Inhibitor
Sameer Agarwal, Jignesh P. Pethani, Hardik A. Shah, Vismit Vyas, Santosh
Sasane, Harsh Bhavsar, Debdutta Bandyopadhyay, Poonam Giri, Kasinath
Viswanathan, Mukul R. Jain, Rajiv Sharma
PII:
DOI:
Reference:
S0960-894X(20)30682-X
https://doi.org/10.1016/j.bmcl.2020.127571
BMCL 127571
To appear in:
Bioorganic & Medicinal Chemistry Letters
Received Date:
Revised Date:
Accepted Date:
28 July 2020
15 September 2020
18 September 2020
Please cite this article as: Agarwal, S., Pethani, J.P., Shah, H.A., Vyas, V., Sasane, S., Bhavsar, H.,
Bandyopadhyay, D., Giri, P., Viswanathan, K., Jain, M.R., Sharma, R., Identification of a Novel Orally
Bioavailable NLRP3 Inflammasome Inhibitor, Bioorganic & Medicinal Chemistry Letters (2020), doi: https://
doi.org/10.1016/j.bmcl.2020.127571
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Identification of a Novel Orally Bioavailable NLRP3 Inflammasome
Inhibitor
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Sameer Agarwal*, Jignesh P. Pethani, Hardik A. Shah, Vismit Vyas, Santosh Sasane, Harsh
Bhavsar, Debdutta Bandyopadhyay, Poonam Giri, Kasinath Viswanathan, Mukul R. Jain, and
Rajiv Sharma*
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Zydus Research Centre, Cadila Healthcare Ltd., Sarkhej-Bavla N.H. No. 8 A, Moraiya, Ahmedabad – 382 210,
India.
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* E-mail: sameeragarwal@zyduscadila.com; (SA); Rajiv.Sharma@zyduscadila.com (RS); Fax: +91-2717-665355; Tel: +91-
2717-665555
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ABSTRACT: NLRP3 inflammasome mediated release of
interleukin-1β (IL-1β) has been implicated in various
diseases, including COVID-19. In this study, rationally
designed alkenyl sulfonylurea derivatives were identified
as novel, potent and orally bioavailable NLRP3 inhibitors.
Compound 7 was found to be potent (IL-1β IC50 = 35 nM;
IL-18 IC50 = 33 nM) and selective NLRP3 inflammasome
inhibitor with excellent pharmacokinetic profile having
oral bioavailability of 99% in mice.
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KEYWORDS: NLRP3, NLRP3 inflammasome, Interleukin-1β (IL-1β), Inflammation, Sulfonylurea,
Coronavirus disease 2019 (COVID-19), acute respiratory distress syndrome (ARDS).
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Coronavirus disease 2019 (COVID-19), a pandemic caused by SARS-CoV2 virus has gripped
more than 200 countries of the world infecting more than 20 million people and causing death
of over 900,000 worldwide. While most of the infected people regain immune function from
1
initial insult by the virus with mild symptoms, patients with comorbid complications have
developed severe clinical conditions with sustained levels of viral load. Severe COVID-19 is
characterized by acute respiratory distress syndrome (ARDS) and multiple organ failure
possibly caused by uncontrolled immune response in the host. Innate immune response is the
first line of defense, warding off the invading pathogens with the help of pattern recognition
receptors and the adaptive immune responses through generation of specific antibodies against
the pathogens. The major cellular component of adaptive response, namely the lymphocytes
2
are suppressed by SARS-CoV2 leading to lymphocytopenia. This suggests that the
uncontrolled immune response observed in severe COVID-19 patients might be resulting
mainly from innate immune cells, monocytes, macrophages and neutrophils. The increased
levels of inflammatory cytokines released by these cells are the key players in triggering the
cytokine storm and ARDS.
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Existing evidence shows that severe COVID-19 patients had increased IL-1β and other
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cytokines in their serum. In light of this observation, therapies targeting neutralization of
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individual cytokines responsible for cytokine storm are being explored. Among others,
Anakinra, a recombinant human IL-1 receptor antagonist in a retrospective cohort study of
patients with COVID-19 and ARDS, managed with non-invasive ventilation outside of the ICU
6
with clinical improvement in 72% of patients. The key pro-inflammatory cytokine, IL-1β is
processed and released from neutrophils and monocytes following the formation of an
intracellular immune complex called NLRP3 inflammasome. NLRP3 is activated by PAMPS
1

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(pathogen associated molecular patterns) and ionic flux in the cells where it oligomerizes,
associates with ASC and activates the caspase-1 leading to the release of active pro-
inflammatory cytokines, IL-1β and IL-18. Active caspase-1 can also trigger pyroptosis, a
7
highly inflammatory driven cell death triggered by infection through orchestration with
8
caspase-11 to protect the cells from pathogens. However, increased expression of caspase-1
could cause uncontrolled cell death, one of the features observed with ARDS. NLRP3 plays a
dual role in activating the cytokines as well as inducing apoptosis in pathological conditions.
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7
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Thus, targeting NLRP3 could provide a beneficial strategy in anti-immune therapy regimen
over individual cytokines as it can also suppress the ARDS associated apoptosis. Further, a
small molecule NLRP3 inhibitor could demonstrate a superior effect compared to IL-1β
antibodies. An accelerated exploration of this in clinical studies might provide the much needed
plausible treatment option for patients affected by COVID-19 infection worldwide.
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5
5
5
5
0
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7
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Additionally, NLRP3 inflammasome is evolving as a promising target for treatment of various
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complex inflammatory and autoimmune diseases. Several structurally diverse small molecule
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0
11
modulators of NLRP3 have been described (Figure 1). MCC950 (also known as CRID3 and
CP-456,773) a small molecule inhibitor of NLRP3 inflammasome was tested in phase II
clinical trials for rheumatoid arthritis but was not developed further as it was found to elevate
1
2
13
18
serum liver enzyme levels in the clinic. In addition, novel boron compound (NBC-6),
1
4
15
16
17
sulfonamide (JC-171) and compounds like CY09 , OLT1177 , Oridonin and Tranilast
have also been reported as NLRP3 inflammasome inhibitors. Recently we have reported the
discovery of a novel N‑cyano-sulfoximineurea derivative ZY19800 as potent and orally
1
9
bioavailable NLRP3 inflammasome inhibitor.
O
NH2
O
O
O
HO
O
B
S
N
N
H
H
O
Cl3C
MCC-950
NBC-6
SO2NHOH
O
O
S
CN
CN
O
O
N
OLT-1177
S
N
N
H
H
S
O
NH
ZY19800
N
S
MeO
O
O
CF3
Cl
CY-09
OH
JC-171
6
6
0
1
Figure 1. Selected known NLRP3 Inflammasome Inhibitors.
6
2
6
6
6
6
6
6
6
3
4
5
6
7
8
9
Expansion of the chemical pool with novel compounds for NLRP3 inflammasome inhibitors
could increase the possibility for finding potential drug candidates. We present, herein, the
identification and pharmacokinetic evaluation of novel thiazolo-alkenyl sulfonylurea
derivative 7 as potent, selective and orally bioavailable NLRP3 inflammasome inhibitor. High
oral bioavailability is an important consideration for the development of bioactive molecules
as therapeutic agents. We introduced an alkenyl group which resulted in structurally novel
2
0
NLRP3 inflammasome inhibitors with improved properties (Figure 2).
2

O
O
O
O
O
O
HO
R2
S
S
N
N
R1
N
N
H
H
H
H
O
MCC-950
7
7
0
1
Figure 2. Schematic representation of ligand optimization.
7
2
7
7
7
7
7
7
7
8
8
8
8
8
8
8
8
8
8
9
9
9
9
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
Accordingly, a series of novel alkenyl sulfonylurea derivatives have been synthesized and
ability of these test compounds to inhibit NLRP3 inflammasome was measured in IL-1β assay
1
1
using THP-1 cells.
The Table 1 describes the structure-activity relationship (SAR) of
replacement of left-hand side group. The most studied NLRP3 inhibitor, MCC950 was found
to be potent with IC of 8 nM. As we sought to introduce the alkenyl group, the MCC950
5
0
equivalent version, represented as compound 2 was the first one synthesized and evaluated in
IL-1β assay. However, 2 was found to exhibit IC of 208 nM. The metabolically reactive furan
5
0
moiety is a known cause for drug-induced liver injury. Hence, we replaced the furan moiety of
MCC950 with various bioisosteric heterocyclic ring systems. The thiophene analogues 3 and
4 were potent with IC of 70 nM and 96 nM respectively. The 4-pyridine derivative 5 was 164
5
0
nM while 2-pyridine analogue 6 lowered the activity. Interestingly, thiazole compound 7
displayed IL-1β inhibition IC of 35 nM. Having good potency of 7, further thaizole analogues
5
0
were evaluated. Introduction of methyl group at 4-position of thiazole (8) was tolerated (IC50
= 76 nM), however, significant drop in potency was observed for 5-methyl analogue 9 (IC =
5
0
1061 nM). Regioisomers of 7, compounds 10 and 11 were also relatively less potent. Next, to
assess the effect of polarity, carbinol 12 and 13 were synthesized and were found to show IC50
of 142 nM and 306 nM respectively. Further, sulfur containing side chain analogue 14 was 93
nM, and its corresponding sulfoxide (15) and sulfone (16) were found to be 243 nM and 79 nM
respectively. Amide substitution of thiazole (17) was also tolerated. However, fused
heterocyclic systems (18) resulted in loss of activity with less than 50% inhibition of secreted
IL-1β at 1 μM (Table 1).
9
9
9
9
9
9
4
5
6
7
8
9
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(thiazol-2-yl)ethene-1-
sulfonamide (7) was next evaluated for inhibition of IL-1β released with NLRP3 inflam-
masome activation in THP-1 cells using nigericin & MSU and was found to be potent in both
the assays with IC of 26 and 24 nM, respectively (Table S1). Furthermore, 7 was also
5
0
evaluated in IL18 assay, which showed dose-dependent IL18 inhibition with IC 0f 33 nM.
5
0
Notably, 7 was highly selective against TNF-α (IC >10 µM). The production of TNF-α was
5
0
1
1
1
1
00
01
02
03
not affected by 7 even at high concentration (Figure S5), indicating its selective activity
towards NLRP3 inflammasome. Moreover, 7 blocked the oligomerisation of ASC during
NLRP3 activation. Furthermore, this compound had no effect on the AIM2 inflammasome,
demonstrating specificity among inflammasomes (Figure S6).
1
1
1
1
1
04
05
06
07
08
3

1
1
09
10
Table 1. Core modification on the left-hand side: In vitro activity of MCC950 (1) and 2-18.
O
O
O
S
R1
N
N
H
H
a
1
IL-1β IC50
b
b
Compound
R
CLogP
tPSA
(nM)
1
(MCC950)
8
3.27
3.52
3.93
3.53
5.25
4.39
2.31
2.94
2.23
4.14
4.34
3.78
3.44
3.35
2.45
104.73
104.73
75.27
75.27
87.63
87.63
87.63
87.63
87.63
87.63
87.63
107.86
107.86
87.63
104.7
HO
2
3
4
5
6
7
8
9
208
70
O
S
96
S
164
N
1000
35
N
N
S
N
76
S
N
1061
126
369
142
306
93
S
S
10
11
12
13
14
15
N
N
S
HO
N
S
N
HO
S
N
S
S
S
S
S
N
N
243
O
16
17
18
79
344
2.15
3.33
4.52
121.77
107.94
87.63
S
O
O
O
N
N
S
N
>1000
S
1
1
11
12
a
b
n =1; Calculated from ChemBioDraw Ultra 16.0.
1
13
1
1
1
14
15
16
Encouraged by the result for 7 we sought to assess the right-hand side tricyclic fragment.
Accordingly, we synthesized a small set of compounds that maintained the features of
hexahydroindacene ring (Table 2). 4-Methyl tricyclic analogue 19 showed a modest level of
4

1
1
1
1
1
1
1
1
1
17
18
19
20
21
22
23
24
25
inhibition compared with 7, while conversion to the oxa-ring yielded only inactive compound
(20). Bis-alkyl and alkoxy substituted phenyls (21 and 22), did not give promising results.
Further, ortho-substituted compounds 23, 24 and 25 were also resulted in ablation of activity.
Finally, tetra-methyl substituted analogue 26 that mimic the hexahydroindacene, resulted in
complete loss of potency. Surprisingly, apart from 4-methyl tricyclic analogue 19, all other
right-hand side variations, compounds 20-26, resulted in loss of activity with less than 50%
inhibition of IL-1β release at 1 μM (Table 2). These results indicates the critical importance of
the tricyclic ring system topography such that any modification on the right hand side in 7
resulted in loss of NLRP3 inhibition activity.
1
1
26
27
Table 2. Modifications on right-hand side of 7: In vitro activity of 7, 19-26.
O
O
O
R2
S
N
N
N
H
H
S
1
28
IL-1β IC50
2
b
b
Compound
7
R
CLogP
tPSA
a
(nM)
35
2.31
3.86
87.63
87.63
19
294
Me
O
2
2
2
2
0
1
2
3
>1000
>1000
>1000
>1000
>1000
1.59
4.19
1.47
2.99
3.82
106.09
87.63
106.09
87.63
87.63
O
MeO
OMe
F
F3C
F3C
F3C
2
4
CF3
2
5
6
>1000
>1000
2.75
3.23
87.63
87.63
2
1
1
29
30
a
b
n =1; Calculated from ChemBioDraw Ultra 16.0.
1
31
1
1
1
1
1
1
32
33
34
35
36
37
An efficient synthetic route was developed for 7 as depicted in Scheme 1. The key intermediate
29 was obtained from commercially available methyl sulfonamide (27) using known
2
1
22
procedure. Horner reaction of 29 with 2-thiazolecarboxaldehyde afforded 30 in good yield.
It is noteworthy to mention that, the Boc-sulfonamide 30 had trans orientation about the double
bond as determined by NMR coupling constants and was isolated essentially as single E-
2
1
isomer; the cis isomer was not observed, which is in agreement with literature. This adduct
5

1
1
1
1
1
1
1
38
39
40
41
42
43
44
was deprotected using trifluoroacetic acid to provide sulfonamide 31 in 84% yield. Another
key intermediate, tricyclic amine (1,2,3,5,6,7-hexahydro-s-indacen-4-amine) (32), and its
2
3
corresponding isocyanate 33, were synthesized using reported protocol on multi gram scale.
The coupling of sulfonamide 31 with 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (33)
2
4
provided sulfonylurea 7. Following the same reaction sequence with various aldehydes
resulted in test compounds 2-18. While, coupling of sulfonamide 31 with different substituted
isocyanates afforded compounds 19 – 26 in good yield and high chemical purity.
1
45
O
O
P
O
O
O
O
O
O
O
a
b
d
Ph
Ph
S
S
S
NH2
N
O
N
O
H
H
2
7
28
29
O
O O
S
O O
S
N
c
N
N
O
NH2
H
S
S
30
31
O
O O
S
N
e
N
N
H
H
S
7
1
46
1
1
1
1
1
47
48
49
50
51
Scheme 1. Synthesis of Compound 7. Reagents and conditions: (a) (Boc) O, trimethylamine,
2
dichloromethane, 0°C to r.t., 16 h (100%); (b) LDA, dry THF, -78 °C, Ph POCl, -78 °C to r.t.,4 h (84%);
2
(c) 2-Thiazolecarboxaldehyde, sodium hydride, dry DMF, 0 °C to r.t., 4 h (64%); (d) TFA,
dichloromethane, r.t., 4h (84%); (e) 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (33), sodium
hydride, dry DMF, 0 °C to r.t., 16 h (32%).
1
52
1
1
1
1
1
1
53
54
55
56
57
58
Compound 7 was next evaluated for physiochemical properties and metabolic stability assays
in addition to in vivo pharmacokinetic profile. Notably, 7 have good aqueous solubility and
acceptable lipophilicity with cLogP in the ideal range and low total polar surface area.
Furthermore, the compound was found to be metabolically stable in mouse, rat, dog and human
liver microsomes and also demonstrated good Caco2 permeability (Table S5). These drug-like
properties of compound 7 further enabled its potential for in vivo pharmacokinetic profiling.
1
59
1
1
1
1
1
60
61
62
63
64
The in vivo pharmacokinetic investigation in C57BL/6 mice revealed that 7 exhibited good oral
absorption having Cmax of 8.49 μg/mL with an AUC of 48.9 μg.h/mL and terminal oral half-
life of 2.86 h, after oral route of administration at 3 mg/kg dose (Table 3). Pharmacokinetic
studies in C57BL/6 mice showed a fast oral absorption, higher plasma exposure, and an
acceptable half-life and demonstrated an excellent oral bioavailability of 99%.
1
1
1
1
65
66
67
68
6

a
1
69
Table 3. Pharmacokinetic profile of MCC950 and 7.
Compound
Species
MCC950
Mouse
3
7
Mouse
3
PO Dose (mg/kg)
Tmax (h)
0.25
11731
46897
1.32
3.07
1
0.25
8488
48937
2.86
4.9
Cmax (ng/mL)
AUC (0-t) (ng.h/mL)
T½,po (h)
MRT (h)
IV Dose (mg/kg)
1
C (ng/mL)
22244
20667
0.15
0.8
6266
16452
0.2
0
AUC (0-t) (ng.h/mL)
Vss (L/kg)
CL (ml/min/kg)
T½, iv (h)
1.01
2.35
3.23
99
3.97
3.22
77
MRT (h)
%F
1
70
1
1
1
71
72
73
aCompounds MCC950 and 7 dosed 1 mg/kg iv and 3 mg/kg po. Mouse PK data is mean data because
of composite study design, n = 3/time point. Formulation: PO, 1% Tween 80 + 99% (0.5%) methyl
cellulose in water; IV, 5% NMP + 5% solutol + 90% normal saline.
1
74
1
1
1
1
1
1
1
1
1
1
75
76
77
78
79
80
81
82
83
84
Evaluation of a drug candidate against the cytochrome P450 (CYP450) enzymes, CYP1A2,
CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 is an important aspect of drug
2
5
discovery and development. Although 7 has excellent pharmacokinetics profile, it does
inhibit both CYP2C8 and CYP2C9, which precludes it from further progression for further in
vivo efficacy studies. Nonetheless, our chemically driven approach has afforded an orally
bioavailable NLRP3 inhibitor. The added in vitro characterization of potency and selectivity,
and the robust evidence in various assay systems, provide a comprehensive data package
supporting the use of 7 in future NLRP3 pharmacological investigations. These NLRP3
inflammasome inhibitors with novel chemical structure having high potency and excellent PK
profile would be helpful in further investigations as potential clinical candidates.
1
1
85
86
Acknowledgement
1
1
87
88
Authors thank management of Zydus Research Centre, Cadila Healthcare Ltd., for support and
encouragement. ZRC Communication No.: 655
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1
89
90
Supporting Information
1
1
91
92
Supplementary data associated with this article can be found, in the online version.
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Abbreviations
1
1
1
94
95
96
NLRP3, NOD-like receptor family, pyrin domain-containing protein 3, AIM2, absent in
melanoma 2; DAMP, damage‐associated molecular pattern; PAMP, pathogen‐associated
molecular pattern; LPS, Lipopolysaccharide; ATP, adenosinetriphosphate; NCE, New
7

1
1
97
98
Chemical Entity; LDA, Lithium diisopropylamide; TFA, Trifluoroacetic acid; tPSA, total polar
surface area; PK, Pharmacokinetic.
1
2
99
00
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1
sulfonamide (7): White powder; mp: 196 ºC; % purity: 96.61% (UPLC); H NMR (400 MHz,
DMSO-d ): δ = 10.63 (br s, 1H,), 8.22 (s, 1H), 8.05 (d, J = 3.2 Hz, 1H), 8.01 (d, J = 3.2 Hz,
6
1H), 7.74 (d, J = 15.2 Hz, 1H), 7.60 (d, J = 15.2 Hz, 1H), 6.95 (s, 1H), 2.79 (t, J = 7.2 Hz, 4H),
1
3
2.66 (t, J = 7.2 Hz, 4H), 1.94 (quin, J = 7.2 Hz, 4H); C NMR and DEPT (100 MHz, DMSO-
d ): δ = 160.9 (C), 150.1 (C), 145.3 (C), 143.5 (CH), 137.7 (C), 132.9 (CH), 130.4 (CH), 129.2
6
+
(C), 125.1 (CH), 118.4 (CH), 32.9 (CH ), 30.7 (CH ), 25.5 (CH ); ESI-Q-TOF-MS: m/z [M+H]
calcd for [C H N O S ] : 390.0946; found: 390.0937; IR (KBr): ν = 3232 (N-H), 2949(CH2)
2
2
2
+
,
1
8
20
3
3 2
-1
1662 (C=O), 1552 (N-H), 1463 (CH2), 1346 (CH3), 1151 (S=O) cm .
25. Kumar, G. N.; Surapaneni, S. Role of drug metabolism in drug discovery and development.
Med. Res. Rev. 2001, 21 (5), 397.
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