Discovery of a new HIV-1 inhibitor scaffold and synthesis of potential prodrugs of indazoles

Article abstract of DOI:10.1016/j.bmcl.2013.03.075

A new oxazole scaffold showing great promise in HIV-1 inhibition has been discovered by cell-based screening of an in-house library and scaffold modification. Follow-up SAR study focusing on the 5-aryl substituent of the oxazole core has identified 4k (EC₅₀ = 0.42 μM, TI = 50) as a potent inhibitor. However, the analogues suffered from poor aqueous solubility. To address this issue, we have developed broadly applicable potential prodrugs of indazoles. Among them, N-acyloxymethyl analogue 11b displayed promising results (i.e., increased aqueous solubility and susceptibility to enzymatic hydrolysis). Further studies are warranted to fully evaluate the analogues as the potential prodrugs with improved physiochemical and PK properties

Full text of DOI:10.1016/j.bmcl.2013.03.075

Bioorganic & Medicinal Chemistry Letters xxx (2013) xxx–xxx
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of a new HIV-1 inhibitor scaffold and synthesis of potential
prodrugs of indazoles
a
a
a
a
Se-Ho Kim a, , Benjamin Markovitz , Richard Trovato , Brett R. Murphy , Harry Austin ,
⇑
Adam J. Willardsen a, Vijay Baichwal a, Scott Morham b, Ashok Bajji a
a Myrexis Inc., 305 Chipeta Way, Salt Lake City, UT 84108, United States
b MesaGen LLC, 2500 South State Street, South Salt Lake, UT 84115, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A new oxazole scaffold showing great promise in HIV-1 inhibition has been discovered by cell-based
screening of an in-house library and scaffold modification. Follow-up SAR study focusing on the 5-aryl
substituent of the oxazole core has identified 4k (EC50 = 0.42 lM, TI = 50) as a potent inhibitor. However,
the analogues suffered from poor aqueous solubility. To address this issue, we have developed broadly
applicable potential prodrugs of indazoles. Among them, N-acyloxymethyl analogue 11b displayed prom-
ising results (i.e., increased aqueous solubility and susceptibility to enzymatic hydrolysis). Further studies
are warranted to fully evaluate the analogues as the potential prodrugs with improved physiochemical
and PK properties
Received 23 January 2013
Revised 13 March 2013
Accepted 20 March 2013
Available online xxxx
Keywords:
HIV
Drug target
Oxazoles
Ó 2013 Elsevier Ltd. All rights reserved.
Prodrugs of indazoles
The HIV life cycle encompasses a variety of steps (e.g., attach-
ment to the host cell, viral entry, proviral integration, gene expres-
sion to viral budding) and many stages in the life cycle have
already been exploited in the search for better HIV inhibitors,
resulting in the discovery of ꢀ30 approved drugs for the treatment
of this pandemic disease.1 However, there is still an urgent need for
new HIV drug discovery with novel modes of action due to the
rapid emergence of drug resistance in HIV patients.2
lead-like5 characteristics (MW 6400, rings 64, hydrogen-bond do-
nors 65, hydrogen-bond acceptors 69, and logP 1.9–5.5), exhibited
some cytoprotective effect (EC50 of 6–13 lM, MT4 cells) and can
serve as a starting point for chemical modifications (Fig. 1). Struc-
turally, compounds 1–3 have similar pharmacophore features.
Each compound commonly contains an aminoindazole ring and
an aryl ring, but its structure differs in core (piperidine, quinazo-
line, and urea for 1, 2, and 3, respectively).
With an aim to find a new chemical scaffold with HIV-1 inhib-
itory activity, we screened an in-house library consisting of small
molecular weight (MW <500) compounds using an MT4 cell-based
assay. An MT4 cytoprotection assay has the advantage of detecting
compounds inhibiting all stages of HIV life cycles; this provides
greater possibilities in identifying a novel chemical structure with
a unique mechanism of action. Recently, such traditional cellular
phenotypic screening approaches are gaining increased attention
for drug discovery due to the advantage in discovering first-in class
drugs as compared to target-based screening.3 Furthermore, recent
advances in chemical proteomic technology now enable faster,
more efficient target identification after phenotypic screening.4
After screening of the library using the MT4 cytoprotection
assay, we identified compounds 1–3 which have relatively good
Initial screening results indicated that the modification of the
core structure could be an effective lead optimization approach
and this consideration prompted us to investigate a scaffold morp-
hing strategy.6 Consequently, oxazole 4a was designed based on
the structure of urea 3, synthesized, and evaluated (Scheme 1).
To our delight, oxazole 4a exhibited improved potency and a wider
therapeutic index (EC50 = 2 lM, TI >45). Encouraged by this result,
we initiated a SAR study around this scaffold to find more potent
and non-toxic HIV-1 inhibitors that can ultimately be used to iden-
tify the molecular target and understand the mechanism of HIV-1
inhibition.
Herein we report the synthesis and SAR study of the oxazole
scaffold as well as the design and synthesis of potential prodrugs
of indazoles that were developed in an effort to improve the aque-
ous solubility of the analogues.
A representative example depicted in Scheme 2 is the synthesis
of analogue 4d. We used an iminophosphorane-mediated cycliza-
tion for the 2-aminooxazole ring formation.7 Isothiocyanate 6
was conveniently prepared by treatment of aminoimidazole 5 with
Abbreviations: CDKs, cyclin-dependent kinases; CKII, casein kinase 2; DMAP,
dimethylaminopyridine; EDCI, N-ethyl-3-(3-dimethylaminopropyl)carbodiimide
hydrochloride; LIMK, LIM kinases; PK, pharmacokinetics; TFA, trifluoroacetic acid.
⇑
Corresponding author. Tel.: +1 801 733 9791; fax: +1 801 214 7991.
E-mail address: seho.kimkim@gmail.com (S.-H. Kim).
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.03.075
Please cite this article in press as: Kim, S.-H.; et al. Bioorg. Med. Chem. Lett. (2013), http://dx.doi.org/10.1016/j.bmcl.2013.03.075

2
S.-H. Kim et al. / Bioorg. Med. Chem. Lett. xxx (2013) xxx–xxx
H
N
N C S
NH2
H
N
a
b
N
N
N
N
H
N
H
F
HN
N
N
H
6
N
5
7
N
F
O
O
N
N3
Br
2
1
NO2
OMe
M
Cl
N
μ
M
EC50 = 13
Cl
μ
EC50 = 11
TI = 10
8
TI = 10
c
4d
+
8
NO2
6
H
N
H
N
N
C
O
N
O
F
N
N
H
N
H
3
μ
EC50 = 6
TI = 15
M
Cl
9
Figure 1. Hits identified through the MT4-cell cytoprotection assay.
Scheme 2. Reagents and conditions: (a) 1,10-thiocarbonyldi-2(1H)-pyridone (or
thiocarbodiimidazole), CH2Cl2, rt, 2 h, 64%; (b) NaN3, acetone/water, 50 °C, 0.5 h,
92%; (c) PPh3, dioxane, 90 °C, 0.5 h, 85%.
H
NO2
N
N
H
N
H
N
O
N
N
N
H
O
F
N
H
was found to be the most potent compound in this series. Methyl-
3
4a
enedioxyphenyl analogue 4h maintained potency (EC50 = 2.7
and 3,4-dichlorophenyl analogue 4j resulted in a big loss in
potency (EC50 = 35 M). This brief SAR study revealed that anti-
lM)
μ
μ
EC50 = 2 M, TI >45
EC50 = 6 M, TI = 15
l
Scheme 1. Core modification.
HIV-1 activity was quite sensitive to the substituents and their
positions on the 5-aryl ring; the electron-donating methoxy group
at 3-position and electron withdrawing chloro group at 4-position
were tolerant. The potency of dimethoxyphenyl analogue 4k could
also be fine-tuned by modifying the alkoxy group.
Having identified leads showing good HIV-1 inhibitory activity,
we decided to evaluate the PK properties of the analogues. Early PK
studies guide decision making in drug discovery process and help
reduce the attrition rate in drug development.9 Initially, compound
4d was selected for this study because it had reasonable HIV-1
inhibitory potency (EC50 = 3.0 lM), good lead like properties
(MW = 310, logP = 3.3) along with an excellent metabolic stability
(%R40 min = 83, mouse liver microsome). However, the poor
aqueous solubility of 4d (0.2 lM at pH 7.4 in phosphate buffer)
was a major hurdle for preclinical PK evaluation and these ana-
logues in general suffered from poor solubility properties.
To address this issue, we envisaged a prodrug approach. The
indazole nitrogen of 4d, rather than 2-amino group of the oxazole
core, was considered to be a preferred site for attachment of a
prodrug moiety because of easy chemical modifications and a
stronger acidity of the N–H group that increases the self cleavage
rate of a double prodrug.10 There are relatively few precedents in
the literature for prodrugs of indazoles. One is a tetrahydropyridi-
nyl moiety.11 The mechanism of cleavage of the tetrahydropyridi-
nyl promoiety was proposed to partially mimic bioactivaton
pathway that is catalyzed by monoamine oxidase B (MAO-B).
Phosphate prodrugs12 of indoles were also used to overcome for-
mulation problems (e.g., phosphate prodrugs of PD15407510, a
highly potent and selective NK1 receptor antagonist). Inspired by
many prodrug strategies designed for amines13, we designed three
types of potential prodrugs of indazoles: (a) double prodrugs con-
taining N-acyloxymethyl group as a promoiety, (b) N-mannich
bases, (c) N-acyl prodrugs (Scheme 3). In the following section,
the synthesis and preliminary evaluation of the potential prodrugs
are described.
1,10-thiocarbonyldi-2(H)-pyridone or thiocarbodiimidazole. Acyl
bromide 7 was easily converted into acyl azide 8 by use of NaN3.
The synthesis of oxazole 4d was achieved in good yield (85%) via
intermediate 9 by heating a mixture of 6 and 7 in the presence
of PPh3. This protecting-group-free two-step procedure allowed
for the rapid generation of related analogues.
The Topliss approach has been known as a popular tool in lead
optimization for identifying optimal substituents. The approach in-
volves systematic changes in electronic, steric and hydrophobic
properties of substituents, and is particularly useful in cases where
no structural information about the biological target is available.8
In our initial study, a similar strategy was used to examine the
effect of the substituents (Cl and OMe) on the 5-phenyl moiety
in 4a on the potency. Thus, ortho-, meta-, and para-subsituted phe-
nyl analogues 4b–4k were prepared. As summarized in Table 1,
these analogues had markedly different potency. For chloro substi-
tuted phenyl analogues 4b–d, the order of potency was para-
>ortho- >>meta-chlorophenyl analogues (EC50 = 3, 9, 54 lM, 4d,
4b and 4c, respectively). The para-chlorophenyl analogue 4d
showed a similar potency to parent 4a but exhibited significantly
improved metabolic stability (%R40 min = 83 for 4d and 9 for 4a,
mouse liver microsome). These results clearly indicated that the
para-position of the phenyl moiety is a major metabolic site. The
opposite SAR trend was observed for methoxyphenyl analogues
4e–g; meta-methoxyphenyl analogue 4f showed anti-HIV-1
activity (EC50 = 2
para-methoxyphenyl analogues 4e,g lacked the potency
(EC50 = 100 M). It was expected that combination of the favorable
lM) similar to that of 4a,d whereas ortho- and
l
4-chloro and 3-methoxy substituents might act synergistically for
the in vitro anti-HIV-1 activity. Although the combination of the
substitutents did not induce a significant synergistic effect, 4-
chloro-3-methoxyphenyl analogue 4i exhibited comparable or
slightly better potency (EC50 = 1.5
ingly, 3,4-dimethoxyphenyl analogue 4k (EC50 = 0.42
l
M) to analogues 4d,f. Interest-
Type A prodrugs are designed to form double prodrug systems
that utilize N-acyloxymethyl or N-alkoxycarbonyloxymethyl
lM, TI = 50)
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S.-H. Kim et al. / Bioorg. Med. Chem. Lett. xxx (2013) xxx–xxx
3
Table 1
H
N
N
EC50 data for 4a–k in MT4-cell cytoprotection assay
a
N
4d
H
O
N
N
N
X1
HO
O
10
N
N
H
X2
b,c,d or e
Cl
X3
H
N
N
Compd X1
X2, X3
MT4 cells EC50
M)
MT4 cells TC50
M)
TIc
a
b
N
(
l
(l
O
N
R1
4a
4b
4c
4d
4e
4f
4g
4h
4i
H
Cl
H
H
H, H
H, H
Cl, H
H, Cl
2
9
54
3
100
2
100
>90
>100
>100
>90
>100
>90
>100
83
>45
>11
>1.9
>30
>1
>45
>1
31
O
O
Cl
OMe H, H
O
11a: R1 =
∗
O
O
H
H
H
H
H
H
OMe, H
H, OMe
–OCH2O– 2.7
OMe, Cl
Cl, Cl
OMe,
O
11b: R1
11c: R1
=
=
1.5
35
0.42
80
>100
21
53
>2.9
50
∗
CO2H
CO2H
4j
4k
O
O
OMe
∗
∗
The data are an average of two experiments; the standard deviations are normally
less than 20%.
a
EC50: 50% effective concentration.
TC50: 50% toxic concentration.
Therapeutic index: TC50/EC50
11d: R1
=
O
b
c
N
.
Scheme 4. Reagents and conditions: (a) CH2O (37% in water), NaOH, EtOH, 80%; (b)
carbonic acid, 2,5-dioxo-1-pyrrolidinyl 2-(2-methoxyethoxy)ethyl ester, DMAP,
pyridine, rt, 65% for 11a; (c) succinic anhydride, DAMP, pyridine, rt, 81% for 11b; (d)
phthalic anhydride, DMAP, pyridine, rt, 47% for 11c; (e) 4-(4-morpholinometh-
yl)benzoic acid, EDCI, DMAP, CH2Cl2, 42% for 11d.
H
N
H
N
N
N
N
O
N
enzymatic
hydrolysis
HO
the identical condition, the acylation reactions with succinic
anhydride and phthalic anhydride yielded 11b and 11c, respec-
tively. EDCI-mediated coupling reaction of 10 with 4-(4-morpholi-
nylmethyl)benzoic acid provided 11d.
R
O
chemical
Type A
hydrolysis
CH2O
H
N
H
N
We also designed double prodrug 15 that consists of a phos-
phate group and an aminocarbonyloxymethyl linker (Scheme 5).
The initial synthetic plan for 15 involved a functionalization of
the primary hydroxyl group in compound 10. This approach,
however, proved to be unsuccessful. In the second approach,
5-nitroindazole (12) was used as the starting material. After
N-hydroxymethylation of 12 with formaldehyde, the resulting hy-
droxyl moiety was converted to a reactive carbonate by reacting
with p-nitrophenylchloroformate. The reactive carbonate interme-
diate formed was then reacted with 2-aminoethanol to provide
carbamate 13. The hydroxyl group of 13 was phosphorylated using
di-t-butyl N,N-diisopropylphosphoramidite with subsequent
hydrogen peroxide oxidation of the phosphite intermediate. After
reduction of 5-nitro group of the indazole moiety, the resultant
aniline compound was transformed to isothiocyanate 14. Oxazole
15 was obtained in good yield from acyl azide 8 and 14 under
the identical condition as described above for synthesis of 4d.
Unfortunately, deprotection of t-butyl group of 15 under standard
TFA conditions resulted in the formation of parent 4d, suggesting
the poor stability of the promoiety under acidic conditions and
the need of different protecting groups. In spite of the failure in
the final deprotection step, this synthetic route will be amenable
to the synthesis of diverse phosphate prodrugs12 such as prodrug
15 bearing different protecting groups (e.g., R2 = benzyl or acyl-
oxymethyl ester).
N
N
N
H
N
enzymatic
hydrolysis
R
O
chemical
Type C
R2N
hydrolysis
H
N
N
N
R
N
R
Type B
Scheme 3. Design of potential prodrugs of indazoles.
groups as a promoiety where the hydroxymethyl group acts as a
self-cleavable second linker. The bioconversion of these prodrugs
is generally initiated by enzymatic hydrolysis or intramolecular
activation by carboxylate nucleophiles (for 11b,c) and the newly
revealed N-hydroxymethyl intermediates rapidly release the par-
ent drugs and formaldehyde (Schemes 3 and 4).
The synthesis of type A compounds 11a–d began with N-hydro-
ymethylation of indazole moiety of 4d with formaldehyde (37% in
water) that proceeded in good yield to form 10 under acidic or
basic conditions (Scheme 4).14 The primary hydroxyl group of 10
was then acylated to afford potential prodrugs 11a–d. Compound
11a bearing a ethylene glylcol promoiety was prepared by reaction
of 10 with carbonic acid, 2,5-dioxo-1-pyrrolidinyl 2-(2-methoxy-
ethoxy)ethyl ester in the presence of DMAP in pyridine. Under
Various Mannich-base prodrugs (type B) have been developed
to increase the aqueous solubility or the stability of the parent
molecule (e.g., rolitetracycline and hetacillin).13 In this study,
Mannich-base prodrugs 16a–c were designed and synthesized
using a standard Mannich reaction condition (Scheme 6).
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4
S.-H. Kim et al. / Bioorg. Med. Chem. Lett. xxx (2013) xxx–xxx
NO2
H
N
N
N
NO2
N
a,b,c,d,or e
a,b
N
O
4d
N
N
N
H
O
R4
OH
O
N
H
12
13
Cl
O
O
O
17a: R4 =
∗
∗
O
O
c,d,e
17b: R4
17c: R4
17d: R4
=
H
N
CO2H
NH2
NCS
N
O
N
O
O
O
N
O
f
N
N
∗
∗
=
=
O
O
O
O
OR2
O
O
N
H
P
P
N
H
R2O OR2
O
Cl
R2O
N
H
15: R2 = tBu
14: R2 = tBu
17e: R4 = ∗
N
H
Scheme 5. Reagents and conditions: (a) CH2O (37% in water), NaOH, EtOH, 84%; (b)
p-nitrophenylchloroformate, NEt3, CH2Cl2, 0 °C to rt, then 2-aminoethanol, rt, 45%;
(c) di-t-butyl N,N-diisopropylphosphoramidite, 1H-tetrazole, H2O2 (30% wt/wt in
water), CH2Cl2, 68%; (d) H2 (1 atm), Pd/C (10% w/w), EtOAc, 93%; (e) 1,10-
thiocarbonyl-2(H)-pyridone, CH2Cl2, 86%; (f) PPh3, 8, dioxane, 78%.
Scheme 7. Reagents and conditions: (a) carbonic acid, 2,5-dioxo-1-pyrrolidinyl 2-
(2-methoxyethoxy)ethyl ester, DMAP, pyridine, rt, 35%; (b) succinic anhydride,
DAMP, pyridine, 65 °C, 10 h, 26%; (c) 2,5-dioxopyrrolidin-1-yl 3-(tert-butoxycar-
bonylamino)propanoate, DMAP, pyridine, rt; TFA, CH2Cl2, 27% (two-steps), (d)
phenyl isocyanate, CH3CN, 100 °C, 76%; (e) cyclopentyl isocyanate, CH3CN, 100 °C,
59%.
The synthesis of N-acyl prodrugs (type C) is shown in Scheme 7.
Although several successful N-acyl prodrugs are in clinical use,
their utility in prodrug design has been limited due to the rela-
tively high enzymatic stability in vivo.13 Acylation of 4d with
appropriate succinimidyl carbonate, succinimidyl ester, or anhy-
dride in the presence of DMAP in pyridine proceeded to give pro-
drugs 17a–c. In addition, potential urea prodrugs 17d–e were
also prepared by treatment of 4d with cyclopentyl isocyanate or
phenyl isocyanate.
These indazole analogues were briefly evaluated as potential
prodrugs with improved aqueous solubility. The preliminary solu-
bility screening showed that analogues 11b and 11c exhibited a
remarkably improved aqueous solubility (ꢀ300-fold) compared
to that of the parent compound 4d (aqueous solubility = 0.2, 60,
(pH 7.4) at 37 °C, analogue 11b underwent enzymatic hydrolysis
(ꢀ35% remaining of 11b after 40 min) and the time dependent for-
mation of the parent 4d was observed whereas analogue 11c was
quite stable and almost no conversion was observed under identi-
cal conditions. Analogue 11b was stable at pH 7.4 in phosphate
buffer at 37 °C over 40 min and no significant hydrolysis was ob-
served. The improved aqueous solubility of 11b and its susceptibil-
ity to enzymatic hydrolysis suggested that 11b could be
promising prodrug and was selected for further evaluation. Poten-
tial prodrug 11b retained the potency of parent 4d even it had a
relatively narrow value of TI (EC50 = 2
EC50 = 3 M and TI >30 for 4d).
a
lM, TI = 15 for 11b,
66 lM at pH 7.4 in phosphate buffer, 4d, 11b and 11c, respec-
l
tively). However, no improvement in aqueous solubility was ob-
served in other analogues such as N-hydroxymethyl analogue 10,
N-alkoxycarbonyloxymethyl analogue 11a, N-acyloxymethyl ana-
logue 11d, analogue 15 containing a phosphate group and Man-
nich-base analogues 16a–c. The insufficient aqueous solubility
led us to eliminate these analogues from further study. Also, N-acyl
and N-urea analogues 17a–e were not considered suitable as a
prodrug due to their well known enzymatic stability. Therefore,
analogues 11b,c with adequate aqueous solubility were selected
to assess for their ability to undergo conversion to the parent 4d
in vitro. When incubated in phosphate buffered 80% human plasma
Further investigations such as various in vitro HIV assays, ki-
nase profiling and chemical proteomics studies are needed to iden-
tify the cellular targets and elucidate the mechanism underlying
the anti-HIV activity of the new analogues. A possible mechanism
could be an inhibition of protein kinases since the molecules con-
tain motifs common to kinase inhibitors15 and several kinase
inhibitors (e.g., CDKs, CKII, and LIMK inhibitors) have been found
to have effective anti-HIV activity.16 Analogue 17c particularly at-
tracted our attention because it did not impede HIV inhibitory po-
tency (EC50 = 2 lM, TI = 24, 17c) and contains a primary amine
moiety that is required for immobilization of a compound on a
solid support. Thus, the immobilized inhibitor can be used in an
affinity chromatography based chemical proteomics study for tar-
get identification.4,17
H
N
N
N
In summary, new oxazole containing inhibitors of HIV-1 have
been discovered through cell-based screening of an in-house
library and subsequent scaffold modification. The SAR study focus-
ing on substituent on the 5-aryl moiety of the oxazole core led to
O
a
N
4d
R3
the identification of potent inhibitor 4k (EC50 = 0.42 lM, TI = 50,
3
3
∗
∗
Cl
16a
16b
NEt2
N
: R
: R
=
=
MT4 cells). In an effort to improve the aqueous solubility of the
analogues, broadly applicable potential prodrugs of indazoles were
designed and synthesized. A preliminary evaluation has shown
that N-acyloxymethyl analogue 11b is a promising prodrug of
indazoles. Additional studies are needed to evaluate full potential
of the prodrug approach and determine cellular targets of these
inhibitors.
3
∗
16c
: R
=
N
O
Scheme 6. Reagents and conditions: (a) CH2O (37% in water), diethylamine,
piperidine, or morpholine, MeOH, 60 °C, 63–76%.
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S.-H. Kim et al. / Bioorg. Med. Chem. Lett. xxx (2013) xxx–xxx
5
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Acknowledgment
We thank Dr. Kraig M. Yager for his encouragement and support
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Please cite this article in press as: Kim, S.-H.; et al. Bioorg. Med. Chem. Lett. (2013), http://dx.doi.org/10.1016/j.bmcl.2013.03.075