Identification of N-{[6-chloro-4-(2,6-dimethoxyphenyl)quinazolin-2-yl]carbonyl}-l-leucine (NTRC-808), a novel nonpeptide chemotype selective for the neurotensin receptor type 2

Article abstract of DOI:10.1016/j.bmcl.2014.11.047

Compounds acting via the GPCR neurotensin receptor type 2 (NTS2) display analgesic effects in relevant animal models. Using a pharmacophore model based on known NT receptor nonpeptide compounds, we screened commercial databases to identify compounds that

Full text of DOI:10.1016/j.bmcl.2014.11.047

Bioorganic & Medicinal Chemistry Letters 25 (2015) 292–296
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Identification of N-{[6-chloro-4-(2,6-dimethoxyphenyl)quinazolin-2-
yl]carbonyl}-L-leucine (NTRC-808), a novel nonpeptide chemotype
selective for the neurotensin receptor type 2
a
a
a
a
James B. Thomas a, , Angela M. Giddings , Srinivas Olepu , Robert W. Wiethe , Danni L. Harris ,
Sanju Narayanan a, Keith R. Warner a, Philippe Sarret b, Jean-Michel Longpre b, Scott P. Runyon a,
Brian P. Gilmour a
⇑
a Center for Organic and Medicinal Chemistry, Research Triangle Institute, PO Box 12194, Research Triangle Park, NC 27709, United States
b Department of Physiology and Biophysics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, 3001, 12th Ave. North, Sherbrooke, QC J1H 5N4, Canada
a r t i c l e i n f o
a b s t r a c t
Article history:
Compounds acting via the GPCR neurotensin receptor type 2 (NTS2) display analgesic effects in relevant
animal models. Using a pharmacophore model based on known NT receptor nonpeptide compounds, we
screened commercial databases to identify compounds that might possess activity at NTS2 receptor sites.
Modification of our screening hit to include structural features known to be recognized by NTS1 and
NTS2, led to the identification of the novel NTS2 selective nonpeptide, N-{[6-chloro-4-(2,6-dimethoxy-
Received 21 October 2014
Revised 13 November 2014
Accepted 17 November 2014
Available online 24 November 2014
phenyl)quinazolin-2-yl]carbonyl}-L-leucine (9). This compound is a potent partial agonist in the FLIPR
assay with a profile of activity similar to that of the reference NTS2 analgesic nonpeptide levocabastine
(5).
Keywords:
Neurotensin
NTS2 receptor
Levocabastine
SR142948a
SR48692
Ó 2014 Published by Elsevier Ltd.
FLIPR assay
Pain
The identification of novel analgesics remains a key goal of
medicinal chemistry. Despite years of effort, the opioids remain
the treatment of choice for severe acute pain even with their dele-
terious adverse effect profile that includes constipation, respiratory
depression as well as development of tolerance and addiction. Also,
patients experiencing chronic pain, a persistent pain that can fol-
low from peripheral nerve injury, often fail to find relief with opi-
oids. Although antidepressant and antiepileptic drugs are currently
the treatment of choice for this type of pain, it is estimated that
more than half of these patients are not treated adequately. Thus,
the identification of nonopioid analgesics that are also effective
for management of chronic pain would represent a significant
advancement of the field.
The tridecapeptide neurotensin (NT, Glu-Leu-Tyr-Glu-Asn-Lys-
Pro-Arg-Arg-Pro-Tyr-Ile-Leu), identified forty years ago from
bovine hypothalamus, operates via interaction with two G-protein
coupled receptors named NTS1 and NTS2 (NTR1, NTR2) and the
multi-ligand type-I transmembrane receptor sortilin (NTS3).1–3
NT acts as both a neuromodulator and neurotransmitter in the
CNS and periphery and oversees a host of biological functions
including regulation of dopamine pathways, hypothermia, hypo-
tension and importantly, nonopioid analgesia.4–6 Although the lat-
ter behavior highlighted the potential for NT-based analgesics, the
lions’ share of early research efforts were aimed at development of
NT-based antipsychotics acting at the NTS1 receptor site. Interest-
ingly, this work failed to produce nonpeptide compounds despite
intense discovery efforts. Undeterred, researchers focused on the
active fragment of the NT peptide (NT(8-13), 1, Chart 1), to create
a host of peptide-based compounds that, to this day, remain at the
forefront of NT research.7–14
Studies with NTS1 and NTS2 have shown that NT, and NT-based
compounds, modulate analgesia via both of these receptor sub-
types.15,16 These studies also revealed that NT compounds are
active against both acute and chronic pain and that there exists a
synergy between NT and opioid-mediated analgesia.17–20 Together,
these findings highlight the NT system as a potential source of
novel analgesics that could act alone or in concert with opioid
receptor-based drugs.18,21
Many of these compounds produce analgesia along with hypo-
thermia and hypotension, behaviors attributed to signaling via the
NTS1 receptor.22,23 In vivo evidence in support of these findings
⇑
Corresponding author. Tel.: +1 (919) 541 6375; fax: +1 (919) 541 6499.
E-mail address: jbthomas@rti.org (J.B. Thomas).
http://dx.doi.org/10.1016/j.bmcl.2014.11.047
0960-894X/Ó 2014 Published by Elsevier Ltd.

J. B. Thomas et al. / Bioorg. Med. Chem. Lett. 25 (2015) 292–296
293
(5) behaves as a potent partial agonist and NT was an antagonist
of the calcium release mediated by 4. This evidence guided our dis-
covery efforts toward identification of compounds displaying
either potent partial agonist or antagonist activity in the FLIPR
assay.
We reported recently that this effort resulted in the identifica-
tion of several nonpeptide compounds that met these criteria.
The first of these was the NTS2 selective potent partial agonist 6
(NTRC-739) that was obtained from an SAR study starting with
the nonselective full agonist 3.30 More recently, we identified an
NT-like antagonist 7 starting from the screening of a library of
substituted indole compounds based upon the NTS1 partial agonist
8.31,32 In this article, we report the discovery of N-{[6-chloro-4-
(2,6-dimethoxyphenyl)quinazolin-2-yl]carbonyl}-L-leucine
(NTRC-808, 9) a novel nonpeptide chemotype that shows potent
partial agonist activity in the FLIPR functional assay and is selective
for NTS2 versus NTS1. The discovery of this compound was accom-
plished in a different manner from the two described above as we
used a pharmacophore model and database mining strategy to
obtain our initial hit compound rather than adjusting the activity
of a scaffold previously shown to bind NT receptors. The details
of the effort that provided 9 are described below.
The target compounds described herein were synthesized as
shown in Scheme 1 using methods similar to those reported by
Castellano et al.33 Thus, benzoxazinone 1134 was available starting
from 2-amino-5-chlorobenzoic acid (10) by treatment with acetic
anhydride at reflux. This was then coupled with lithiated veratrole
at 0 °C followed by hydrolysis with HCl at reflux to give intermedi-
ate 12.35 Synthesis of the key phenylquinazoline carboxylic acid
intermediate 13 was then accomplished by treating 12 first with
glyoxylic acid and ammonium acetate, followed by stirring under
air in dimethylformamide (DMF) for three days. The target com-
pounds 14b, 9 and 16b were then available by first coupling 13
to the appropriate amino acid ester using O-benzotriazol-1-yl-
N,N,N0,N0-tetramethyluronium hexafluorophosphate (HBTU) and
triethylamine to give ester intermediates 14a, 15 and 16a. Target
Chart 1. Structures of neurotensin reference peptides (1, 2), reference nonpeptides
(3–5), and recently described NTS2 selective nonpeptide compounds (6, 7) and title
compound (9).
has been provided using the NTS2-selective peptide NT79 (2) as it
was found to be active in models of acute pain but without effect
on temperature or blood pressure.12 These results were recently
confirmed by the development of the compound ANG2002, a con-
jugate of NT and the brain-penetrant peptide Angiopep-2, which is
effective in reversing pain behaviors induced by the development
of neuropathic and bone cancer pain.24 Taken together, the prom-
ise of activity against both acute and chronic pain as well as a more
balanced ratio of desired versus adverse effect profile directed our
discovery efforts toward NTS2-selective analgesics.
The work to identify NT-based antipsychotics was directed at
the NTS1 receptor as little was known about the NTS2 receptor
at that time. This suggested to us that the failure to find nonpep-
tide compounds might be a phenomenon peculiar to NTS1 and that
this barrier would not exist for NTS2. Three nonpeptide com-
pounds in total were known to bind NTS1 and/or NTS2 and these
included two pyrazole analogs SR48692 (3) and SR142948a (4)
and levocabastine (5). While compounds 3 and 4 were found to
antagonize the analgesic and neuroleptic activities of NT in a vari-
ety of animal models, 5 showed selectivity for NTS2 versus NTS1
and analgesic properties in animal models of acute and chronic
pain16,25–28 thus demonstrating that nonpeptide NTS2-selective
analgesic compounds could be identified.
NH2
NH2
O
N
O
CH3
ii
i
O
Cl
O
Cl
Cl
H3CO
OCH3
OH
12
10
11
O
O
For 14b use v,viii
N
N
X
OH For 9 use vi, viii
For 16b use vii,ix
N
H
iii,iv
N
N
Cl
Cl
H3CO
OCH3
H3CO
OCH3
13
Where X =
OR
OR
OR
O
O
O
14a: R = t-butyl
14b: R = H
15: R = t-butyl
9: R = H
16a: R = methyl
16b: R = H
To find novel nonpeptide compounds, we developed a medium
throughput FLIPR assay in a CHO cell line stably expressing rNTS2
based on reports that compound 3 mediated calcium release at the
NTS2 receptor in this cell line. We planned to follow up this assay
with a binding assay using [125I]NT to confirm interaction with
NTS2.29,30 Profiling compounds 3, 4, 5 and NT in our FLIPR assay
revealed that 3 and 4 were full agonists whereas levocabastine
Scheme 1. Synthetic route to target compounds 9, 14b and 16b. Reagents and
conditions: (i) Ac2O, Et2O, reflux; (ii) veratrole, n-BuLi, 0 °C; HCl, EtOH, H2O; (iii)
aqueous glyoxalic acid, NH4OAc; (iv) DMF, RT, air, 3 days; (v) HBTU, Et3N, CH2Cl2,
cyclohexylglycine tert-butyl esterꢀHCl; (vi) HBTU, Et3N, CH2Cl2, -leucine tert-butyl
esterꢀHCl; (vii) HBTU, Et3N, CH2Cl2, -aminocyclohexylcarboxylic acid methyl
esterꢀHCl; (viii) TFA, CH2Cl2; (ix) LiOH, dioxane.
L-
L
1

294
J. B. Thomas et al. / Bioorg. Med. Chem. Lett. 25 (2015) 292–296
compounds 14b and 9 were prepared by treating 14a and 15 with
trifluoroacetic acid (TFA) in CH2Cl2 while 16b was available via
hydrolysis of 16a using LiOH and dioxane.
endeavor was considered an overall success as the strategy identi-
fied a previously unidentified nonpeptide scaffold that could be
used to develop novel NTS2 ligands.
Our initial work to identify nonpeptide NTS2 receptor based
analgesics began with SAR studies of known NTS1 and NTS2 active
nonpeptide chemotypes (such as 3, 5 and 8) as we did not have
access to vast chemical libraries that could be screened for starting
points. We thus relied on small, targeted libraries of compounds
based on the chemotypes defined above that could be screened
using our FLIPR assays.
As an alternative method of identifying starting points, we also
explored a scaffold-hopping method using molecular modeling and
chemical library database mining to obtain novel chemotypes. To
accomplish this, we developed a 3D-pharmacophore hypothesis
based on commonalties of the training set that included com-
pounds 3, 4, 5 and 6. Conformational libraries of each were devel-
oped using an MMFF94 force field and 20 genetic algorithm runs
based on independent random number seeds and a radial dielectric
screening model of 80. Libraries were then filtered for unique con-
formations using both a 30-degree torsion angle uniqueness crite-
ria and symmetry. A 3D-pharmacophore was then developed using
MOLMOD36,37 employing the conformational libraries, a distance
tolerance of 1.5 angstroms and 3–10 kcal energy windows to
obtain the distance matrix (Fig. 1).
This consisted of a central set of hydrogen bond acceptors and
donors (1, 2 and 3), a terminal hydrophobic tail (4), 2-centroids
of aromatic rings (5 and 6) and a carboxyl group (7) near the ter-
minus of the ligands. Because of the training set used, this model
necessarily embodies many of the same elements delineated by
Quéré in the pharmacophore of NTS1 antagonists.38 We then con-
ducted virtual screening of the Life Chemicals Stock Collection and
the Chembridge Express Hit Collection and obtained a set of com-
pounds that were compliant with the 3D-pharmacophore.
We purchased 36 compounds identified in the search described
above and screened for agonist and antagonist activity in parallel
To improve upon this, we devised analogues of 17 that incorpo-
rated molecular features previously shown to promote activity at
the NT receptors. The highest priority was given to those features
that were embodied in the training set but absent in 17. The high-
lights of this plan are illustrated in Chart 2 and included the addi-
tion of a carbonyl group to provide an H-bond acceptor/donor in
the central region of future analogues. This had an added benefit
for analogue generation as the carboxylate precursor would enable
parallel synthesis efforts. In addition to this, we planned to add 2,6-
dimethoxy groups to the phenyl ring in 17 as these are known to
be important to NT receptor recognition, calcium mobilization
and selectivity.30,38,39 Finally, we believed that replacement of
the aminobenzoic acid in 17 for alpha amino acids known to be
active at NT receptors would improve overall activity and receptor
recognition. From previous experience, we chose the amino acids
illustrated in Scheme 1 as the first set to be investigated.30,38,39
The data from the FLIPR assay (NTS2) and binding assays (NTS1
and NTS2) for 9, 14b and 16b are provided in Table 1 along with
the data obtained for our reference compounds NT, 4 and 5. The
target compounds 9, 14b and 16b, as a group, failed to show activ-
ity in the calcium mobilization assay at NTS1 (data not shown).
Taken together, their failure to compete with [125I]NT at NTS1 sup-
ports the notion that their lack of calcium mobilization in the NTS1
FLIPR assay follows directly from a lack of interaction with NTS1.
Table 1
Data for reference compounds NT, 4, 5, 6 and test compounds 9, 14b and 16b at the
rNTS1 and rNTS2 receptors
#
FLIPR assay
NTS2
Binding assaya
NTS1
NTS2
Ki
b
c
EC50
Emax
IC50
42
Ki
at a single concentration (10 lM) at NTS1 and NTS2. Only one of
NT
4
>100
l
M
4
1.7 0.3
2.0 0.4
21
7.0 2.3
33
153 10
88 27
474 112
959 119
9
the 36 compounds purchased was active, compound 17 in Chart 2.
This compound demonstrated very weak antagonist activity (ꢁ20%
inhibition) at NTS2 but was devoid of activity at NTS1. Attempts to
obtain dose response curves for 17 proved problematic due to the
combination of low activity and low solubility. However, this
18
28
12
14
>10
5
4
6
4
l
100
16
7
5
3
2
3
5d
>25
>10
>25
>25
>25
lM
lM
lM
lM
lM
5
d
6
9
14b
16b
18
M
1067 187
145 10
26
3
a
b
c
[
125I]NT.
EC50, IC50 and Ki values are nM SEM.
Emax value is % of 4.
Data taken from Ref. 30.
d
Figure 1. 3D-Pharmacophore derived from compounds 3, 4, 5, and 6.
Use alpha amino acid
Introduce carbonyl
N
O
O
H
N
R
N
OH
OH
OH
N
H
N
N
O
Cl
Cl
H3CO
OCH3
17
Add 2,6-methoxy groups
Figure 2. Compound 9 shows potent partial agonist activity versus the agonist
standard compound 4 in the rNTS2 FLIPR assay.
Chart 2. Targeted modifications of latent hit 17 to improve activity at NT receptors.

J. B. Thomas et al. / Bioorg. Med. Chem. Lett. 25 (2015) 292–296
295
Table 2
NTS2 calcium signaling as a function of amino acid and scaffold combination
R
9: agonista 14 nM (18%)
18: agonista,c 710 nM (24%)
19: agonista,d 217 nM (86%)
21: antagoniste <30% @ (10
22: agonista,d 271 nM (22%)
lM)
CO2H
14b: antagonistb 1067 nM
CO2H
16b: agonista 145 nM (26%)
20: agonista,d 29 nM (82%)
23: agonista,d 19 nM (12%)
CO2H
a
EC50 nM (Emax%).
Ke nM.
Ref. 39.
Data taken from Ref. 30.
b
c
d
e
Screening data at single concn, % inhibition of calcium release mediated by 4.
In the NTS2 assay, however, these same compounds revealed a
greatly improved activity relative to 17. Compound 9, with the iso-
butyl side chain, proved to be the most active of the three target
compounds tested. Unlike 17, it displayed potent partial agonist
activity with an EC50 of 14 nM and Emax of 18% relative to 4, Fig-
ure 2. This activity profile is very similar to that previously
described for the NTS2 selective compounds levocabastine (5)
and 6.30 In the binding assay, its affinity fell between that of 5
and 6, with a Ki of 88 nM.
partial agonist or antagonist behavior whereas B displays near full
agonist behavior in two examples (19 and 20). These similarities in
data appear to align with the fact that scaffolds A and C are more
alike in overall size compared with B.
However, the counter trend must also be appreciated. Scaffold A
is most active when substituted with the smallest side chain (iso-
butyl), whereas both of the pyrazole-based scaffolds are most
active with the larger, more bulky side chains (compare com-
pounds 9 and 23). This dichotomy in behavior appears to be related
to the difference in scaffold structure. However, at this juncture,
given the limited data set, we cannot ascertain whether it is the
difference in the rigidity of the backbone or the different heterocy-
cles that make up the backbone that is responsible for this phe-
nomenon. Neither can we determine if both conditions must
exist. This will only be revealed through testing of additional
compounds.
Target compound 14b, bearing the L-cyclohexylglycine side
chain, did not show partial agonist activity in the functional assay
at NTS2 but instead antagonized the activity of 4 with an IC50 of
1067 nM. This was an improvement over the screening hit 17 but
still 25-fold less active than NT in the functional assay as indicated
in Table 1. It was also less active in binding with a Ki 5-fold greater
than 9 at 474 nM.
Target compound 16b, with the symmetrically disposed amin-
ocyclohexyl side chain, showed partial agonist activity in the FLIPR
assay like 9, but with much lower activity, roughly 10-fold less
(EC50 values of 145 and 14 nM respectively) though both shared
similar efficacies (Emax of 26 vs. 18% respectively). Comparison of
the binding assay data revealed that while 16b was selective for
NTS2 it was also 11-fold less effective than 9 in competing with
NT for binding at NTS2. Overall, the modifications made to com-
pound 17, demonstrated significantly improved activity for NTS2
and provided a novel nonpeptide chemotype selective for the
NTS2 receptor.
A comparison of the NTS2 FLIPR data collected for the benzoqui-
nazoline-based compounds 9, 14b and 16b to that obtained from
other scaffolds using an identical set of amino acids, provides
insight into the SAR of calcium signaling at NTS2. This is readily
appreciated by inspection of the data provided in Table 2. Here
the data from test compounds 9, 14b and 16b bearing the benzo-
quinazoline scaffold (A) are compared to that obtained from two
different pyrazole-based scaffolds (B and C) using the set of amino
Altogether, this study demonstrates that novel NTS2 nonpep-
tide scaffolds can be obtained using a virtual screening approach
even with a pharmacophore model based on a limited training
set. The discovery of compound 9 provides a novel nonpeptide
potent partial agonist in the FLIPR assay that is selective for NTS2
versus NTS1 and is significant since compounds known to show
antipsychotic and analgesic activity in vivo possess either partial
agonist (5) or antagonist (NT) activity in the NTS2 FLIPR assay.
The novel scaffold provides another dimension of data from which
to draw and will contribute to our understating of the SAR of cal-
cium signaling at NTS2. We are continuing our SAR studies with
this scaffold to improve activity as well as building a larger data
set that will be useful for comparison with other nonpeptide scaf-
folds. We are also working to establish an in vitro to in vivo corre-
lation for compound 9 in relevant animal models to determine if it
is an analgesic or an antagonist of NTS2 mediated analgesia.
Acknowledgments
acids that included
L
-leucine,
L
-cyclohexylglycine and 2-aminocy-
This research was supported by the National Institute on Drug
Abuse, Grant DA029961. We gratefully acknowledge the NIMH
Chemical Synthesis and Drug Supply Program for providing us with
the samples of SR142948a (4), and SR48692 (3).
clohexane carboxylic acid (19–23).30,39 The most readily apparent
trend in the data shows that scaffolds A and C are more alike func-
tionally compared with A and B as the former pair exhibited only

296
J. B. Thomas et al. / Bioorg. Med. Chem. Lett. 25 (2015) 292–296
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in
the
online
version,
at
http://dx.doi.org/10.1016/
j.bmcl.2014.11.047. These data include MOL files and InChiKeys
of the most important compounds described in this article.
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