The discovery of indole full agonists of the neurotensin receptor 1 (NTSR1)

Article abstract of DOI:10.1016/j.bmcl.2014.06.033

Neurotensin (NT) is an endogenous tridecapeptide found in the central nervous system (CNS) and in peripheral tissues. Neurotensin exerts a wide range of physiological effects and it has been found to play a critical role in a number of human diseases, suc

Full text of DOI:10.1016/j.bmcl.2014.06.033

Bioorganic & Medicinal Chemistry Letters 24 (2014) 3974–3978
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
The discovery of indole full agonists of the neurotensin receptor 1
(
NTSR1)
Paolo Di Fruscia, Yuanjun He, Marcel Koenig, Sahba Tabrizifard, Ainhoa Nieto, Patricia H. McDonald,
⇑
Theodore M. Kamenecka
Department of Molecular Therapeutics and Translational Research Institute, The Scripps Research Institute, Scripps Florida, 130 Scripps Way #A2A, Jupiter, FL 33458, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Neurotensin (NT) is an endogenous tridecapeptide found in the central nervous system (CNS) and in
peripheral tissues. Neurotensin exerts a wide range of physiological effects and it has been found to play
a critical role in a number of human diseases, such as schizophrenia, Parkinson’s disease and drug addic-
tion. The discovery of small-molecule non-peptide neurotensin receptor (NTSR) modulators would rep-
resent an important breakthrough as such compounds could be used as pharmacological tools, to
further decipher the cellular functions of neurotensin, and potentially as therapeutic agents to treat
human disease. Herein, we report the identification of non-peptide low-micromolar neurotensin receptor
Received 28 April 2014
Revised 9 June 2014
Accepted 11 June 2014
Available online 20 June 2014
Keywords:
SR-12062
Neurotensin
Neurotensin receptors
Neurotensin agonists
Indole agonists
1
(NTSR1) full agonists, discovered through structural optimization of the known NTSR1 partial agonist 1.
2
+
In vitro cellular screenings, based on an intracellular Ca mobilization assay, revealed our best hit mol-
ecule 8 (SR-12062) to have an EC50 of 2 M at NTSR1 with full agonist behaviour (Emax = 100%), showing a
higher efficacy and ꢀ90-fold potency improvement compared to parent compound 1 (EC50 = 178 M;
max = 17%).
l
l
E
Ó 2014 Elsevier Ltd. All rights reserved.
Neurotensin (NT), a tridecapeptide (pGlu-Leu-Tyr-Glu-Asn-
Lys-Pro-Arg-Arg-Pro-Tyr-Ile-Leu) isolated in 1973 from bovine
hypothalami, is widely distributed throughout the central and
the potential as an interesting therapeutic target.11 In addition, the
crystal structure of Rattus Norvegicus NTSR1, bound to a peptide
1
12
agonist, has been recently reported. This finding, combined with
peripheral nervous systems where it acts as a neurotransmitter
and neuromodulator, and in the gastrointestinal tract where it
behaves as a hormone. Neurotensin has been found to modulate
numerous cellular signalling pathways, playing a critical role in a
suitable molecular modeling techniques, may assist medicinal
chemistry efforts towards the discovery of small molecule NTSR1
ligands, which could be used as valuable tools to help further
define the biological roles of neurotensin, and potentially as
candidate agents to treat NT-dependent pathologies. Since its
discovery, roughly 40 years ago, efforts to design and synthesize
both peptidomimetic and small molecule modulators of NTSR1
have led to a better understanding of the receptors function
2
variety of physiological and pathological processes. Indeed, neuro-
tensin has important roles in the modulation of dopamine neuro-
transmission, hypothermia, hypotension, opioid-independent
analgesia and food intake.3 In addition, neurotensin has been
shown to be implicated in numerous brain disorders such as
,4
1
3–19
in vivo.
Most of this work has focused on the identification
5,6
schizophrenia, Parkinson’s disease and drug addiction. Both cen-
tral and peripheral actions of neurotensin depend on recognition of
the peptide by specific receptors. To date, four different neuroten-
sin receptors (NTSRs) have been cloned from human: NTSR1 and 2
are seven-transmembrane spanning domain G-protein-coupled
receptors (GPCRs), whereas NTSR3 and NTSR4 are members of
the sortilin protein family with a single-transmembrane spanning
domain.7
of abbreviated peptide fragments and improving their oral and
1
8–21
CNS exposure.
Despite the challenge of developing peptide
therapeutics, some of these efforts have advanced as far as early
clinical trials. In contrast, the generation of small molecule agonists
of NTSR1 remains a challenge, however, reports characterizing
novel agonist scaffolds are beginning to appear in the primary
literature.
The majority of NTSR1 modulators reported in the literature are
represented by peptides, which often show poor in vivo pharmaco-
kinetic profiles (e.g., low oral bioavailability and CNS penetration).
Nonetheless, a number of orally bioavailable and brain penetrant
peptidic neurotensin mimetics have been described in the litera-
ture and currently employed as useful pharmacological probes.
–10
Among the neurotensin receptors, NTSR1 is the most widely
studied, mediates most of the known neurotensin effects and holds
⇑
Corresponding author. Tel.: +1 561 228 2207; fax: +1 561 799 8980.
E-mail address: kameneck@scripps.edu (T.M. Kamenecka).
http://dx.doi.org/10.1016/j.bmcl.2014.06.033
960-894X/Ó 2014 Elsevier Ltd. All rights reserved.
0

P. Di Fruscia et al. / Bioorg. Med. Chem. Lett. 24 (2014) 3974–3978
3975
OMe
N
O
S
HN
O
OH
O
OMe
N
N
NH
OMe
O
N
N
O
N
N
OMe
N
N
HN
OH
O
Cl
1
2
3 (ML314)
EC50 = 2.0 µM
Emax = 100%
EC50 = 178 µM
Emax = 17%
EC50 = 220 nM
Emax = 81%
OH
O
OH
OH
O
OMe
OMe
NH
O
O
NH
OMe
OMe
NH
OMe
O
O
N
N
N
N
N
N
N
OMe
Cl
N
Cl
O
N
N
4
(ML301)
5 (SR 48692)
6 (SR 142948A)
EC50 = 298 nM (Emax = 93%)
IC50 = 82 nM
IC50 = 4 nM
Figure 1. Molecular structures and activities of several NTSR1 agonists (1–4) and antagonists (5 and 6) reported in the literature.
O
O
S O
S
O
N
HN
N
HN
N
N
N
N
O
O
O
HN
HN
HN
OH
OH
OH
O
O
O
1
(Wyeth)
7
8 (SR-12062)
Figure 2. Molecular structures of compounds 1, 7 and 8 (SR-12062). The structure-activity relationship (SAR) investigation is highlighted in compound 1.
Conversely, only a small number of non-peptide positive and neg-
ative modulators of the NTRS1 have been discovered to date
has only poor potency (EC50 = 178 lM) and poor efficacy
(Emax = 17%). In an effort to discover potent small-molecule NTSR1
full agonists we decided to embark on the chemical synthesis and
biological evaluation of analogues of compound 1, variously deco-
rated at the 1-, 5- and 6-positions of the indole core structure. Suc-
cessfully, many of the newly synthesized compounds showed
NTSR1 full agonist activity with EC50 values in the low micromolar
range, validating this chemical series as a robust chemotype for
effective NTSR1 modulation. We found it crucial to begin our inves-
tigation exploring the stereochemistry of compound 1. Encourag-
(
Fig. 1). These include the partial agonist 1 reported by researchers
2
2
23
at Wyeth, the pyrazole-derived agonist 2, the b-arrestin biased
24
brain penetrant agonist ML314 (3) and the recently discovered
positive modulator ML301 (4).25 Among NTSR1 antagonists, stand
out two trisubstituted pyrazole derivatives structurally related to
agonists 2 and 4: SR 48692 (5)26 and SR 142948A (6), which show
binding affinities in the low nanomolar range.
27
However, the need for more potent, selective and brain perme-
able NTSR1 modulators still remains a major challenge. Herein, we
report the discovery of single-digit micromolar NTSR1 full agonists
based on an indole scaffold. Molecular design, synthetic strategies,
SAR investigation and in vitro cellular assays are presented and
discussed.
ingly, inversion of configuration at the
a-carbon of the leucine
residue, from -leucine (compd 1) to standard
D
L
-leucine (compd
7), significantly improved both potency and efficacy. Furthermore,
compound 8 (SR-12062), our best hit, was found to have an EC50 of
2
l
M and a full efficacy profile (Emax = 100%), showing ꢀ90-fold
Previously, researchers at Wyeth reported the identification,
through a ligand-based virtual screening campaign, of compound
potency improvement to parent compound 1 (Fig. 2).
Compound 8 was efficiently prepared in 5 steps and 42% overall
yield from commercially available 5-bromoindole (9) (Scheme 1).
The synthesis commenced with a palladium-catalyzed Suzuki
1
as a partial agonist of the NTSR1 (Fig. 1).22 Compound 1 repre-
sents a promising starting point for hit-to-lead development but

3
976
P. Di Fruscia et al. / Bioorg. Med. Chem. Lett. 24 (2014) 3974–3978
Table 1
SAR of 5-substituted indoles 1, 7, 8, 12–24 against NTSR1
Br
a
b, c
R
N
N
H
N
O
9
10
N
H
HN
COOH
EC50a
(
l
M)
E
max (%)
a
Compd
R
N
À5
N
NT(8–13)
1
—
—
4.16 Â 10
100
—
d, e
N
>100
O
N
O
O
O
HN
11
8
7
S
HN
8.99 ± 3.14
64.80 ± 19.13
OH
OH
N
O
N
Scheme 1. Synthesis of compound 8. Reagents and conditions: (a) Quinolin-3-
ylboronic acid, Pd(PPh , K CO , dioxane, H O, 80 °C (MW), 30 min, 68%. (b) (i)
NaH, DMF, 0 °C, 30 min; (ii) ethyl 2-bromoacetate, rt, 16 h, 72%. (c) LiOHÁH O, THF,
O, rt, 4 h, 98%. (d) -Leucine methyl ester hydrochloride, HATU, DIPEA, DMF, rt,
6 h, 92%. (e) LiOHÁH O, THF, H O, rt, 4 h, 95%.
3
)
4
2
3
2
8
2.05 ± 0.96
99.44 ± 3.03
2
H
1
2
L
1
1
1
2
3
4
H
Br
NH
6.65 ± 5.35
9.99 ± 2.40
25.82 ± 4.06
112.55 ± 20.71
87.29 ± 0.78
57.58 ± 9.29
2
2
2
C–C cross coupling reaction between 9 and quinolin-3-ylboronic
acid. This allowed the preparation of the arylindole framework in
good yield (68%). N-alkylation of the indole nitrogen was accom-
plished with NaH and ethyl 2-bromoacetate in DMF. The resulting
ethyl ester was hydrolyzed with LiOH to furnish compound 11 in
high yield (71% over 2 steps). HATU-mediated amide coupling of
1
1
5
6
9.44 ± 2.79
81.81 ± 15.77
73.78 ± 8.76
15.38 ± 4.31
N
1
1 with L-leucine methyl ester and subsequent hydrolysis of the
1
1
7
8
3.26 ± 0.80
9.39 ± 3.87
100.84 ± 14.06
78.02 ± 14.67
ester group afforded compound 8 in excellent yield (87% over 2
steps). Analogous compounds of hit 8 were synthesized according
to the synthetic route outlined in Scheme 1.
O
q
NTSR1 preferentially couples to the G class of G proteins;
S
O
hence, all compounds of the newly synthesized chemical series
were screened using a cell-based functional assay that monitors
HN
ligand-mediated changes in intracellular Ca2 levels. NT(8-13)
+
28
N
2
9
(
Arg-Arg-Pro-Tyr-Ile-Leu), the active fragment of neurotensin,
O
was employed as the positive control. After exploring the stereo-
chemistry at the leucine residue of compound 1, we turned our
attention to the sulfonamido substituent at the 5-position of the
indole scaffold. A variety of aryl and arylamino groups were inves-
tigated as alternatives to the quinoline-8-sulfonamido moiety, and
remarkably all the explored substituents were highly tolerated,
giving low-micromolar agonists (Table 1). Interestingly, analogues
bearing small groups at the 5-position (compds 12, 13 and 14)
maintained high activity, with compound 12 (R = H) showing also
high efficacy (Emax = 112%). These data suggest that bulky aromatic
groups in position 5 of the indole core may not be necessary to gain
potency and efficacy.
19
55.07 ± 4.50
38.18 ± 10.58
HN
20
21
4.96 ± 1.39
3.24 ± 0.46
74.33 ± 11.51
90.94 ± 15.74
N
N
N
2
2
2
3
7.72 ± 1.97
78.07 ± 12.86
55.91 ± 4.64
In order to develop robust structure-activity relationships
NH
(
SARs), we decided to replace the leucine residue in compound 8
with alternative amino acid residues. Clearly, such a drastic change
was not tolerated, with all the analogues significantly losing activ-
ity or efficacy (Table 2). Notably, this is in line with a similar inves-
tigation, previously reported for compound 2, where the isobutyl
group appeared to be preferred.23 Compound 31, bearing a phenyl-
H
MeO
N
24.20 ± 17.73
O
N
24
N
2.12 ± 0.74
79.40 ± 10.63
alanine residue, retained activity (EC50 = 4
max = 15%). Only compound 27,30 in which the carboxylic acid
group of leucine was replaced with a bioisosteric tetrazole moiety,
had comparable activity and efficacy (EC50 = 5 M; Emax = 92%) to
l
M) but not efficacy
(E
N
a
l
NTSR1 potency was measured relative to the EC100 (100 nM) of the NT(8–13)
peptide control average ± SEM (n = 4 unless otherwise indicated). Emax was calcu-
lated as the % of the response obtained with the NT(8–13) peptide.
hit analogue 8. In addition, the loss of activity observed for com-
pounds 25 and 26, in which the carboxylic acid group of leucine
was replaced with a methyl ester or alcohol moiety respectively,
showed the importance, in this chemotype, of the acidic function-
ality for NTSR1 activity. Moreover, compound 32, enantiomer of 8,
displaying no activity against NTSR1 confirmed that the stereo-
chemistry at the
activity.
a-carbon of the leucine residue is critical for

P. Di Fruscia et al. / Bioorg. Med. Chem. Lett. 24 (2014) 3974–3978
3977
Table 2
Table 3
SAR of 5-(quinoline-3-yl)indoles 25–33 against NTSR1
SAR of 5-(naphthalen-1-yl)indoles 34–38 against NTSR1
N
N
N
O
O
R
R
EC50a
(lM)
E
max (%)
a
EC50a
Emaxa (%)
Compd
R
Compd
R
(l
M)
4.16 Â 10À5
100
NT(8–13)
—
4.16 Â 10À5
100
NT(8–13)
—
2
5
6
>100
—
34
>100
—
N
H
COOMe
OH
N
H
COOMe
COOH
3
3
5
6
N
H
>100
>100
—
—
2
>100
—
N
H
N
H
COOH
CO OH
COOMe
2
7
5.17 ± 1.09
92.35 ± 4.15
N
N
H
NH
37
>100
>100
—
—
N
N
N
H
2
2
8
9
N
H
COOH
COOH
>100
>100
—
—
38
N
H
N
H
a
NTSR1 potency was measured relative to the EC100 (100 nM) of the NT(8–13)
3
3
0
1
>100
—
peptide control average ± SEM (n = 4 unless otherwise indicated). Emax was calcu-
lated as the % of the response obtained with the NT(8–13) peptide.
N
H
COOH
Finally, as a further step of our large program of structural
manipulations, we decided to explore the significance, in control-
ling potency, of substituents at the 6-position of the indole hetero-
cycle (Table 4). Three analogues (compds 39, 40 and 41) were
synthesized and screened against NTSR1. All three compounds
showed similar trends in potency and efficacy observed with com-
pounds bearing identical substituents in position 5 of the indole
nucleus (compds 8, 17 and 21). According to these biochemical
data we can speculate that aromatic rings placed in either position
4.33 ± 3.23
14.94 ± 20.97
N
H
COOH
CO OH
COOMe
3
3
2
3
>100
>100
—
—
N
H
5
or 6 of the indole scaffold may partially protrude outside the
N
H
NTSR1 binding domain, establishing weak intermolecular interac-
tions with the binding site amino acid residues and therefore mak-
ing only little contribution to activity and efficacy.
a
NTSR1 potency was measured relative to the EC100 (100 nM) of the NT(8–13)
peptide control average ± SEM (n = 4 unless otherwise indicated). Emax was calcu-
lated as the % of the response obtained with the NT(8–13) peptide.
In order to confirm our small molecules were indeed acting as
agonists at the neurotensin-1 receptor, we screened selected key
compounds in the presence and absence of an antagonist. In the
presence of antagonist 5 the NTSR1 stimulatory activity of
NT(8-13), 7, 8, 12, 17, 21, 27, 39 and 40 was abolished, proving
these compounds as robust NTSR1 agonists (Supplementary
material, Fig. S1).
To further demonstrate the importance of the leucine residue
for NTSR1 activity in this chemical series, an identical SAR investi-
gation, previously generated for compound 8, was developed for
compound 17 (EC50 = 3 lM; Emax = 100%). Consistent with data
reported in Table 2, replacement of the leucine side chain in com-
pound 17 with alternative amino acid residues was found to be
detrimental for activity (Table 3). Again, masking the carboxylic
acid of leucine as methyl ester (compd 34) abolished activity. Col-
lectively, these data suggest that the bulky aliphatic isobutyl group
and the carboxylic acid functionalities of leucine are essential
structural features for NTSR1 agonist activity. Notably, this is not
surprising as both neurotensin and several small-molecule NTSR1
agonists reported in the literature (e.g., compds 2 and 4) contain
a leucine residue in their chemical structures.
In summary, structural optimization of the known indole-based
NTSR1 partial agonist 1, identified at Wyeth, led us to the discovery
of NTSR1 agonists with improved potency and efficacy. Indeed,
several compounds of this chemical series were found to have sin-
gle-digit micromolar potency against NTSR1 and full agonist
behaviour, showing ꢀ90-fold potency improvement compared to
Wyeth compound 1 (EC50 = 178 lM; Emax = 17%). Further biological
evaluation and potency optimization of our best hit compound 8
are currently underway in our laboratories. As neurotensin is
believed to elicit most of its biological functions in the brain, the

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Acknowledgments
This work was supported by the National Institute on Drug
Abuse (DA029968 to P.H.M. and T.M.K.).
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Supplementary data
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