N-[5-(5-fluoropyridin-3-yl)-1H-pyrazol-3-yl]-4-piperidin-1-ylbutyramide (SEN78702, WYE-308775): A medicinal chemistry effort toward an α7 nicotinic acetylcholine receptor agonist preclinical candidate

Article abstract of DOI:10.1021/jm3013568

α7 nicotinic acetylcholine receptors (α7 nAChR) represent promising therapeutic candidates for the treatment of cognitive impairment associated with Alzheimer's disease (AD) and schizophrenia. A medicinal chemistry effort around previously reported compound 1 (SEN15924, WAY-361789) led to the identification of 12 (SEN78702, WYE-308775) a potent and selective full agonist of the α7 nAChR that demonstrated improved plasma stability, brain levels, and efficacy in behavioral cognition models.

Full text of DOI:10.1021/jm3013568

Brief Article
pubs.acs.org/jmc
N‑[5-(5-Fluoropyridin-3-yl)‑1H‑pyrazol-3-yl]-4-piperidin-1-
ylbutyramide (SEN78702, WYE-308775): A Medicinal Chemistry Effort
toward an α7 Nicotinic Acetylcholine Receptor Agonist Preclinical
Candidate
Riccardo Zanaletti,*,† Laura Bettinetti,† Cristiana Castaldo,† Ilaria Ceccarelli,† Giuseppe Cocconcelli,†
Thomas A. Comery,‡ John Dunlop,‡ Eva Genesio,† Chiara Ghiron,† Simon N. Haydar,‡ Flora Jow,‡
Laura Maccari,† Iolanda Micco,† Arianna Nencini,† Carmela Pratelli,† Carla Scali,† Elisa Turlizzi,†
and Michela Valacchi†
†Siena Biotech SpA, Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy
‡Neuroscience Research Unit, Pfizer, Eastern Point Road, Groton, Connecticut 06340, United States
S
* Supporting Information
ABSTRACT: α7 nicotinic acetylcholine receptors (α7 nAChR) represent promising therapeutic candidates for the treatment of
cognitive impairment associated with Alzheimer’s disease (AD) and schizophrenia. A medicinal chemistry effort around
previously reported compound 1 (SEN15924, WAY-361789) led to the identification of 12 (SEN78702, WYE-308775) a potent
and selective full agonist of the α7 nAChR that demonstrated improved plasma stability, brain levels, and efficacy in behavioral
cognition models.
approach is the use of positive allosteric modulators (PAMs),
which enhance the effect elicited by the endogenous ligand
without directly activating or desensitizing the target
receptor.10
Concerning the discovery and development of novel α7
nAChR agonists, we have previously reported 1 (SEN15924,
WAY-361789, Table 1). This exhibited a promising profile,
efficacy in rodent cognition models but limited plasma
stability and brain exposure.11 We describe herein the
chemical exploration around this compound aimed at
improving these properties.
INTRODUCTION
■
Neuronal nicotinic acetylcholine receptors are a family of
ligand gated ion channels that participate in many
physiological functions. They are distributed in the central
and peripheral nervous system and are permeable to cations
such as Na+, K+, and Ca2+. These receptors are combinations
of five subunits that can assemble as homopentamers or
heteropentamers of 12 distinct subunits (α2−α10, β2−β4).
They share a common basic structure but have specific
pharmacological and functional properties due to the different
subunit combinations. Changes in their number and/or
function are associated with a number of pathophysiological
conditions.1−3
The homomeric α7 nAChR is one of the most abundant
nicotinic receptors in the human brain and is highly expressed
in regions associated with learning and memory such as the
cerebral cortex and the hippocampus.4 Experimental evidence
supports the involvement of the α7 neuronal nAChR in
schizophrenia and Alzheimer’s disease.5,6 Schizophrenia is
characterized by positive (hallucinations, delusions) and
negative symptoms (reduced affect, social withdrawal, low
motivation, disorganized thoughts) and cognitive impairment
(decreased attention, memory deficits). While positive
symptoms are partially managed with current medications,
cognitive deficits and negative symptoms still remain an
unmet medical need. Cognitive impairment is an important
hallmark of Alzheimer’s disease as well. Modulators of the α7
nAChR have extensively been studied for the treatment of
cognitive deficits in schizophrenia and AD.7−9
Table 1. Effect of Chain Length on Activity
rotatable
bonds
a
compd
n
ClogP
MW
α7 pEC50 SEM (n)
1
2
3
4
3
1
2
4
1.9
1.7
1.4
2.4
413.5
385.5
399.5
427.5
8
6
7
9
6.90 0.02 (28)
5.07 0.11 (2)
6.04 0.04 (2)
5.92 0.11 (2)
a
All functional activities were measured in a calcium flux assay. Data
were averaged from multiple experiments (n). All the reported
compounds gave Emax > 90% of nicotine and were considered to be full
agonists. Nicotine under the same conditions had pEC50 = 5.97
0.01, Emax = 102% 1.3 (n = 62).
In the past decade there has been a continuing effort to
develop new α7 nAChR agonists with better properties, and
many of them have advanced into clinical trials. An alternative
Received: June 19, 2012
Published: October 19, 2012
© 2012 American Chemical Society
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Journal of Medicinal Chemistry
Brief Article
α7 activity.11 This observation is in agreement with the results
reported in Table 2 where the least active compound 7 is the
one with the weakest basic center.
The steric hindrance, exemplified by the modulation of the
ring size, has limited impact on the α7 activity; no relevant
loss of potency is noted moving from 5 to 6 and from 7 to 8.
Compound 5, bearing a piperidine moiety, was the most
promising in terms of α7 activity and selectivity for the
subsequent SAR investigation (no agonist activity was ever
observed on the α1, α3, and 5HT3 receptors for any of the
compounds tested).
RESULTS AND DISCUSSIONS
■
The initial focus of the present study was the exploration of
carbon chain (CC) length to establish the most favorable
distance between two pharmacophoric points, typical of our
series: the basic center and the amide group (Figure 1).
The exploration of the second ring of the biaryl system was
the next focus. A series of collected data are reported in Table
3. In general, these modifications modestly affected α7
Figure 1. 2D interaction map of our series from docking studies into
α7 homology model: green, hydrophobic residues; purple, positively
charged residues; blue, polar residues; red, negatively charged
residue; dotted lines, H-bond with amino acid side chain; pink
solid lines, H-bond with amino acid backbone; green solid line,
stacking interaction; red empty circle, water molecule.
Table 3. ClogP, Activity, and hERG inhibition for 5−12
According to our docking studies into a homology model
for the human α7 receptor,11 the basic center is involved in
the well-known interaction with the backbone carbonyl of
W143 while the amide−pyrazole system is prone to give
hydrogen bonding contacts to Y185. The CC acts as a spacer
between these two and is therefore expected to play a
significant role in modulating receptor activity.
Starting from 111 (Table 1), we noticed that a reduction of
two methylene units of the chain length resulted in less active
2. It is lacking the required distance to allow the basic
nitrogen and the amide−pyrazole system to engage the
pharmacophoric interactions with the protein. On the
contrary, the reduction and the elongation by one methylene
unit of the carbon chain length were well tolerated and led to
similarly active 3 and 4.
a
b
All functional activities were measured in a calcium flux assay. hERG
response was obtained from CHO cells stably expressing the channel.
NT indicates not tested.
Since it is commonly accepted that a high molecular weight
and a high number of rotatable bonds could unfavorably affect
the brain permeability,12 we opted for the 3CC analogue 3 as
the initial tool for further SAR studies.
We then moved to the exploration of the region bearing
the basic center in 3. A representative set of the molecules
synthesized is shown in Table 2 with their α7 activity and
selectivity over homologous receptor subtypes (α1, α3, and
5HT3). We previously noted for our series that as long as the
pKa is sufficient to have the basic nitrogen protonated at
physiological pH, the basicity has no dramatic effect on the
activity, and when the phenyl ring was replaced by an alkyl
group, such as in 9, complete loss of activity was recorded.
The related receptors (α1, α3, and 5HT3) were usually
unaffected. Limited and unpredictable activity was sometimes
observed for α3 and α1 such as in 10 and 11, respectively
(Table 1, Supporting Information). Compounds 5, 10, and 11
were advanced into our ADME characterization stage, and
they proved to have a fair overall profile (Table 2, Supporting
Information).
Interestingly the 3CC analogues showed a consistent
improvement of the plasma stability compared with the
corresponding 4CC counterpart (1 and 3 Table 2, Supporting
Information). We made the hypothesis that the closer
proximity of the basic center to the amide bond in the
3CC analogues results in decreased affinity for the proteases/
esterase binding site compared to the 4CC analogues. These
result in lower amide hydrolysis rates.
Table 2. pKa, Activity, Selectivity for 5−8
b
selectivity pIC50 (μM)
b
α7 activity
a
compd
X
n
pKa
pEC50 SEM (n)
α1
α3
5HT3
The most promising of these molecules were also
characterized in a hERG inhibition assay; 5, 10, and 11
presented some inhibition (Table 3), indicating a potential
cardiac toxicity.
5
6
7
8
CH2
CH2
O
1
2
1
2
9.4
9.6
7.2
8.6
6.38 0.05 (5)
6.04 0.04 (2)
5.18 0.11 (2)
5.93 0.02 (2)
<4.5
<4.5
NT
<4.5
5.1
<4.5
<4.5
NT
NT
NT
O
NT
NT
In light of the known effect of the ClogP on the hERG
inhibition,13 we decided to modulate this parameter in our
compounds by means of single point modifications. As the
replacement of a phenyl ring with the corresponding pyridyl
gives an approximate ClogP reduction of 1 log unit, we
a
b
pKa was calculated using ACD/pKa DB, release 12.00. All functional
activities were measured in a calcium flux assay. Only compounds with
α7 pEC50 higher than 6 were considered suitable for the selectivity
evaluation. NT indicates not tested.
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Journal of Medicinal Chemistry
Brief Article
synthesized the pyridine analogue of 11, compound 12 (Table
3), having an acceptable hERG inhibition (15.8 μM).
Compound 12 displayed physicochemical properties (MW,
ClogP, ClogD, and MPSA) predictive of good brain
penetration and a promising ADME profile (Table 3,
Supporting Information). The molecule met all the desired
criteria to be advanced to PK studies, where it showed
moderate clearance (23 mL min−1 kg−1), excellent bioavail-
ability, and a rapid absorption. This is demonstrated by the
Tmax that occurs within 1 h of dosing. The BBB assessment
highlights a good brain penetration with good brain levels
(Cmax of 55 ng/g).
(PPI, Figure 3), a classic paradigm for evaluating potential
treatment for schizophrenia.
The affinity of 12 for its target was confirmed in a binding
assay using the rat receptor (0.39 μM), while the potency was
further demonstrated in electrophysiological studies in rat and
human receptor expressing cell lines (10.7 and 10.0 μM,
respectively, full agonist functional responses). The difference
(14-fold) between the EC50 values, obtained using the oocyte
expression system (10.7 μM) and the calcium influx
methodology (0.74 μM), is in line with other literature
observations. This could be ascribed to an overestimation of
the EC50 values recorded in electrophysiology.14,15 In addition,
12 (evaluated at 10 μM) showed inhibition of < 50% in a
panel of 70 receptors with the only exception of the α2a, α2b,
α2c adrenergic receptors and the H3 histaminic receptor (%
inhibition at 10 μM: 73, 64, 57, and 62, respectively). Good
selectivity profile was then confirmed when these results are
compared to the functional ion-flux EC50.
In light of the optimal results obtained, 12 was evaluated in
in vivo efficacy models. The molecule displayed efficacy in a
rat model of cognitive functions, in particular a form of
episodic memory measured in the novel object recognition
test (NOR, Figure 2A). In perceptual processing 12 showed
the ability to attenuate pharmacologically induced deficits via
the glutamatergic system in a prepulse inhibition rat model
Figure 3. Ability of 12 to normalize an MK-801 induced disruption
of PPI of the acoustic startle response in rats: blue column, vehicle,
no MK-801; red columns, vehicle or 12 at several doses administered
orally.
Treatment with 12 induced memory enhancement in the
NOR at several doses when administered orally using a 24 h
delay time as amnesic factor, with a minimum efficacious dose
of 3 mg/kg po (Figure 2A). Importantly, the induced memory
enhancement in the NOR experiment was blocked by
pretreatment with the α7 antagonist methyllycaconitine
(MLA, 5 mg/kg ip), demonstrating the direct involvement
of the α7 nAChR (Figure 2B). Moreover, 12 reversed a
dizocilpine (MK-801, 0.085 mg/kg po) induced deficit in PPI
with a minimum efficacious dose of 3 mg/kg po. (Figure 3).
It is known that the brain concentrations of other α7
agonists (for example, PHA-543,613)16 to achieve efficacy in
vivo during behavioral tests are unable to activate α7 nAChRs
in vitro. Recently the positive outcome of in vivo experiments,
even at in vitro subpharmacological doses, has been
interpreted as coagonist activity of EVP-6124 with acetylcho-
line on α7 nAChRs.17 To benchmark our compound in this
respect, we attempted some pharmacokinetic/pharmacody-
namic considerations. After a single oral dose of 3 mg/kg,
corresponding to the minimum efficacious dose in both our
behavioral in vivo tests (NOR and PPI), 12 achieved a free
brain concentration of 33 nM.18 The fold EC50 of 0.045,
calculated as the ratio between the unbound concentration in
the brain (Cfu brain, 33 nM) and the α7 EC50 (740 nM),
indicates that in vivo efficacy is achieved at brain levels that
are a small fraction of the EC50. This observation is in
agreement with the previously mentioned literature stating
that limited receptor activation is enough to obtain in vivo
efficacy.17
In terms of safety, 12 was subjected to a preliminary
toxicology assessment with a 7-day tolerability study in rat
and found to be well tolerated up to a dose of 100 mg kg−1
day−1.
In conclusion, the overall characterization of 12 demon-
strated good in vitro properties, optimal in vivo efficacy, and a
low toxicity risk. In particular, the minimum efficacious dose
in conjunction with the tolerability study promises the
potential for a wide therapeutic window.
Figure 2. Induced memory enhancement of 12 in NOR using
spontaneous decay of memory (24 h time interval) as amnesic factor
in rats: blue columns, exploration time of new object; red columns,
exploration time of familiar object; (A) effects of several doses of 12
administered orally 30 min before T1 exploration; (B) reversion of
memory enhancement induced by 12 using pretreatment (5 min
before the orally administration of 12 at 3 mg/kg) with MLA.
CHEMISTRY
■
All the compounds investigated were prepared using two
general synthetic strategies (route A and route B).
Route A (Scheme 1) consisted of a three-step synthesis:
commercially available 4-bromobutyric acid ethyl ester (13)
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Journal of Medicinal Chemistry
Brief Article
Scheme 1. Synthesis of 4-Aminobutyric Acid Amide via
Route A
EXPERIMENTAL SECTION
■
a
N-[5-(5-Fluoropyridin-3-yl)-2H-pyrazol-3-yl]-4-piperidin-1-
ylbutyramide (12). To a suspension of 4-piperidin-1-ylbutyric acid
hydrochloride (175 mg, 0.84 mmol) in 1,2-dichloroethane (3 mL)
was added N,N′-carbonyldiimidazole (136 mg, 0.84 mmol). The
mixture was stirred at room temperature for 2 h (when activation of
the amino acid was complete, dissolution of the suspension was
generally observed). 5-(5-Fluoropyridin-3-yl)-2H-pyrazol-3-ylamine
20 (100 mg, 0.56 mmol) was added. The mixture was stirred for
a further 10 h until reaction completion (as monitored by LC−MS).
The solvent was washed with saturated Na2CO3 solution, extracted,
and removed under reduced pressure. The crude product was
purified by preparative HPLC to give 130 mg of the title compound
a
(a) R1R2NH, toluene, reflux; (b) NaOH, water, reflux; (c) CDI, 1,2-
dichloroethane, 50 °C.
was reacted through a nucleophilic substitution with different
amines to afford the corresponding amino esters (14 and 15),
which were then hydrolyzed with NaOH to give the desired
4-aminobutyric acids (16 and 17). The amino acids obtained
were activated with N,N′-carbonyldiimidazole and coupled to
3-aminopyrazoles (18−20, Chart 1, Supporting Information)
in dichloroethane to afford the targeted products amino-
butyric acid amide (8, 9, and 12).
1
as formate salt (61%, yield). H NMR (400 MHz, methanol-d4) δ
8.39 (s, 1H), 8.30 (ddd, J = 9.7, 7.6, 1.9 Hz, 1H), 8.19 (dt, J = 5.0,
1.5 Hz, 1H), 7.41 (ddd, J = 7.6, 4.8, 1.9 Hz, 1H), 6.87 (s, 1H),
3.21−3.09 (m, 4H), 2.60 (t, J = 6.7 Hz, 2H), 2.18−2.03 (m, 2H),
1.78 (d, J = 72.5 Hz, 8H). 13C NMR/DEPT (101 MHz, methanol-
1
d4) δ 172.62, 159.78 (d, JCF = 245 Hz, Cquat), 148.12 (Cquat), 147.87
2
(d, JCF = 15 Hz, CH), 145.18 (Cquat), 139.88 (CH), 123.59 (CH),
Route B (Scheme 2) was a one-pot synthesis comprising
amide coupling between ω-bromoalkanoyl chlorides (21a,
115.84 (Cquat), 98.17 (CH), 58.30 (CH2), 54.73 (CH2), 34.05
(CH2), 24.89 (CH2), 23.31 (CH2), 21.28 (CH2). MS (ES) m/z: 332
(M + 1). UPLC (basic method): tR = 0.71 min; area 100%. HRMS:
calcd for C17H22N5OF + H+, 332.188 11; found (ESI, [M + H]+
obsd), 332.188 14.
Scheme 2. Synthesis of 5-Aminopentanoic acid Amide via
a
Route B
ASSOCIATED CONTENT
* Supporting Information
■
S
General procedures, characterization data for all new
compounds, additional properties for 1, 3, and 5−12, and
biological assay procedures. This material is available free of
charge via the Internet at http://pubs.acs.org.
a
(a) DIPEA, DMA, −10 °C; (b) R1R2NH, NaI, DMA, 50 °C.
21b, and 21c) and 3-aminopyrazoles (18, 22, and 23, Chart
1, Supporting Information) in dimethylacetamide to give the
corresponding 4-bromoalkanoylamides, followed by in situ
addition of the desired amine and NaI to afford final
compounds 2−7, 10, and 11.
AUTHOR INFORMATION
Corresponding Author
*Phone: +39 0577381474. Fax: +39 0577381323. E-mail:
riccardozanaletti@hotmail.com.
■
Notes
3-Aminopyazoles 18, 19, and 22 were found to be
commercially available. The synthesis of 20 and 23 is
reported in the Supporting Information.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
CONCLUSIONS
We thank Stefano Gotta and Nicola Caradonna for generation
of HRMS results, and Michele Guerrini for supporting
behavioral tests.
■
The evolution of a previously reported chemotype led us to
the identification of 12 (SEN78702, WYE-308775). Although
the activity of this compound was not improved compared to
1, we fulfilled the original goals of the present work: improved
plasma stability and brain penetration (compare data for 12
with data for previously reported 1).11
ABBREVIATIONS USED
■
AD, Alzheimer’s disease; CC, carbon chain; CHO, Chinese
hamster ovary; DMPK, drug metabolism and pharmacoki-
netics; ESI, electrospray ionization; hERG, human ether-a-go-
go related gene; HRMS, high resolution mass spectrometry;
MPSA, molecular polar surface area; nAChR, nicotinic
acetylcholine receptor; NOR, novel object recognition; PPI,
prepulse inhibition; tR, retention time; SAR, structure−activity
relationship
Compound 12 is a novel α7 agonist, which exhibited
overall an excellent balance of potency, selectivity, DMPK
data, and brain penetration. Furthermore our lead molecule
was demonstrated to improve cognitive function in a NOR
test and to reverse a pharmacological disruption in a PPI test.
In common with other reported α7 agonists, the in vivo
pharmacological effects were observed at very low brain levels,
sufficient to activate a small fraction of the receptors. The
compound was furthermore complemented by a favorable
safety profile as demonstrated by the 7-day toxicological study
in rat.
In conclusion the collective preclinical package suggests
potential interest for the progression and evaluation of 12
toward further studies and in a clinical setting for AD and
schizophrenia and raises the interest in the exploration of
novel analogues of 12 bearing a pyridyl ring.
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