Discovery of benzophosphadiazine drug candidate IDX375: A novel hepatitis C allosteric NS5B RdRp inhibitor

Article abstract of DOI:10.1016/j.bmcl.2017.01.017

Hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase (RdRp) plays a central role in virus replication. NS5B has no functional equivalent in mammalian cells, and as a consequence is an attractive target for selective inhibition. This paper describes the discovery of a novel family of HCV NS5B non-nucleoside inhibitors inspired by the bioisosterism between sulfonamide and phosphonamide. Systematic structural optimization in this new series led to the identification of IDX375, a potent non-nucleoside inhibitor that is selective for genotypes 1a and 1b. The structure and binding domain of IDX375 were confirmed by X-ray co-crystalisation study.

Full text of DOI:10.1016/j.bmcl.2017.01.017

Accepted Manuscript
Discovery of Benzophosphadiazine Drug Candidate IDX375: A Novel Hepatitis
C Allosteric NS5B RdRp Inhibitor
Jean-Laurent Paparin, Agnès Amador, Eric Badaroux, Stéphanie Bot, Catherine
Caillet, Thierry Convard, Daniel Da Costa, David Dukhan, Ludovic Griffe,
Jean-François Griffon, Massimiliano LaColla, Frédéric Leroy, Michel Liuzzi,
Anna Giulia Loi, Joe McCarville, Valeria Mascia, Julien Milhau, Loredana
Onidi, Claire Pierra, Rachid Rahali, Elodie Rosinosky, Efisio Sais, Maria Seifer,
Dominique Surleraux, David Standring, Cyril B. Dousson
PII:
S0960-894X(17)30029-X
http://dx.doi.org/10.1016/j.bmcl.2017.01.017
BMCL 24593
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
7 November 2016
6 January 2017
8 January 2017
Please cite this article as: Paparin, J-L., Amador, A., Badaroux, E., Bot, S., Caillet, C., Convard, T., Da Costa, D.,
Dukhan, D., Griffe, L., Griffon, J-F., LaColla, M., Leroy, F., Liuzzi, M., Giulia Loi, A., McCarville, J., Mascia, V.,
Milhau, J., Onidi, L., Pierra, C., Rahali, R., Rosinosky, E., Sais, E., Seifer, M., Surleraux, D., Standring, D., Dousson,
C.B., Discovery of Benzophosphadiazine Drug Candidate IDX375: A Novel Hepatitis C Allosteric NS5B RdRp
Inhibitor, Bioorganic & Medicinal Chemistry Letters (2017), doi: http://dx.doi.org/10.1016/j.bmcl.2017.01.017
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Discovery of Benzophosphadiazine Drug Candidate
IDX375: A Novel Hepatitis C Allosteric NS5B RdRp
Inhibitor
Leave this area blank for abstract info.
Jean-Laurent Paparina, , Agnès Amadorb, Eric Badarouxb, Stéphanie Bota, Catherine Cailletb,Thierry
Convardb, Daniel Da Costaa, David Dukhana, Ludovic Griffeb, Jean-François Griffona, Massimiliano
LaCollab, Frédéric Leroyb, Michel Liuzzib, Anna Giulia Loib, Joe McCarvilleb, Valeria Masciab, Julien
Milhaua, Loredana Onidib, Claire Pierraa, Rachid Rahalia, Elodie Rosinoskyb, Efisio Saisb, Maria
Seiferb, Dominique Surlerauxb, David Standringb and Cyril B. Doussona

Bioorganic & Medicinal Chemistry Letters
Discovery of Benzophosphadiazine Drug Candidate IDX375: A Novel Hepatitis
C Allosteric NS5B RdRp Inhibitor
Jean-Laurent Paparina, , Agnès Amadorb, Eric Badarouxb, Stéphanie Bota, Catherine Cailletb,Thierry
Convarda, Daniel Da Costaa, David Dukhana, Ludovic Griffeb, Jean-François Griffona, Massimiliano
LaCollab, Frédéric Leroyb, Michel Liuzzib, Anna Giulia Loib, Joe McCarvilleb, Valeria Masciab, Julien
Milhaua, Loredana Onidib, Claire Pierraa, Rachid Rahalia, Elodie Rosinoskyb, Efisio Saisb, Maria Seiferb,
Dominique Surlerauxb, David Standringb and Cyril B. Doussona
a Idenix SARL, an MSD Company, Medicinal Chemistry Laboratory, Cap Gamma, 1682 rue de la Valsière, BP50001, 34189 Montpellier Cedex 4 - France.
b Former Idenix employee
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
Hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase (RdRp) plays a central role in
virus replication. NS5B has no functional equivalent in mammalian cells, and as a consequence
is an attractive target for selective inhibition. This paper describes the discovery of a novel
family of HCV NS5B non-nucleoside inhibitors inspired by the bioisosterism between
sulfonamide and phosphonamide. Systematic structural optimization in this new series led to the
identification of IDX375, a potent non-nucleoside inhibitor that is selective for genotypes 1a and
1b. The structure and binding domain of IDX375 were confirmed by X-ray co-crystalisation
study.
Keywords:
Hepatitis C virus
Direct-acting antivirals
NS5B non-nucleoside inhibitors
Allosteric inhibitors
Phosphadiazines
2016 Elsevier Ltd. All rights reserved.
Phophorylated bioisosteres
Thiadiazine bioisosteres
IDX375
———
 Corresponding author. Tel.: +33-(0)-499-52-22-52-; fax: +33-(0)-499-52-22-50; e-mail: jean-laurent.paparin@merck.com

Chronic hepatitis C virus (HCV) infection is a significant
medical concern globally, and was first identified in 1989 as a
positive-stranded RNA virus of the Flaviridae family.1 According
to the World Health Organization, HCV has already infected
approximately 180 million people (around 3% of the worldwide
population) and nearly 4 million new infections occur annually.2
and Gly410, and the methyl sulfonamide group incorporated at at
C-7 significantly improves the polymerase binding affinity of the
whole series.9c In the same year, Setrobuvir (3, ANA-598)
demonstrated efficacy in Phase I clinical trials,10a but its structure
was only disclosed in 2011 when Roche acquired Anadys10b and
a review was published on this chemotype. 10c
A majority of HCV infections progress to chronic liver problems
such as cirrhosis and hepatocellular carcinoma requiring liver
transplantation, with morbidity and mortality rates projected to
double in this decade.3 Recent reviews have comprehensively
described the current state of research in the field and emphasize
the critical growing medical need for the development of
combination therapies.4
In 2011, Idenix disclosed11 a novel series of HIV-1 non-
nucleoside reverse transcriptase inhibitors, among other
phosphorous-based bioisosteres, featuring a 3-arylphosphoindole
bearing
a
key phosphinate moiety as
a
sulfonamide
replacement.12 This work led to the discovery of NNRTI
Fosdevirine (IDX899) and demonstrated the potential of the
phosphorous chemistry as bioisostere strategy. The replacement
of key pharmacophores with bioisosteres is an important tool in
medicinal chemistry that can be leveraged to improve potency,
selectivity, physicochemical properties and the pharmacokinetic
profile of key compounds.12
Drugs targeting three major classes of HCV drug target have
reached clinical trials: NS3/4A serine protease inhibitors, NS5A
phosphoprotein inhibitors, and two main categories of HCV
NS5B RdRp inhibitors, which include active site nucleoside
prodrugs and allosteric non-nucleoside inhibitors.5
When we started this HCV project in 2006, we chose to
explore a novel phosphodiazine series based on thiadiazine 2,
seeking to alter the physicochemical properties of the scaffold
and to harness the chiral center of the phosphorous atom to
further probe the polymerase binding site. We report herein the
synthesis and optimization of this benzophosphodiazine series,
which led to the discovery of IDX375.
In 2002, GlaxoSmithKline reported several new classes of
non-nucleoside benzothiadiazine-substituted quinolinedione
HCV polymerase inhibitors (Figure 1, 1) with nanomolar IC50’s.6
These molecules bind to the ‘‘palm” region of NS5B, also now
known as the allosteric site 4, located within the -hairpin loop
(Palm site II) and in close proximity to the active site, thought to
be involved in primer-independent initiation of RNA replication.7
When we initiated our efforts, few synthetic examples
describing this scaffold class were reported.13 To this end, we
developed a short and convergent synthetic route, first inspired
by Palacios publications,13a,b to access this new family of
products.14 The key step of the synthesis features a condensation
between a phosphinate and a nitrile (obtained from chiral
aminoester), activated with trimethyl aluminium. Our general
convergent route for the preparation of substituted
benzophosphodiazines is presented in Scheme 1.
A parallel synthetic effort was reported subsequently by
researchers at Roche, highlighting the discovery of tetramic acid
derivatives as potential mimetics for the quinolinone moiety
(Figure 1, 2).8
The synthesis of the tetramic acid moeity starts with a
reductive amination between diverse amino acid methyl esters 4
and aldehydes 5. Condensation with cyanoacetic acid 7 and
cyclisation of intermediate 8 under basic conditions yield the
desired substituted cyano-tetramic acid 9. The synthesis of the
second moiety begins with substituted 1-nitro-2-phenyl
compound 10 or directly from the corresponding bromo-aniline
13, with palladium-catalyzed substitution providing the desired
phosphinate moiety 12. Finally, the benzophosphodiazine core 14
is obtained as a mixture of diastereomers by condensation of 9
and 12 in the presence of trimethyl aluminium.
Figure 1. Thiadiazines Inhibitors of HCV polymerase
In 2009, still Roche reported9 the synthesis and evaluation of
benzothiazine analogs and published
a crystal structure
confirming that these thiazines bind in the “palm” site of the
NS5B polymerase near the catalytic site. The quinolinedione
phenyl projects into an hydrophobic pocket formed by Met414
Scheme 1. Convergent synthesis of benzophosphodiazines. Reagents and conditions: (a) NaBH3CN, TEA, MeOH, rt; (b) DCC,
CH2Cl2, DMF, rt; (c) tBuOK, tBuOH, rt, 1h; (d) P(OEt)3, Pd(OAc)2, CH3CN, 160°C, 30min microwaves; (e) H2, Pd/C, MeOH,
rt; (f) AlMe3, dioxane, 80°C, 3h.

Scheme 1 presents the synthesis with ethylphosphinate
derivatives only as they were found to provide the most active
compounds (see Figure 2). In addition, their improved chemical
stability over methyl phosphinate derivatives and their potential
to liberate ethanol as a benign metabolite provided additional
support for this core.
H
H
0.055
0.216
>1500
>350
0.067
0.097
0.008
0.007
28
29
H
5.510
>13
0.728
0.040
30
Me
H
H
6.950
0.610
>10
0.961
0.227
0.021
0.024
31
32
As exemplified in Table 1, a large range of core substitutions
were evaluated off the tetramic acid. Monosubstitution with
cycloalkyl groups (Table 1, Entries 27–30) and alkyl groups
(Table 1, Entries 31–34) were discovered to be the only
functionalities providing acceptable 1b-HCV polymerase
inhibition. However, this discovery was made subsequent to our
initial optimization studies. As such, we learned that large
aromatic moieties and polar groups (Table 1, Entries 15–20)
yielded poor potencies. Additionally, disubtituted tetrameric
acids bearing cycloalkyl and alkyl disubstitution (Table 1, Entries
21–26), although lipophilic, exhibited poor potency in the cell
replicon assay. Finally, we idenitified t-butyl to be an optimal
substituent, and favoured in the cell replicon assay, with 34
exhibiting an EC50 = 0.009 M.
>123
H
H
0.842
0.009
>89
0.247
0.059
0.012
0.012
33
34
>8333
a Inhibition of HCV replication cells in the HCV Replicon Luciferase assay;
EC50 values were determined from 50% inhibition versus concentration data.
b Biochemical assay for inhibition capacity on the 1a-H77 HCV NS5B
polymerase; IC50 values were determined from the percent inhibition versus
concentration data.
c Biochemical assay for inhibition capacity on the 1b-J4 HCV NS5B
polymerase; IC50 values were determined from the percent inhibition versus
concentration data.
d Selectivity index (CC50/ EC50)
n.d.: not determined
Table 1. R1, R2 substitution-based SAR
With optimal substitution identifed at R1 and R2, we
examined the SAR of the C7 R4 position based on our most
potent lead, 34. While we identified interesting analogs
exhibiting H-bond donor properties (Table 2, Entries 42–46),
none of these substituents provided any improvement in
compound Gt1a,1b potency, as shown in Table 2.
Table 2. R4 substitution-based SAR
a
b
c
R1
R2
H
EC50
SId
>9
IC50
IC50
(M)
(M)
Gt-1a
(M)
Gt-1b
>8.300
1.143
0.300
15
H
H
>8.300
>8.300
>9
>9
2.597
0.972
0.490
0.200
16
17
R4
EC50a (M)
SId
IC50b (M) IC50c (M)
Gt-1a
Gt-1b
35
36
37
38
39
40
41
H
F
3.418
4.800
6.158
3.269
4.400
>8.300
3.180
5
6
3.534
3.609
n.d.
0.044
0.116
H
H
>8.300
>8.300
>9
>9
4.540
1.311
0.021
0.055
18
19
OMe
NH2
Me
CF3
CN
3
0.707
>20
4
3.727
>10.000
n.d.
0.114
0.451
H
>8.300
4.390
>9
n.d.
0.915
0.064
3<
12
>10.000
0.085
20
21
4.959
Me
>17
1.363
7.930
0.130
>9
2.951
0.182
0.279
0.017
42
43
Et
Me
Me
Me
>8.300
>8.300
>8.300
>9
>9
>9
n.d.
>10.000
n.d.
0.800
0.183
1.370
22
23
24
>576
CF3
Me
0.019
0.056
>3947
>1339
0.817
n.d.
0.065
0.008
45
5.514
0.185
1.204
>13
278
>62
5.327
0.186
0.206
0.187
0.006
0.012
25
26
27
46 NHSO2NH2
a Inhibition of HCV replication cells in HCV Replicon Luciferase assay;
EC50 values were determined from 50% inhibition versus concentration data.
H

b Biochemical assay for inhibition capacity on the 1a-H77 HCV NS5B
polymerase; IC50 values were determined from the percent inhibition versus
concentration data.
0.039
>8.300
>8.300
>1923
>9
0.020
1.002
8.126
0.009
0.065
0.091
56
57
58
c Biochemical assay for inhibition capacity on the 1b-J4 HCV NS5B
polymerase; IC50 values were determined from the percent inhibition versus
concentration data.
d Selectivity index (CC50/ EC50)
>9
n.d.: not determined
a Inhibition of HCV replication cells in HCV Replicon Luciferase assay;
EC50 values were determined from 50% inhibition versus concentration data.
Finally, we turned our attention to optimization of the R3
position. Diverse substituted benzyl groups were evaluated along
with simple alkyl chains in order to optimally occupy the
aforementioned hydrophobic pocket. As shown in Table 3, all
compounds displayed reasonable activity. Interestingly, the
benzyl subseries (Table 3, Entried 50–56) was favored in the
polymerase enzymatic assay while the replicon cell-based assay
indicated a slight advantage to the neohexyl chain (Table 3, Entry
34). It is noteworthy that changing from a terminal isopropyl
(Table 3, Entry 49) to a t-butyl (Table 3, Entry 34) provided a
10- fold improvement in activity in the replicon assay, providing
our optimal lead benzophosphadiazine. More polar heteroaryl
replacements of the phenyl were detrimental to the replicon
activity, likely due to poor cell penetration.
b Biochemical assay for inhibition capacity on the 1a-H77 HCV NS5B
polymerase; IC50 values were determined from the percent inhibition versus
concentration data.
c Biochemical assay for inhibition capacity on the 1b-J4 HCV NS5B
polymerase; IC50 values were determined from the percent inhibition versus
concentration data.
d Selectivity index (CC50/ EC50)
Through our optimization efforts, we generated a large array
of compounds all of which were evaluated for in vitro potency in
the NS5B polymerase and replicon assay. An overview of our
structure activity relationship (SAR) studies based on EC50 is
presented in Figure 2.
Table 3. R3 substitution-based SAR
R3
EC50a (M)
SId
IC50b (M)
Gt-1a
IC50c (M)
Gt-1b
1.003
>75
0.167
0.007
47
Figure 2. General benzophosphadiazine SAR
0.126
0.095
>595
>789
0.080
0.040
0.014
0.010
48
49
We have found this qualitative SAR as a useful tool for
structure optimization. Indeed, we can see clearly that R1= t-Bu is
prefered over all alkyls across substitution patterns. In addition,
the SAR at R4 directed us toward hydrogen bond donors in
position 7, with a simple methanesulfonyl group being optimal.
Finally, further R5 optimization guided us to select the ethyl
phosphonate as optimal, as previously discussed in this
publication.
0.090
0.044
>833
0.057
0.031
0.008
0.015
50
51
>1704
Ultimately, the mixture of isomers of 34 was separated by
chiral preparative purification and yielded four individual
diastereoisomers (compounds 59-62) whose the stereochemistry
was confirmed by X-ray crystallography (vide infra).
0.162
0.018
>462
0.104
0.015
0.006
0.005
52
53
Table 4. Selection of the optimal diastereoisomer for
>4166
preclinical studies
Compound
Stereo-
EC50a (M)
SId
IC50b (M) IC50c (M)
chemistry
Gt-1a
Gt-1b
0.015
0.031
>5000
>2419
0.017
0.028
0.005
0.006
54
55
59
60
61
62
R, Sp
S, Sp
R, Rp
S, Rp
1.397
0.003
0.568
1.390
>53
>25000
>132
>53
1.757
0.012
0.015
0.324
1.757
0.005
0.014
0.701
a Inhibition of HCV replication cells in HCV Replicon Luciferase assay;
EC50 values were determined from 50% inhibition versus concentration data.

b Biochemical assay for inhibition capacity on the 1a-H77 HCV NS5B
polymerase; IC50 values were determined from the percent inhibition versus
concentration data.
Figure 4. Binding pocket of HCV NS5b (N316Y) containing
ligand IDX375 (PDB code: 4EAW) compared to
a
benzothidiazine (PDB code: 3G86) 9c.
c Biochemical assay for inhibition capacity on the 1b-J4 HCV NS5B
polymerase; IC50 values were determined from the percent inhibition versus
concentration data.
From preclinical studies, in three days cell-based replicon
assay, IDX375 generally showed additivity in combination with
the HCV PI IDX320 or the nucleotide IDX184, but exhibited
very strong synergy when combined with both classes of direct
acting antiviral agents.15
d Selectivity index (CC50/ EC50)
We found the most potent diastereoisomer to be compound
60 which was elected as lead candidate and named IDX375: IC50
1a&1b = 0.015 M & 0.005 M with EC50 = 0.003 M and was
inactive against all tested human cellular polymerases (>75M).
According to its promising profile, IDX375 was profiled in
vivo and PK data were supportive of further development leading
to its selection as clinical candidate. Importantly, significant
plasma exposures were obtained following oral administration in
the rodent and cynomolgus monkey (Table 5).
In order to study its interactions with the viral protein, co-
crystals were obtained (PDB code: 4EAW) and binding to the
“palm” domain was confirmed. The PDB ID: 4EAW (backbone
and carbons of residues in cream and ligand colored by elements,
water in red) binding interaction is compared to those of PDB ID:
3G869c (backbone, carbons of residues and carbons of ligand in
light green, water in blue). These active sites differ in the residue
at position 316, which is a Tyr in 4EAW and an Asn in 3G86.
Table 5. Good PK and exposures levels in rodent and monkey
Dose
(mg/kg)
10
Cmax Tmax AUCinf/dose T1/2
Cl
(L/h/kg)
0.84
F%
(ng/mL)
(h)
(ng*h/mL) (h)
Monkey
Mouse
Rat
2251
569
4
4
4
11915
3287
4077
5.5
5.1
1.3
28
35
16
15
1.58
Despite this difference we observe a number of binding
similarities in both crystal structures. In particular, the same kind
of hydrogen bonding interaction between the nitrogen backbone
of Tyr448 and the tetramic acid or the hydroxyl of the phenol are
observed in both structures. In addition, both also bind through a
water molecule to Gln446 and Gly449. The benzophosphadiazine
ring system also interacts in a T-shaped π-stacking mode with
Phe193 (which one is also stabilized by two similar T-shaped
π-stacking interactions), similar to the benzothiadiazine ring
system.
15
2210
0.61
In summary, investigation of benzophosphadiazine
derivatives, inspired by their potential to be bioisosteres of
thiadiazine analogs, led to the discovery of a new class of potent
HCV NS5B inhibitors and a new phosphorylated bioisostere.
Systematic optimization around the scaffold led to the discovery
of our lead compound 60 (IDX375), which displayed excellent
antiviral activity on the genotypes 1a and 1b, and a good PK
profile in multiple animal models. Critical interactions with the
viral protein at the NS5B PalmII domain were confirmed by co-
crystallization X-ray studies. While its further clinical
development was discontinued in favour of pan-genotypic direct
antiviral agents, IDX375 monotherapy achieved a significant
reduction in HCV RNA level (up to 2.7 log) in a 3-day proof of
concept study in HCV genotype 1 infected.16
The sulfonamide group makes two hydrogen bonds with the
carboxamide nitrogen of Asn291 (interatomic distance dO-N
=
2.94Å) and the carboxylate group of Asp318 (dO-O= 3.0Å).
Finally, in both crystal structures, the neohexyl chain and the the
fluorobenzyl moiety are well positioned in the known
hydrophobic pocket formed by M414, Cys366 and Tyr415
(Figure 4).
Based on the analysis of these crystal structures,
benzophosphadiazines and benzothiadiazines are structurally
similar bioisosteres for this binding pocket.
Acknowledgments
We thank Proteros Biostructure GmbH, Dr. Martin Augustin for
X-ray structure determination of HCV NS5B polymerase in
complex with the ligand (60). We also thank our many
colleagues and our HCV discovery and development teams at
Idenix Pharmaceuticals. Finally, J.L. Paparin thanks Izzat
Raheem and Sylvie Capelle for their invaluable assistance.
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