Discovery of Fevipiprant (NVP-QAW039), a Potent and Selective DP2 Receptor Antagonist for Treatment of Asthma

Article abstract of DOI:10.1021/acsmedchemlett.7b00157

Further optimization of an initial DP₂ receptor antagonist clinical candidate NVP-QAV680 led to the discovery of a follow-up molecule 2-(2-methyl-1-(4-(methylsulfonyl)-2-(trifluoromethyl)benzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acetic acid (compou

Full text of DOI:10.1021/acsmedchemlett.7b00157

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Letter
Discovery of fevipiprant (NVP-QAW039), a potent and
selective DP2 receptor antagonist for treatment of asthma
David A. Sandham, Lucy Barker, Lyndon Brown, Zarin Brown, David Budd, Steven J. Charlton,
Devnandan Chatterjee, Brian Cox, Gerald Dubois, Nicholas Duggan, Edward Hall, Julia
Hatto, Janet Maas, Jodie Manini, Rachael Profit, Darren Riddy, Catherine Ritchie, Bindi
Sohal, Duncan E. Shaw, Rowan Stringer, David A. Sykes, Matthew Thomas, Katharine L
Turner, Simon J Watson, Ryan West, Elisabeth Willard, Gareth Williams, and Jennifer Willis
ACS Med. Chem. Lett., Just Accepted Manuscript • Publication Date (Web): 25 Apr 2017
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Discovery of fevipiprant (NVP-QAW039), a potent and selective DP2
receptor antagonist for treatment of asthma
David A Sandham,*† Lucy Barker, Lyndon Brown, Zarin Brown, David Budd, Steven J Charlton,
Devnandan Chatterjee, Brian Cox, Gerald Dubois, Nicholas Duggan, Edward Hall, Julia Hatto,
Janet Maas, Jodie Manini, Rachael Profit, Darren Riddy, Catherine Ritchie, Bindi Sohal, Duncan
Shaw, Rowan Stringer, David A Sykes, Matthew Thomas, Katharine L Turner, Simon J Watson,
Ryan West, Elisabeth Willard, Gareth Williams, Jennifer Willis
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Novartis Institutes for Biomedical Research, Horsham Research Centre, Wimblehurst Road, Horsham, West Sussex
RH12 5AB, United Kingdom.
ABSTRACT: Further optimization of an initial DP2 receptor antagonist clinical candidate NVP-QAV680 led to the discov-
ery of a follow up molecule 2-(2-methyl-1-(4-(methylsulfonyl)-2-(trifluoromethyl)benzyl)-1H-pyrrolo[2,3-b]pyridin-3-
yl)acetic acid (compound 11, NVP-QAW039, fevipiprant) which exhibits improved potency on human eosinophils and Th2
cells, together with a longer receptor residence time and is currently in clinical trials for severe asthma
Keywords: DP2 receptor antagonist; severe asthma; clinical candidate
Antagonism of the action of the lipid mediator prosta-
glandin D2 (PGD2) at the DP2 (also known as CRTh2:
Chemoattractant Receptor Homologous expressed on Th2
cells) receptor represents a potential new approach for
treatment of asthma and allergic rhinitis.1 PGD2 is pro-
duced primarily from IgE activated mast cells and pro-
motes activation and migration of eosinophils, Th2 lym-
phocytes and basophils through activation of the DP2 re-
ceptor expressed on these cell types, which are the princi-
pal drivers of the late phase allergic inflammatory re-
sponse.2 More recently, Type-2 innate lymphoid cells
(ILC2) have emerged as an additional DP2 dependent cell
type important in the immune response in allergic asth-
ma.3 Conversely, the majority of the homeostatic func-
tions of PGD2 appear to be mediated by the classical pros-
tanoid DP1 receptor,4 which has further increased the at-
tractiveness of selectively targeting DP2. Multiple drug
discovery campaigns have been reported in the literature,
culminating in a number of compounds (selected exam-
ples in Chart 1) which have progressed to clinical studies
in allergic rhinitis, asthma, chronic obstructive pulmo-
nary disease and eosinophilic esophagitis patients. 5
and consequently a follow up compound was sought with
potential for improved duration of action.
In this Letter we disclose SAR associated with the further
optimization of 1, which has culminated in discovery of
2-(2-methyl-1-(4-(methylsulfonyl)-2-
(trifluoromethyl)benzyl)-1H-pyrrolo[2,3-b]pyridin-3-
yl)acetic acid 11 (NVP-QAW039, fevipiprant) a potent
selective DP2 receptor antagonist suitable for once daily
dosing with improved potency and slower receptor disso-
ciation compared to QAV680 and other reported DP2 an-
tagonists which have progressed to the clinic.10 Fe-
vipiprant reduces eosinophilic airway inflammation in
patients with persistent asthma and raised sputum eosin-
ophil counts. This is associated with improved lung func-
tion and asthma-related quality of life, and a favorable
safety profile.11
During the hit-to-lead phase of the project, some varia-
tions of the core substituents of the azaindole scaffold
had been investigated without leading to potency im-
provements. Notably substitution, truncation or exten-
sion of the C-3 acetic acid moiety, or deletion of the C-2
methyl group all suppressed DP2 affinity, in line with
subsequently disclosed SAR on related indole series.12
However with the 4-(methylsulfonyl)benzyl moiety es-
tablished as an optimal N-1 substituent in 1, we revisited
selected substitutions of the 7-azaindole scaffold, the re-
sults of which are presented in Table 1.
Amongst these is NVP-QAV680 1, of which we have re-
cently disclosed the discovery and characterization as a
clinical candidate.6 Following demonstration of excellent
safety and tolerability in single and multiple ascending
dose Phase I healthy volunteer studies, positive results in
two clincial proof of concept (PoC) studies were obtained
in allergic rhinitis.7-9 However, the twice or four times
daily daily dosing regime utilized was considered a limita-
tion in respect of patient convenience and compliance
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pounds 3-5) delivered up to an order of magnitude reduc-
1
2
3
4
tion in binding affinity. C-6 was the only position where
comparable activity to the prototype was retained (com-
pounds 6-7). Next we briefly explored the sulfone alkyl
substituent, which indicated the ethyl and isopropyl sul-
fone analogues 8 and 9 were broadly equivalent to 1.
5
6
7
8
9
At this point, in the absence of any additional potency
breakthrough compared to 1, and building on the initial
binding SAR preferences for electron-deficient N-1 aro-
matic substituents,6 we executed a more diverse array of
polysubstituted electron-deficient N-1 benzyl analogues
lacking the sulfone moiety. The key result from this exer-
cise was the 2,4-bis(trifluoromethyl) analogue 10, which
exhibited similar binding potency to 1, albeit with a signif-
icant drop off in WB potency. With this result in hand, a
follow-up array of analogs re-incorporating the sulfone
moiety together with a second aromatic ring substituent
was prepared (Table 2). Several 2,4-disubstituted sulfones
11, 12, 15 and 16 exhibited sub-10 nM binding affinity, with
the 3,4-disubstitution pattern clearly less favourable as
exemplified by compound 14. However compound 11 was
the stand out example in the WB assay, where sub-nM
potency was attained, an approximately 40-fold im-
provement on 1, although the difference in DP2 binding
affinity was somewhat lower at approximately 8-fold.
10
11
12
13
14
15
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Chart 1: Selected indole and azaindole DP2 antagonists pro-
gressed to the clinic
Compounds were prepared by alkylation of the appropri-
ate indolyl- or 7-azaindolyl-3-acetic acid methyl ester
with a benzyl bromide derivative as previously described.6
Synthetic schemes for preparation of the substituted
azaindolyl-3-acetic acid methyl esters are included in the
Supplementary Information. In contrast to the synthesis
of 1, N-alkylation with the benzyl bromide precursor to 11
afforded only modest regioselectivity in favor of the de-
sired N-1 alkyl product (Scheme 1), and the further the
reaction was driven to completion, the more N-7 product
was observed. However the pure compound 11 could be
readily separated from the undesired N-7 isomer by crys-
tallization after ester hydrolysis. This alkylation product
ratio proved refractory to variations in base or benzyl hal-
ide selection and the development of an alternative syn-
thetic route will be the subject of a separate publication.
Table 1: Core modified and sulfone analogues of 1
compd
DP2
Eosinophil SC IC50 (µM)
Ki (µM)a
isolatedb
WBc
Scheme 1: Synthesis of compound 11
1
0.036
0.019
0.356
0.005
0.031
2
3
0.02
0.08
0.188
nd
4
0.735
nd
nd
5
1.335
nd
nd
nd
nd
Reagents and conditions: i) Cs2CO3, MgSO4, acetone, re-
flux; ii) 1-(bromomethyl)-4-(methylsulfonyl)-2-
(trifluoromethyl)benzene, RT-reflux, 42%, ratio N-7:N-1
17:83; iii) aq NaOH, acetone RT, 44%
6
0.072
Excision of the 7-azaindole nitrogen delivered the indole
2 with similar DP2 binding affinity, although a significant
loss of potency in both the isolated and whole blood (WB)
human eosinophil shape change (SC) functional assays
was observed, while substitution at C-4 or C-5 (com-
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Further in vitro data comparing 1 with 11 for blockade of
7
0.047
0.006
nd
1
2
3
4
5
6
7
8
DP2 agonist-induced IL-5 and IL-13 cytokine production in
human primary CD4+ Th2 cells is shown in Table 4,
where again a potency difference somewhat larger than
anticipated based on binding affinity was observed. In
addition, compound 11 was also a potent inhibitor of DP2
agonist-induced IL-4 production. Blockade of the signal-
ing of IL-4 and IL-13 using an antibody to the IL-4 recep-
torα (which binds both cytokines) has recently been
shown to positively impact on both rates of exacerbations
and lung function in persistent asthmatic patients.13
8
9
0.050
0.086
0.004
nd
nd
nd
9
10
11
a human DP2 receptor scintillation proximity binding assay
Table 2: Disubstituted analogues of 1
with [3H]-PGD2; isolated human eosinophil shape change
b
12
13
14
15
16
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c
assay; human whole blood eosinophil shape change assay;
nd not determined. See reference 6 for assay descriptions.
For all assays data represents the mean of at least two exper-
iments.
Rat pharmacokinetic data generated on a selection of the
potent analogues (Table 3) revealed good to excellent oral
biovailability combined with generally lower clearance
compared to 1. While this pre-clinical data did not pro-
vide significant differentiation from 1 based on half life,
we reasoned that a more potent compound with a similar
half life could faciliate extended exposure coverage at the
DP2 receptor. Consequently, based on the human in vitro
data, 11 was selected for a head to head comparison dosed
Compd
10
R
DP2
Ki (µM)a
Eosinophil SC IC50 (µM)
isolatedb
WBc
0.029
0.014
0.214
orally with
1
in
a
PK-PD (pharmacokinetic-
11
0.004
0.0004
0.0004
pharmacodynamic) mechanistic target engagement mod-
el of pulmonary eosinophilia induced by the DP2 specific
agonist 14,15-dihydro-15-ketoprostaglandin D2 (DK-PGD2)
as previously described.6 As before, we did not have access
to a rat in vitro DP2 assay, however compound 11 was ap-
proximately 6-fold more potent for inhibition of eosino-
philia in broncho alveolar lavage (BAL) fluid than 1 based
on free fraction derived from in vitro rat plasma protein
binding data (Figure 1).
12
13
14
0.004
0.031
0.031
0.0017
0.004
0.004
0.047
0.032
0.011
Figure 1: PK-PD comparison of 1 and 11 in a rat model of
pulmonary eosinophilia
100
90
80
70
60
50
40
30
20
15
16
0.006
0.007
0.0013
0.007
0.004
IC50 40 nM
IC50 6.5 nM
10
0
1
10
Free drug concentrations in plasma (nM)
100
0.0008
Data expressed as mean ± SEM for n = 8 animals per
group. compound 11 dosed p.o. at 0.03 and 0.1 mg/kg; ●
▲
compound 1 dosed p.o. at 0.1 and 0.3 mg/kg. Y axis represents
inhibition of BAL eosinophilia window between i.t. DK-PGD2
challenged and vehicle treated animals. X-axis represents
free drug concentration from unbound fractions (fu) in rat
plasma determined by equilibrium dialysis. Compound 1 rat
plasma fu 0.34; compound 11 rat plasma fu 0.08. See reference
6 for assay descriptions
a human DP2 receptor scintillation proximity binding assay
with [3H]-PGD2; isolated human eosinophil shape change
b
c
assay; human whole blood eosinophil shape change assay.
See reference 6 for assay descriptions. For all assays data rep-
resents the mean of at least two experiments.
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Table 3: Rat in vivo pharmacokinetic dataa,b
Table 5: DP2 receptor kinetic data determined at 37˚Ca
5
6
7
8
compd
Cl
Vss
i.v. T
Fpo
compd
kon
(M-1min-1)
koff
(min-1)
Dissociation
pKd
½
T
(min)
½
(ml/min/kg)
(L/kg)
(hr)
17.1
13.2
7.7
1
15.2
1.6
5.5
1.1
54%
43%
71%
1
4.80 x 107
2.23 x 108
6.27 x 107
1.69 x 108
0.66
4.05
0.061
0.22
1.29
0.18
7.82
7.60
8.99
8.72
9
11
15
2
10
11
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4.4
2.9
1.1
11
15
12.04
3.36
16
1.2
9.2
97%
a
b
Compounds dosed i.v. 0.5 mg/kg in PEG-PBS vehicle;
a Determined by [3H]-11 radioligand binding. See reference
10 for assay descriptions. For all assays data represents the
mean of at least two experiments.
Compounds dosed p.o. 3 mg/kg suspension in 1% NaCMC
vehicle. See reference 6 for experimental descriptions.
Table 4: In vitro human CD4+ Th2 cell data: inhibition of
DK-PGD2 induced cytokine production
Further profiling of 11 against related prostanoid receptor
targets showed minimal affinity (IC50 >10 μM) for the DP1,
EP2, EP4, FP and TP receptors together with minimal ac-
tivity as a functional agonist or antagonist (EC50/IC50 >10
μM) at the EP3 and IP receptors. (EP1 activity was not de-
termined due to non-availability of the radioligand) In
broader off-target screening, compound 11 was inactive
(IC50 >10 μM or < 50% inhibition at 10 μM) against 165
receptors, ion channels, transporters and enzymes targets
in Novartis and external (MDS, now Eurofins-Panlabs)
screening panels. This favorable profile was also con-
firmed by the absence of unexpected adverse findings in
the toxicology studies performed in rats and dogs. The
overall selectivity of this molecule was further under-
scored by the lack of activity (IC50 > 100 μM) against hu-
man CYP1A2, CYP2C9, CYP2D6 and CYP3A4 isoforms and
in a PXR-based CYP3A4 induction assay a similar lack of
activity was exhibited. Taken together, this latter data
indicates a low potential for cytochrome P450 mediated
drug-drug interactions involving 11 in the clinical context.
compd
IC50 (µM)
IL-4 inhibition
nd
IL-5 inhibition IL-13 inhibition
1
0.059
0.025
11
0.0031
0.0026
0.0014
See references 6 and 10 for assay descriptions; for all assays
data represents the mean of at least two experiment; nd: not
determined
While this improved human potency was critical in selec-
tion of 11 for development as a follow up to 1 with poten-
tial for improved duration of action, it also prompted fur-
ther post-lead optimization exploration of the in vitro DP2
receptor kinetics of 1 and selected analogs utilizing [3H]-11
as a radioligand.10 (Table 5). Interestingly the effect of
deleting the N-7 nitrogen (indole analog 2) appears to
confer a pronounced reduction in target residence time,
while 11 clearly exhibits the most favourable kinetic pro-
file of the four compounds. The slower off-rate of 11 from
the DP2 receptor could potentially deliver improved effi-
cacy, as it can insurmountably block the DP2 receptor10
even in the face of high local concentrations of PGD2. This
may be an explanation for the increased potency of 11 in
the primary human eosinophil and Th2 cell assays and
may positively impact clinical efficacy. Since this work
was completed, the first reports of structure-kinetic rela-
tionships for DP2 antagonists have appeared14-17 together
with characterization of a compound LAS191859 reported
to have a half life of 21 hours based on GTPγS assay data
and a duration of action apparently independent of plas-
ma levels in a guinea pig mechanistic model of systemic
eosinophilia.18 It is noteworthy that the kinetics in that
work were determined at ambient temperature, whereas
our studies were all undertaken at physiological tempera-
ture. This difference in experimental conditions can have
a significant impact on reported receptor half life values.19
In summary, further optimization of the initial clinical
candidate NVP-QAV680 1 identified a compound 11 with
improved potency across in vitro human primary cellular
DP2 assays and also in a rat pulmonary DP2 dependent
mechanistic target engagement model. Additional charac-
terization identified a slower DP2 receptor off rate for 11,
which may afford improved efficacy in the face of high
local concentrations of PGD2 during the allergic inflam-
matory response. Clinical studies in healthy volunteers
confirmed safety and tolerability, combined with an im-
proved human pharmacokinetic profile suitable for once
daily dosing in comparison with 1.21 These data enabled a
PoC study in mild-moderate uncontrolled allergic asth-
matics.22 Subsequently, in patients with persistent asth-
ma and raised sputum eosinophil counts, a reduction of
eosinophilic airway inflammation was observed, which
was associated with improved lung function and asthma-
related quality of life.11 Compound 11 (NVP-QAW039, fe-
vipiprant) is currently ongoing in Phase III clinical studies
for treatment of severe asthma.23-25
ASSOCIATED CONTENT
Supporting Information. Synthetic schemes, experimental
details and characterization data for preparation of com-
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ACS Medicinal Chemistry Letters
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M.F.M.; Bacher, G.; Holzhauer, B.; Bourne, M.; Mistry, V.; Pavord
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available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
* Address correspondence to david.sandham@novartis.com,
tel + 1 (617)-871-8000.
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Present Addresses
†Global Discovery Chemistry, Novartis Institutes for Biomed-
ical Research, 100 Technology Square, Cambridge MA-02139,
United States of America
Author Contributions
The manuscript was written through contributions of all
authors.
ABBREVIATIONS
BAL, broncho alveolar lavage; CRTh2, Chemoattractant Re-
ceptor Homologous expressed on Th2 cells; DK-PGD2, 14,15-
dihydro-15-ketoprostaglandin D2; DP2, Prostaglandin D2 re-
ceptor 2; fu, unbound fraction; PGD2, prostaglandin D2; PK-
PD, pharmacokinetic-pharmacodynamic; PoC, proof of con-
cept; SAR, structure activity relationship; SC, shape change;
WB, whole blood.
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IC50 40 nM
IC50 6.5 nM
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Free drug concentrations in plasma (nM)
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Table 2: Disubstituted analogues of 1
37x38mm (300 x 300 DPI)
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Table 1: Core modified and sulfone analogues of 1
68x47mm (300 x 300 DPI)
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Scheme 1: Synthesis of compound 11
145x102mm (300 x 300 DPI)
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Selected indole and azaindole DP2 antagonists progressed to the clinic
141x111mm (300 x 300 DPI)
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Graphical abstract
54x61mm (300 x 300 DPI)
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