Novel 2-Substituted 7-Azaindole and 7-Azaindazole Analogues as Potential Antiviral Agents for the Treatment of Influenza

Article abstract of DOI:10.1021/acsmedchemlett.6b00487

JNJ-63623872 (2) is a first-in-class, orally bioavailable compound that offers significant potential for the treatment of pandemic and seasonal influenza. Early lead optimization efforts in our 7-azaindole series focused on 1,3-diaminocyclohexyl amide and urea substitutions on the pyrimidine-7-azaindole motif. In this work, we explored two strategies to eliminate observed aldehyde oxidase (AO)-mediated metabolism at the 2-position of these 7-azaindole analogues. Substitution at the 2-position of the azaindole ring generated somewhat less potent analogues, but reduced AO-mediated metabolism. Incorporation of a ring nitrogen generated 7-azaindazole analogues that were equipotent to the parent 2-H-7-azaindole, but surprisingly, did not appear to improve AO-mediated metabolism. Overall, we identified multiple 2-substituted 7-azaindole analogues with enhanced AO stability and we present data for one such compound (12) that demonstrate a favorable oral pharmacokinetic profile in rodents. These analogues have the potential to be further developed as anti-influenza agents for the treatment of influenza.

Full text of DOI:10.1021/acsmedchemlett.6b00487

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Letter
Novel 2-Substituted 7-Azaindole and 7-Azaindazole Analogs
as Potential Anti-Viral Agents for the Treatment of Influenza
Upul K. Bandarage, Michael P. Clark, Emanuele Perola, Huai Gao, Marc D. Jacobs, Alice Tsai,
Jeffery Gillespie, Joseph M. Kennedy, Francois Maltais, Mark Willem Ledeboer, Ioana Davies,
Wenxin Gu, Randal A Byrn, Kwame Nti-Addae, Hamilton B Bennett, Joshua R. Leeman, Steven
M Jones, Colleen O'Brien, Christine Memmott, Youssef L Bennani, and Paul S. Charifson
ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.6b00487 • Publication Date (Web): 18 Jan 2017
Downloaded from http://pubs.acs.org on January 19, 2017
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Novel 2-Substituted 7-Azaindole and 7-Azaindazole Analogs as Po-
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Upul K. Bandarage*, Michael P. Clark, Emanuele Perola, Huai Gao, Marc D. Jacobs, Alice Tsai, Jeffery
Gillespie, Joseph M. Kennedya, François Maltais, Mark W. Ledeboerb, Ioana Davies, Wenxin Gu, Ranꢀ
dal A. Byrn, Kwame Nti Addae, Hamilton Bennettc, Joshua R. Leeman, Steven M. Jonesd, Colleen
O’Brien, Christine Memmott, Youssef Bennanie, and Paul S. Charifson.
Vertex Pharmaceuticals Incorporated, 50 Northern Avenue, Boston, MA 02210, USA.
Supporting information
ABSTRACT: JNJꢀ63623872 (2) is a firstꢀinꢀclass, orally bioavailable compound that offers significant potential for the treatment
of pandemic and seasonal influenza. Early lead optimization efforts in our 7ꢀazaindole series focused on 1,3ꢀdiaminocyclohexyl
amide and urea substitutions on the pyrimidineꢀ7ꢀazaindole motif. In this work, we explored two strategies to eliminate observed
aldehyde oxidase (AO)ꢀmediated metabolism at the 2ꢀposition of these 7ꢀazaindole analogs. Substitution at the 2ꢀposition of the
azaindole ring generated somewhat less potent analogs, but reduced AOꢀmediated metabolism. Incorporation of a ring nitrogen
generated 7ꢀazaindazole analogs that were equipotent to the parent 2ꢀHꢀ7ꢀazaindole, but surprisingly, did not appear to improve
AOꢀmediated metabolism. Overall, we identified multiple 2ꢀsubstituted 7ꢀazaindole analogs with enhanced AO stability and we
present data for one such compound (12) that demonstrate a favorable oral pharmacokinetic profile in rodents. These analogs have
the potential to be further developed as antiꢀinfluenza agents for the treatment of influenza. KEYWORDS: Influenza, PB2 subu-
nit, 7-azaindole, aldehyde oxidase, metabolic stability
Seasonal influenza causes high morbidity and mortality
around the globe annually. The impact of influenza epidemics
is estimated to be approximately 3.5 million cases for severe
illness and 300,000 to 500,000 deaths annually.1 Transmission
of novel strains of influenza from other species (mammals and
.
birds) can cause human pandemics, such as the 2009 H1N1
swine flu pandemic as well as the H5N1 avian flu outbreaks.2
Figure 1. Inhibitors of influenza virus: NA inhibitor
oseltamivir (1), 2 and azaindole screening hit 3.
Influenza is caused by three orthomyxoviridae family viruses,
influenza A, B, and C.3 The current antiviral standard of care
The molecular target for these compounds was identified as
the PB2 subunit of the influenza viral polymerase. The PB2
subunit contains a cap binding domain for 7ꢀmethyl GTP (m7ꢀ
GTP) on the 5’ꢀend of the host preꢀmRNA. Once bound to
PB2, the polymerase acidic protein (PA) endonuclease subunit
cleaves the host RNA strand, leaving a 10ꢀ13 nucleotide
primer. The PB1 subunit contains the conserved polymerase
domain and utilizes the primer for viral mRNA elongation.
Soon after identification of PB2 as the target for these 7ꢀ
azaindole screening hits, the Xꢀray crystal structure of initial
screening hit 3 bound to the PB2 capꢀbinding domain was
determined.7 During early lead optimization efforts we
identified a set of promising lead compounds containing a 1,3ꢀ
diaminocyclohexyl functionality appended to the azaindoleꢀ
pyrimidine core.7,8 Of particular early interest was the tertiary
morpholine urea analog 4 (Figure 2) that showed potency in
both the cellular protection assay (CPE IC50 = 4 nM) and
(SOC) for treatment of influenza cases in the United States are
the neuraminidase inhibitors, oseltamivir 1, (Figure 1) and
zanamivir. While these agents can be effective against a
variety of type A and B influenza viruses, they suffer from two
main limitations. First, the neuraminidase inhibitors have only
a moderate impact on the severity of symptoms as well as
duration of sickness and they must be administered within 24ꢀ
48 h of the infection.4 Second, resistance to this class of
antivirals has generated significant concern5, especially with
the report that the H5N1 influenza virus has shown resistance
to oseltamivir6, reinforcing the critical need for new antiꢀ
influenza therapeutics with novel mechanisms of action.
We have previously reported a series of potent 7ꢀazaindoleꢀ
based influenza inhibitors, highlighted by JNJꢀ63623872 (2)
(formerly known as VXꢀ787).7
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branched DNA assay (bDNA EC50 = 12 nM) as well as ethyl(1R,3S)ꢀ3ꢀaminocyclohexanecarboxylate
Page 2 of 5
2,4ꢀ
and
encouraging oral exposure in both rat and mouse.7 This
compound was advanced into a mouse influenza model
showing 75% survival in a + 48 h delay to treatment model
(30 mg/kg b.i.d. for 10 days).7 One of the primary metabolites
observed for compound 4 in human hepatocytes was the result
of oxidation at the 2ꢀposition of the 7ꢀazaindole ring to form
2ꢀhydroxyꢀ7ꢀazaindole 5 via aldehyde oxidase (AO). This
was evidenced by differential stability in cytosol incubation
+/ꢀ addition of an AO inhibitor followed by detailed
metabolite ID (data are not shown). AO is a cytosolic drugꢀ
metabolism enzyme which is not present in human liver
microsomes (HLM). The emerging importance of AO to drug
discovery and development has been highlighted.9 AO
oxidation could lead to metabolic products that can cause liver
injury and renal toxicity through formation of reactive oxygen
species or toxic metabolites.9 Generally, nitrogenꢀcontaining
heterocycles are more labile to AOꢀmediated oxidation.9 We
have reported a similar AOꢀmediated oxidation of 2ꢀposition
of the 7ꢀazaindole recently.10
dichloroꢀ5ꢀfluoropyrimidine, as outlined in Scheme 2.
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8
Scheme 1. Synthesis of Compound 12
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Reagents and conditions: (a)
, Pd(PPh3)2Cl2, CuI, THF,
Et3N, 80 oC, 1 h, 82%; (b) tꢀBuOK, THF, 85 oC, 2 h, 64%; (c)
NIS, DMF, DCM, RT, 1 h, 99%;(d) i. NaH, THF, RT, 30 min;
ii. PhSO2Cl,
1
h, 97%; (e) bis(pinacolato)diboron,
o
PdCl2(dppf).DCM, KOAc, DMF, 85 C, 3 h, 60%; (f) i. 14,
o
Pd(PPh3)4, THF, aq. Na2CO3, 80 C, 18 h; ii. TFA, MeOH,
o
H2O, 1 h, 80%; (g) 4N HCl, 1,4ꢀdioxane, CH3CN, 65 C, 1 h,
68%.
Scheme 2. Synthesis of compound 14
Reagents and conditions:
(a) i. Ethyl (1R, 3S)ꢀ3ꢀ
aminocyclohexanecarboxylate, THF, reflux, 18 h, 92%; ii
LiOH, THF, water, 95o C, 1 h, 97%; (b) DPPA, Et3N,
pyrrolidine, Et3N, THF, RT, 85o C, 2 h, 85%.
Figure 2. Potent antiꢀinfluenza compounds and primary
metabolite (5).
This communication describes two strategies that potentially
eliminate the formation of this metabolite. One strategy was to
substitute the 2ꢀposition with a group that would not be a
substrate for AO. The second strategy involved the
incorporation of an additional nitrogen atom at the 2ꢀposition
to generate an azaindazole ring, thus eliminating the
metabolically labile site.
Compounds 16 and 17 (Table 1) with methyl and cyclopropyl
substitutions at the 2ꢀposition of the 7ꢀazaindole ring were
synthesized adapting the procedure described for compound
12 starting from propꢀ1ꢀyne and ethynylcyclopropane as
Sonagashira coupling partners.
Scheme 3. Synthesis of compounds 19, 20 and 21
Compound 6 features a pyrrolidine urea moiety and is 12ꢀfold
more potent than compound 4 in the bDNA assay (Table 1)
and was used as a reference compound for comparative
studies. One of the first analogs targeted was 2ꢀposition
hydroxymethyl group substituted 7ꢀazaindole 12. The
synthesis of compound 12 was accomplished in seven steps
starting from commercially available 2ꢀaminoꢀ3ꢀiodoꢀ5ꢀ
fluoropyridine. (Scheme 1). Sonagashira coupling of 2ꢀaminoꢀ
3ꢀiodoꢀ5ꢀfluoropyridine with THP protected propargyl alcohol
afforded compound 7 in good yield. Compound 7 was cyclized
to the 7ꢀazaindole ring system 8 by heating with potassium
tertꢀbutoxide (tꢀBuOK) in THF in 64% yield. Selective
iodination at the 3ꢀposition of 8 with NIS generated compound
9. Following protection of the pyrrole nitrogen with
benzenesulfonyl chloride, treatment of the resulting product
with bis(pinacolato) diborane afforded the desired boronate
10. During this study, it was discovered that tosylate
protection at the 2ꢀposition of the substituted 7ꢀazaindole was
unstable and therefore, benzenesulfonyl group was selected as
the preferred protective group. Suzuki coupling of the
boronate 10 with chloropyrimidine intermediate 14 afforded
compound 11 in moderate yield. Deprotection of the THP
group from compound 11 with TFA followed by removal of
the benzenesulfonyl protective group with 4N HCl afforded
the desired target compound 12 in 68% yield. Intermediate 14
was prepared in two steps from commercially available
o
Reagents and conditions: (a) (COCl)2, DMSO, Et3N,ꢀ78 C, 2
h, 86%; (b) i. Na2HPO4, NaClO2, 2ꢀbutene, tꢀBuOH, RT, 18 h
, 88% ii. 4N HCl, 1,4ꢀdioxane, CH3CN, 65 oC, 1 h, 68%; (c) i.
NH2OH, EtOH, reflux, 3 h; ii. 4N HCl, 1,4ꢀdioxane, CH3CN,
o
65 C, 1 h, 68%; (d) i. CH3MgBr, THF, RT, 1 h; ii. 4N HCl,
1,4ꢀdioxane, CH3CN, 65 oC, 1 h, 68%.
The carboxylic acid group of compound 19 was introduced in
three steps from intermediate 11 (Scheme 3). Swern
oxidation of alcohol 11 afforded aldehyde 18 in 86% yield.
Pinnick oxidation of 18 with
a mixture of sodium
hypophosphate, sodium chlorite and 2ꢀbutene followed by the
removal of the benzenesulfonyl protective group provided
compound 19 in 88% yield. Reaction of aldehyde 18 with
hydroxylamine followed by the removal of the
benzenesulfonyl protective group afforded oxime 20.
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Reaction of aldehyde 18 with methyl magnesium bromide bonding interactions with amino acid residues, Lys 376 and
1
2
3
4
(MeMgBr) followed by removal of the benzenesulfonate
protecting group afforded a 1:1 mixture of diastereomers 21a
and 21b which were separated by reverse phase preparative
chromatography. The stereochemistry of the 2ꢀposition of
substituent these diastereomers was not determined.
Glu 361.
Table 1. SAR of 2ꢀposition substituted 7ꢀazaindole inhibitors
5
6
7
8
9
The second strategy to circumvent the AO metabolism was to
introduce a nitrogen at the 2ꢀposition of the 7ꢀazaindole ring to
afford 7ꢀazaindazole scaffold. Compound 23 as an azaindazole
counterpart of compound 6 was synthesized in five steps
starting from commercially available 5ꢀfluoroꢀ7ꢀazaindazole
(Scheme 4). The synthesis of 23 began with iodination of the
3ꢀposition of commercially available 5ꢀfluoroꢀ7ꢀazaindazole to
afford 24 and followed by protection of NH with a Tr group
to afford compound 25. Formation of boronate 26 from
bis(pinacolato)diboron followed by Suzuki coupling with
intermediate 14 gave compound 27 in good yield.
Deprotection of the Tr group of compound 27 was
accomplished with a mixture of triethylsilane and TFA to
afford desired azaindazole 23 in good yield.
cmpd
R
X
bDNA
EC90a(ꢀM)
0.001
0.028
0.01
6
H
H
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21a
21b
CH2OH
H
CH2OH
(R) -F
H
CH3
0.28
cyclopropyl
COOH
H
>3.3
H
2.2
C=NOH
H
0.091
0.027
0.46
CH(OH)CH3(R/S)
CH(OH)CH3(R/S)
H
H
Scheme 4. Synthesis of compound 23
aThe concentration of test compound resulting in viral RNA
levels equal to that of 10% of the control wells was reported as
EC90.
The pyrimidine ring of 12 interacts by πꢀstacking with the side
chains of His 357, Phe 323 and Phe 404, while the cyclohexyl
group makes an important hydrophobic interaction of
hydrophobic region of the PB2 binding site.7 Additionally, the
hydroxy methyl group of 12 makes hydrogen bonds with Glu
361 and Arg 332. These new hydrogen bonds could explain
the potency difference between the hydroxy methyl group and
the methyl and cyclopropyl groups. The crystal structure of
12 in complex with PB2 helped generate hypotheses to explain
the SAR observed for the 2ꢀsubstituted 7ꢀazaindoles.
Coplanarity of the pyrimidine and the 7ꢀazaindole rings
appeared to be a requirement to ensure optimal πꢀstacking
between the pyrimidine ring and the phenyl ring of Phe 323.
One hypothesis was that the loss of affinity observed for the 2ꢀ
methyl and 2ꢀcyclopropyl analogs relative to the
corresponding unsubstituted compound could be due to the
conformational impact of the orthoꢀsubstitution, leading to a
preferred low energy conformation where the two rings were
not coplanar. As a result, the coplanar conformation required
for binding would have come with an energetic penalty,
resulting in a reduction in the free energy of binding. In order
to test this hypothesis we ran torsional scans around the 7ꢀ
azaindoleꢀpyrimidine bond using highꢀlevel quantum
mechanics. The calculations revealed that in the preferred
conformations for both the 2ꢀmethyl and the 2ꢀcyclopropyl
analogs the 7ꢀazaindole and pyrimidine rings remain coplanar,
thus invalidating the hypothesis. The Xꢀray crystal structure of
compound 16 bound to the PB2 subunit (Figure 3B) showed
that in the preferred conformation for 16, the 7ꢀazaindole and
pyrimidine rings remain coplanar. The second hypothesis was
that the 2ꢀmethyl group causes a partial desolvation of the
carboxylic group of Glu 361, and the resulting desolvation
penalty translates into a reduced free energy of binding. This
hypothesis is consistent with the further decrease in affinity
observed for the 2ꢀcyclopropyl analog 17, where the size of
the 2ꢀsubstitution is larger and the desolvation may extend to
the side chain of the neighboring Arg 332. The reason for loss
of potency of 19 is likely explained by the repulsion between
the carboxylic group of the ligand and Glu 361.
o
Reagents and conditions: (a) NIS, DCM, RT, 100 C, 2 h,
80%; (b) trityl chloride, K2CO3, DMF, RT, 18 h, 81%; (c)
bis(pinacolato)diboron, PdCl2(dppf).DCM, KOAc, DMF, 95
oC, 1 h, 100%; (d) 14, Pd2(dba)3, XꢀPhos, K3PO4, 2ꢀ
o
methylTHF, H2O,120 C, 2 h, 48%; (e) Et3SiH, 30 molꢀequiv
TFA, DCM, RT, 30 min, 92%.
Table 1 summarizes in vitro bDNA assay data for selected 2ꢀ
substituted azaindole analogs. Compounds 16 and 17 that
contain small alkyl substitutions such as methyl and
cyclopropyl at the 2ꢀposition led to a significant loss of
potency compared to the unsubstituted compound 6. However,
compound 12 containing hydroxymethyl substitution at the 2ꢀ
position maintained potency although not quite to the same
level as 6. Substituting a fluorine atom at the 3ꢀposition of the
pyrrolidine ring, compound 15 boosts the bDNA potency by 3ꢀ
fold relative to 12. We explored additional functional groups
that could potentially interact with neighboring amino acid
residues such as Glu 361 and Arg 332. Compound 19,
containing a carboxylic acid functional group at the 2ꢀposition
reduced potency compared to the hydroxymethyl compound
12 by ~100ꢀfold. Compound 20 containing an oxime moiety at
the 2ꢀposition showed similar bDNA potency (within 3ꢀfold)
when compared to compound 12. For the secondary alcohols,
one diastereomer 21a showed similar potency to 12 while the
other diastereomer 21b lost more than 10ꢀfold potency. The
four most potent compounds in this series contained a
hydroxyl group that may interact with neighboring amino acid
residues of PB2. We obtained the Xꢀray crystal structure of
compound 12 bound to the PB2 subunit (Figure 3A). As
expected, the azaindole ring of 12 is involved in two hydrogen
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metabolism to another site of the molecule and/or incurred
additional metabolic pathways.
1
2
3
4
5
6
7
Table 3. Human Liver Cytosol Stability of 7ꢀAzaindole and 7ꢀ
Azaindazole Analogs
cmpd
% Remaining@ 4h %Remaining @ 4h
without raloxifene
with raloxifene
4
7
103
8
6
4
99
9
12
15
16
21b
23
29
30
31
100
105
103
99
1
96
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114
103
99
Figure 3. A. Xꢀray crystal structure of 12 bound to PB2 (PDB
ID: 5BUH). B. Xꢀray crystal structure of 16 bound to PB2
(PBD ID: 5F79).
101
98
0.6
40
0
103
107
Table 2. 7ꢀAzaindazole based PB2 Inhibitors
We determined rat pharmacokinetic profiles of compounds 6,
12 and 23 as shown in Table 4.
Table 4. Rat and mouse pharmacokinetic parameters (PK) for
compound 6, 12 and 23
cmpd
R
bDNA
EC90a(ꢀM)
cmpd
6
12
23
Rat IV PK (1 mg/kg)
CL (mL/min/kg)
t1/2 (hr)
23
28
29
30
0.002
1.2
3.2
0.3
6.2
2.3
0.6
7.7
1.5
0.4
0.014
0.001
0.015
Vss (L/kg)
Rat PO PK (3mg/kg) Dosea
AUC0ꢀinf (µg.h/mL)
Cmax (µg/mL)
%F
30.3
2.6
82
9.7
2.8
100
1.2
31
32
0.001
0.003
0.2
15.3
Mouse PO PK (30mg/kg)
AUC
aThe concentration of test compound resulting in viral RNA
levels equal to that of 10% of the control wells was reported as
EC90.
336
101
44.5
32.1
Cmax (µg/mL)
61.1
37.7
All three compounds showed promising PK profiles with IV
clearance values of 1.2, 6.2 and 7.7 mL/min/kg, respectively.
The 7ꢀazaindole urea 6 showed the highest oral exposure and
the 2ꢀhydroxymethyl analog 12, showed 3ꢀfold lower AUC
with a similar Cmax as 6. The 7ꢀazaindazole 23, showed
significantly reduced exposures as measured by both AUC and
Cmax relative to 6 and 12. When we dosed compounds 6, 12
and 23 in mice (30 mg/kg), we also observed a significant loss
in exposure from the 7ꢀazaindole to 7ꢀazaindazole with a 2ꢀ
fold loss in Cmax and 7ꢀfold loss in AUC in mice (30 mg/kg).
While attempts at blocking AO metabolism were not
demonstrated by improved pharmacokinetics in these rodent
studies, AO is known to exhibit large species differences with
high levels in human and monkey and low levels in rat and
mouse.9 Thus, the in vitro results suggest the possibility of
improved human pharmacokinetics for some of these 2ꢀ
substituted 7ꢀazaindoles.
A small set of 7ꢀazaindazole analogs were designed and
synthesized to explore different substituents on the cyclohexyl
ring system (Table 2). The pyrrolidine and morpholine ureas,
compounds 23 and 28 respectively were both potent and
showed similar potency trends to those observed in the 7ꢀ
azaindole series. Additionally, the amides 30 and 31 showed
good potency with the thiophene amide 31, matching the best
potency of urea 29. We also synthesized the 7ꢀazaindazole
analog 32 of 2 and retained potency relative to the 7ꢀ
azaindole.7
To determine whether AOꢀmediated metabolism of these new
2ꢀposition substituted azaindole and azaindazole analogs had
been modulated, selected analogs were incubated in triplicate
at 1 µM in 1 mg/mL human liver cytosol protein at 37 °C for 4
hours, with and without the AO inhibitor, Raloxifene. The
results are summarized in Table 3. All of the tested
compounds were stable in human liver cytosol in the presence
of raloxifene. Most of the 2ꢀposition substituted azaindole
analogs including 12, 15, 16 and 21b appeared to be very
stable without raloxifene in cytosol. Surprisingly, most of the
azaindazole analogs were unstable in cytosol, except acidic
compound 32. It is possible that incorporation of the extra ring
nitrogen in the azaindole ring has shifted AOꢀmediated
In summary, our efforts to block the observed metabolism at
the 2ꢀposition of the 7ꢀazaindole ring involved an explorative
strategy which functionalized the 2ꢀposition or incorporated a
ring nitrogen atom at the 2ꢀposition. We discovered that
certain functionalities containing a specifically placed Hꢀbond
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donor such as 12, 20 and 21a maintained cellular potency. recommendations of the advisory committee on immunization
1
2
3
4
5
6
7
8
Moreover, 2ꢀsubstituted 7ꢀazaindole analogs showed excellent
stability in human liver cytosol. The 7ꢀazaindazole
modifications resulted in equipotent analogs, however these
compounds were less stable in the human cytosol assay and
are likely substrates for AOꢀmediated metabolism. We
identified compound 12 with enhanced in vitro metabolic
stability in human liver cytosol and a favorable oral
pharmacokinetic profile in both rat and mouse in vivo studies.
Thus, the data supports and warrants advancement of
compound 12 for further evaluation for the treatment of
influenza.
practices (ACIP), 2008. MMWR Recomm Rep 57: 1–60.
2. Li, Q.; Zhou, L.; Zhou, M.; Chen, Z.; Li, F.; Wu, H.; Xiang,
N.; Chen, E.; Tang. F.; Wang, D.; Meng, L.; Hong, Z.; Tu, W.;
Cao, Y.; Li, L.; Ding, F.; Liu, B.; Wang, M.; Xie, R.; Gao, R.;
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S.; Gao, Y.; Jin, L.; Zhang, Y.; Luo, H.; Yu, H.; Gao, L.;
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ABBREVIATIONS
Howley, P.M., Ed.; Lippincott Williams
& Wilkins:
Philadelphia, PA, 2001,1487.
dppf=1,1'ꢀbis(diphenylphosphino)ferrocene,
DCM=dichloromethane,
DPPA=diphenylphosphorylazide,
4. Moscona, A. Neuraminidase inhibitors for influenza.
NIS=Nꢀiodoscucinimide, THP=tetrahydropyranyl acetal,
N.Engl. J.Med. 2005, 353, 1363ꢀ1373.
Tr=trityl,
triisopropylbiphenyl
Xꢀphos=2ꢀdicyclohexylphosohinoꢀ2′,4′,6′ꢀ
5. Thorland, K.; Awad, T.; Boivin, G.; Thabane, L. Systematic
review of influenza resistance to the neuraminidase inhibitors.
BMC Infect. Dis. 2011, 1,134ꢀ147.
ASSOCIATED CONTENT
6. Imai, M.; Watanabe, T.; Hatta, M.; Das, S.C.; Ozawa, M.;
Shinya, K.; Zhong, G.; Hanson, A.; Katsura, H.; Watanabe, S.;
Li, C.; Kawakami, E.; Yamada, S.; Kiso, M.; Suzuki, Y.;
Maher, E. A.; Neumann, G.; Kawaoka, Y. Experimental
adaptation of an influenza H5 HA confers respiratory droplet
transmission to a reassortment H5 HA/H1N1 virus in ferrets.
Nature 2012 486, 420ꢀ428.
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI:ꢀꢀꢀꢀꢀ Experimental
procedures and analytical data for compounds 7ꢀ32; Xꢀray
crystallographic data (12 and 16); Protocols for bDNA cellular
assays and Cytosol Stability assay.
7. Clark, M. P.; Ledeboer, M. W.; Davies, I.; Byrn, R. A.;
Jones, S. M.; Perola, E.; Tsai,A.; Jacobs, M.; NtiꢀAddae, K.;
Bandarage, U. K.; Boyd, M J.; Bethiel, R. S.; Court, J. J.;
Deng, H.; Duffy, J. P.; Dorsch, W. A.; Farmer, L. J.; Gao, H.;
Gu, W.; Jackson, K.; Jacobs, D. H.; Kennedy, J. M.; Ledford,
B.; Liang, J.; Maltais, F.; Murcko, M.; Wang, T.;
Wannamaker, M. W.; Bennett, H. B.; Leeman, J. R.; McNeil,
C.; Taylor, W. P.; Memmott, C.; Jiang, M.; Rijnbrand, R.;
Bral, C.; Germann, U.; Nezami, A.; Zhang, Y.; Salituro, F.
G.; Bennani, Y. L; Charifson, P. S. Discovery of a novel, firstꢀ
inꢀclass, orally bioavailable azaindole inhibitor (VXꢀ787) of
influenza PB2.
AUTHOR INFORMATION
Corresponding Author
* Eꢀmail: upul_bandarage@vrtx.com.
Notes
The authors declare no competing financial interest.
Present Addresses
aSage Therapeutics, Inc. 215 First St, Cambridge, MA 02142,
b
USA, Goldfinch Bio, 215 First St, 4th Floor, Cambridge, MA
c
02142, USA, Moderna Therapeutics, Inc. 200 Technology
J. Med. Chem. 2014, 57, 6668ꢀ6678.
Square, Cambridge, MA 02139, USA, dContrafect
Corporation, 28 Wells Ave, 3rd floor, Yonkers, New York
8. Liang, J.L.; Cochran, J.E.; Dorsch, W.A.; Davies, I.; Clark,
M.P. Development of a scalable synthesis of an azaindolylꢀ
pyrimidine inhibitor of influenza virus replication. Org.
Process Res. Dev. 2016, 20, 965ꢀ969.
e
10701, USA, Vertex Pharmaceuticals Incorporated (Canada)
Inc., 275 ArmandꢀFrappier, Laval, Quebec H7V 4A7, Canada.
9. Pryde, D.C.; Dalvie, D.; Hu, Q.; Jones, P.; Obach, R.S.;
Tran,T.D, Aldehyde oxidase: an enzyme of emerging
importance in drug discovery. J.Med. Chem.2010, 53, 8441ꢀ
8460.
ACKNOWLEDGMENTS
The authors thank Barry Davis and Frank Holland for
analytical chemistry support and Jeremy Green and Simon
Giroux for helpful discussions.
10. Zetterberg,C.; Maltais, F.; Laitinen, L.; Liao, S.; Tsao, H.;
Chakilam, A.; Hariparsad, N. VXꢀ509 (Decernotinib)ꢀ
Mediated CYP3A timeꢀdependent inhibition: An aldehyde
oxidase metabolite as a perpetrator of drugꢀdrug interactions.
Drug. Metab. Dispos. 2016, 44, 1286-1295.
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