An orally available 3-ethoxybenzisoxazole capsid binder with clinical activity against human rhinovirus

Article abstract of DOI:10.1021/ml2002955

Respiratory infections caused by human rhinovirus are responsible for severe exacerbations of underlying clinical conditions such as asthma in addition to their economic cost in terms of lost working days due to illness. While several antiviral compounds

Full text of DOI:10.1021/ml2002955

Letter
pubs.acs.org/acsmedchemlett
An Orally Available 3-Ethoxybenzisoxazole Capsid Binder with
Clinical Activity against Human Rhinovirus
Susanne C. Feil,‡ Stephanie Hamilton,† Guy Y. Krippner,†,∥ Bo Lin,† Angela Luttick,†
Darryl B. McConnell,†,⊥ Roland Nearn,† Michael W. Parker,‡,§ Jane Ryan,† Pauline C. Stanislawski,†
Simon P. Tucker,† Keith G. Watson,† and Craig J. Morton*,†,‡
†Biota Holdings Ltd., 10/585 Blackburn Road, Notting Hill, Victoria 3168, Australia
‡Biota Structural Biology Laboratory, St. Vincent's Institute, 9 Princes Street, Fitzroy, Victoria 3065, Australia
§Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of
Melbourne, 30 Flemington Road, Parkville, Victoria 3010, Australia
S
* Supporting Information
ABSTRACT: Respiratory infections caused by human
rhinovirus are responsible for severe exacerbations of under-
lying clinical conditions such as asthma in addition to their
economic cost in terms of lost working days due to illness.
While several antiviral compounds for treating rhinoviral
infections have been discovered, none have succeeded, to date,
in reaching approval for clinical use. We have developed a
potent, orally available rhinovirus inhibitor 6 that has
progressed through early clinical trials. The compound
shows favorable pharmacokinetic and activity profiles and
has a confirmed mechanism of action through crystallographic studies of a rhinovirus−compound complex. The compound has
now progressed to phase IIb clinical studies of its effect on natural rhinovirus infection in humans.
KEYWORDS: antiviral, rhinovirus, capsid, inhibitor
he family picornaviridae includes a diverse range of
pathogens causing disease in both humans and other
against all enteroviruses including multiple HRV serotypes and
HRV clinical isolates6 as well as showing low toxicity and
acceptable safety and tolerability in intranasal dosing.7
Rupintrivir performed well in experimental HRV challenge
studies, reducing the severity of both viral load and
symptomatic illness,8 but failed to show a clinically significant
impact in a natural infection study.9 Following this lack of
efficacy, further clinical development of rupintrivir for HRV
ceased.
Pleconaril 1 (Chart 1), the only HRV inhibitor so far to be
submitted for regulatory approval to the U.S. Food and Drug
Administration, shows broad spectrum antiviral activity across a
range of enterovirus species, inhibiting 90% of clinical isolates
at a concentration of 0.18 μM.10 A phase III clinical trial
showed that pleconaril 1 caused a significant reduction in both
the severity and the duration of disease symptoms.11,12 Safety
and drug interaction concerns, however, led the assessment
panel to reject the application for pleconaril 1.13 Subsequently,
the compound is being developed as an intranasal treatment
with a phase II study completed in 2007, although no results
have been released to date (http://www.clinicaltrials.gov/ct/
gui/show/NCT00394914).
T
animals.1 Of these, the rhinovirus, a species of the enterovirus
genera, is perhaps the most ubiquitous of human respiratory
pathogens causing the majority of cases of the common cold2 as
well as being responsible for sometimes severe exacerbations of
underlying illnesses such as asthma, cystic fibrosis, and chronic
obstructive pulmonary disease (COPD).3 The difficulties
inherent in the development of a specific therapeutic for the
treatment of human rhinovirus (HRV) infection have become
almost proverbial, with the lack of a “cure for the common
cold” being used to highlight perceived flaws in scientific and
medical progress. Despite this popular misconception, a range
of specific rhinovirus inhibitors have been identified in recent
years, and some have progressed into clinical development,1,4
although none have as yet been approved for use.
The most productive viral targets for the identification of
HRV inhibitors have been the protein capsid and the 3C
protease. Processing of the viral polyprotein is strictly
dependent on the 3C protease following an initial cleavage
by a second virus-encoded 2A protease.5 Because of its essential
role in the viral lifecycle, the 3C protease has been the target of
numerous research programs with several inhibitory com-
pounds identified.1,4,6 An irreversible 3C protease inhibitor
incorporating an unsaturated ethyl ester Michael acceptor,
rupintrivir (AG7088), demonstrated potent antiviral activity
Received: December 14, 2011
Accepted: February 13, 2012
Published: February 13, 2012
© 2012 American Chemical Society
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ACS Medicinal Chemistry Letters
Letter
prompting further improvement of the series. Given that the
HRV activity of pirodavir 2 requires the precise chemical
characteristics of a terminal ethyl ester functionality, it occurred
to us that ethoxy-substituted 6,5-fused-benzoheterocycles of
general structure 5 could be suitable isosteres of the ethyl
benzoate group and would be much less prone to hydrolysis.
Thus, we devised suitable synthetic methods (Scheme 1) and
Chart 1. Structures of Representative Antirhinoviral Capsid-
Binding Compounds Discussed in the Text
a
Scheme 1. Summary of the Synthetic Route for BTA798 6
a
Mitsunobu reactions were prepared in anhydrous THF with
diisopropylazodicarboxylate at 0 °C and then allowed to react at
room temperature overnight. CDI, carbonyldiimidazole.
prepared many compounds of type 5 including benzisoxazole
and benzisothiazole analogues 6−12 of pirodavir 2 (Table 1).20
Compound 6, for example, was prepared by Mitsunobu
reaction of the appropriate hydroxyethylpiperidine with 3-
ethoxy-6-hydroxy-1,2-benzisoxazole.
All new compounds were initially tested for activity against
two HRV strains (HRV-2 and HRV-14) using cell culture
cytopathic effect (CPE)-based assays as summarized in Table 1.
The results indicated that the ethoxy-benzisoxazole compound
6 (BTA798), the closest structural analogue of pirodavir 2, is
the most active compound and has similar activity to 2 against
HRV2 and HRV14. Various other ethoxy-substituted 6,5- and
6,6-benzoheterocyclic analogues of pirodavir, including 6-linked
2-ethoxybenzoxazole21 and 7-linked 4-ethoxy-quinazoline20
analogues, were also prepared, but testing against HRV showed
lower activity. Overall, our antiviral testing results indicated that
the ethoxy-benzisoxazole of 6 is the preferred bicyclic ring
system.
A panel of 32 HRV serotypes comprising viruses from
species groups A and B, antiviral susceptibility groups A and B,
and both major and minor receptor groups was assessed for
sensitivity to BTA798 6 with comparative data generated for
pleconaril 1, pirodavir 2, rupintrivir,6 and BTA188 4 (Table 2).
The results indicate that BTA798 6 has potent antiviral activity
in vitro for HRV serotypes from both species groups A and B,
both susceptibility groups, and both receptor groups, with a
median EC50 value of 4.3 ng mL−1 (11.2 nM) for the 32 viruses
tested. Similarly, BTA798 6 showed good activity against a
panel of 39 clinical HRV isolates with a median EC50 of 7.3 ng
mL−1 (19.1 nM) and like BTA188 4 is highly potent against a
range of enterovirus species including echovirus, Coxsackie
virus A9, poliovirus, and enterovirus 71.22
On the basis of reported in vitro results, the pyridazine
derivative pirodavir 2 is among the most active of the known
capsid binders and at a concentration of 0.064 μg mL−1 inhibits
80% of 100 HRV strains.14 While effective in experimental
challenge studies when administered very frequently intra-
nasally,15,16 the ester functionality of pirodavir 2 has been
shown to undergo facile hydrolysis in vivo to the carboxylic
acid, which is inactive,17 and this ease of hydrolysis renders the
molecule unsuitable for oral administration.
Several years ago, we began a research project to identify
novel orally active HRV capsid binders, and part of our
investigations was to try to identify metabolically stable isosteric
alternatives to the labile ester functionality on pirodavir 2. In
total, we prepared and tested several hundred new compounds,
confirming in general terms the structure−activity relationships
(SAR) that have been reported for pirodavir 2.17 In summary,
the most active HRV inhibitors are those of general structure 3
comprising a methyl or chloro-substituted-pyridazine linked via
an N-piperidinyl-alkyl group to a 4-oxybenzoate ethyl ester.
With regard to the ethyl ester moiety, we found that the anti-
HRV SAR is quite demanding, the only good alternative being
an oxime ether group so that compound 4 (BTA188) was
found to have equivalent activity to pirodavir 2 against a panel
of HRV18 and superior activity against a wider range of
picornaviruses.19
The specificity of BTA798 6 was examined by testing the in
vitro efficacy of the compound against representative non-
picornaviral species including bovine viral diarrhea virus (Nadl
strain), respiratory syncytial virus (A-2 strain), human influenza
virus (A/Sydney/5/97 strain and B/Harbin/7/94 strain), and
While BTA188 4 was sufficiently potent in vitro and
demonstrated good pharmacokinetic and toxicity profiles in
initial studies, subsequent indications of undesirable metabo-
lism both in vitro and in vivo suggested that the liabilities of the
ester functionality had not been completely resolved,
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ACS Medicinal Chemistry Letters
Letter
Table 1. Structure and Anti-HRV Activity of Compounds 6−12
a
EC50
compd
R
n
X
Y
HRV2
HRV14
6
7
Me
Me
Cl
2
2
2
2
2
2
3
2
O
O
O
O
O
S
OEt
Et
0.001
0.024
0.003
0.003
0.084
0.003
0.003
0.003
0.005
0.088
0.019
0.029
0.013
0.029
0.009
0.004
8
OEt
O-nPr
nPr
9
Me
Me
Me
Cl
10
11
12
2
OEt
OEt
O
Me
a
Activity in μg mL−1.
Table 2. Comparative Activity of BTA798 and Other HRV Inhibitors Across a Panel of 32 HRV Serotypes
species
antiviral susceptibility group
receptor group
a
virus classification method (no. of
virus)
A (26)
3.8
B (6)
5.0
0.8−21.0
A (8)
5.7
B (24)
2.7
major (27)
minor (5)
b
BTA798
pleconaril
pirodavir
BTA188
rupintrivir
median EC50
EC50 range
5.2
1.9
<0.9−>1000
1.3
0.8−>1000
2.1
<0.9−147.3
<0.9−>1000
2.7
0.5−15.9
fold difference
median EC50
EC50 range
37.4
224.1
387.6
33.8
49.2
23.2
7.6−1539.7
6.0
31.7−>1000
31.7−>1000
11.5
7.6−277.1
9.5−>1000
2.1
7.6−45.3
fold difference
median EC50
EC50 range
4.0
11.1
20.6
2.6
5.6
2.3
0.2−>5000
2.8
2.5−35.2
2.5−>5000
8.1
0.2−157.4
0.2−>5000
2.4
0.9−34.2
fold difference
median EC50
EC50 range
5.0
7.9
13.0
4.6
5.45
3.4
0.5−>5000
1.6
<0.05−17
<0.05−>5000
2.8
0.5−>1000
<0.05−>5000
1.6
0.8−6.2
fold difference
median EC50
EC50 range
2.0
1.2
1.2
2.0
1.5
3.0
0.5−7.2
1.7
0.7−2.1
0.5−3.0
1.7
0.8−7.2
0.5−7.2
2.0
1.7−6.4
fold difference
a
b
HRV are classified into subgroups on the basis of genome sequence (species), susceptibility to certain antiviral agents,24 and receptor.25 Activities
in ng mL−1.
Figure 1. Crystal structure of the HRV2−BTA798 6 complex. (a) Diagrammatic representation of the protomer with VP1 (green), VP2 (pink), VP3
(blue), and VP4 (yellow) shown as cartoons, waters are shown as red spheres, and BTA798 6 are shown as rods colored by atom type. The inset
shows one of the capsid pentamers with a single protomer highlighted. (b) View of BTA798 6 in the VP1 binding “canyon”. The protein is shown as
a cartoon with binding residues shown as rods colored by atom type. BTA798 6 is shown as rods colored by atom type with carbons gray. The omit
map Fo − Fc electron density corresponding to BTA798 6 is shown at a σ level of 1.8 as a blue mesh.
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ACS Medicinal Chemistry Letters
Letter
human herpes simplex virus type 2 at concentrations up to
5000 nM (data not shown). No effect of BTA798 6 on CPE for
these viruses was observed, indicating that BTA798 6 lacks
antiviral activity for representatives from five different virus
families that include those with both positive and negative
strand RNA genomes as well as those with a double-stranded
DNA genome.
trial of BTA798 6 in patients with natural rhinovirus infection is
underway.
ASSOCIATED CONTENT
■
S
* Supporting Information
Detailed experimental procedures for the synthesis of
compounds, antiviral assays, and crystallography. This material
is available free of charge via the Internet at http://pubs.acs.org.
As an analogue of pirodavir 2, it was presumed that BTA798
6 would act by a similar mechanism as a capsid binder
interfering with the normal function of the viral protein coat.
Analysis of HRV variants selected for resistance to pleconaril 1
indicated that cross-resistance was seen to BTA798 6 as well as
pirodavir 2 (see the Supporting Information). All variants,
however, remained sensitive to the 3C protease inhibitor
rupintrivir. As further confirmation of the mechanism of action
of BTA798 6, the structure of HRV2 in complex with BTA798
6 was determined by X-ray crystallography (Figure 1a). The
electron density map derived from the crystallographic data
delineated the position of the amino acids in the protein capsid
at 3.0 Å resolution and the cavity within the VP1 protein of the
capsid protomer where other capsid inhibitors have previously
been identified23 was found to contain a region of electron
density consistent with the presence of BTA798 6. Inclusion of
a molecule of BTA798 6 in the structure and further refinement
confirmed the position and orientation in the VP1 pocket
(Figure 1b).
AUTHOR INFORMATION
■
Corresponding Author
*Tel: +61 3 9915 3726. E-mail: c.morton@biota.com.au.
Present Addresses
∥Baker IDI Heart and Diabetes Institute, 75 Commercial Road
Melbourne, Victoria 3000, Australia.
⊥The Department of Medicinal Chemistry, Boehringer
Ingelheim RCV GmbH & Co KG, Dr. Boehringer-Gasse 5-
11, Vienna, Austria.
Funding
Project funding through the AusIndustry Start Grant scheme is
acknowledged.
Notes
The authors declare the following competing financial interest-
(s): All authors were either consultants for (SCF, MWP) or
employees of (others) Biota while working on this project. SH,
BL, AL, MWP, JR, SPT and CJM declare financial interest in
Biota Holdings Ltd.
The preclinical pharmacokinetic profile of BTA798 6 in rat
and dog (Table 3) was found to be better than that of BTA188
Table 3. Pharmacokinetic Parameters of BTA798 Following
Oral Administration in Rat and Dog
a
ACKNOWLEDGMENTS
■
This research was undertaken on the MX1 beamline at the
Australian Synchrotron, Victoria, Australia. M.W.P. is an
Australian Research Council Federation Fellow and a National
Health and Medical Research Council Honorary Fellow.
Infrastructure support from the National Health and Medical
Research Council Independent Research Institutes Infra-
structure Support Scheme and the Victorian State Government
Operational Infrastructure Support Program is gratefully
acknowledged.
rat
dog
parameter
male
(n = 28)
female
(n = 27)
male
(n = 3)
female
(n = 3)
Cmax (ng mL−1
tmax (h)
)
22500
16.0
17700
11.2
11000
14.7
6100
7.7
AUC
483000
489000
202000
121000
(ng h mL−1
)
t1/2 (h)
51.6
94
46.4
95
18.3
15.9
bioavailability
(%)
b
b
a
Single oral dose of 50 mg kg−1 of BTA798 in 1% carboxymethyl-
ABBREVIATIONS
■
b
cellulose. See the Supporting Information for details. Calculated
bioavailability was in excess of 100% indicative of enterohepatic
recirculation.
COPD, chronic obstructive pulmonary disease; HRV, human
rhinovirus; SAR, structure−activity relationship
REFERENCES
418 with improved exposure at a lower dose. The metabolic
stability of BTA798 6 is also improved over that of BTA188 4
and now appears to have completely resolved the liability seen
with pirodavir 2. After oral or iv dosing of either rat or dog,
unmetabolized BTA798 6 is the major component identified in
both plasma and excreta. These observations contrast with
BTA188 4 where a number of metabolites were identified,
including the inactive carboxylic acid (data not shown).
BTA798 6 showed excellent pharmacokinetic and toxico-
logical profiles during phase I studies, with a Cmax of 1890 ng
mL−1, Tmax of 1.03 h, t1/2 of 11.8 h, and an AUC0−∞ of 13758
ng h mL−1 following a single 400 mg dose. No dose-limiting
toxicities or trends in adverse events were seen with single
doses up to 1600 mg or multiple doses of 400 mg twice daily
for seven days. BTA798 6 is progressing through clinical trials,
having shown efficacy in an experimental rhinovirus infection
model phase IIa trial (manuscript in preparation). A phase IIb
■
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