Development of 4-Heteroarylamino-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octanes] as α7 Nicotinic Receptor Agonists

Article abstract of DOI:10.1021/acsmedchemlett.6b00471

We describe the synthesis of quinuclidine-containing spiroimidates and their utility as α7 nicotinic acetylcholine receptor (nAChR) partial agonists. A convergent synthetic route allowed for rapid SAR investigation and provided a diverse set of fused 6,5-heteroaryl analogs. Two potent and selective α7 nAChR partial agonists, (1′S,3′R,4′S)-N-(7-bromopyrrolo[2,1-f ][1,2,4]triazin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (20) and (1′S,3′R,4′S)-N-(7-chloropyrrolo[2,1-f ][1,2,4]triazin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (21), were identified. Both agonists improved cognition in a preclinical rodent model of learning and memory. Additionally, 5-HT_3A receptor SAR suggested the presence of a steric site that when engaged led to significant loss of affinity at that receptor.

Full text of DOI:10.1021/acsmedchemlett.6b00471

Letter
pubs.acs.org/acsmedchemlett
Development of 4‑Heteroarylamino-1′-azaspiro[oxazole-5,3′-
bicyclo[2.2.2]octanes] as α7 Nicotinic Receptor Agonists
Matthew D. Hill,* Haiquan Fang, H. Dalton King, Christiana I. Iwuagwu, Ivar M. McDonald,
James Cook, F. Christopher Zusi, Robert A. Mate, Ronald J. Knox, Debra Post-Munson, Amy Easton,
Regina Miller, Kimberley Lentz, Wendy Clarke, Yulia Benitex, Nicholas Lodge, Robert Zaczek,
Rex Denton, Daniel Morgan, Linda Bristow, John E. Macor, and Richard Olson
Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States
S
* Supporting Information
ABSTRACT: We describe the synthesis of quinuclidine-containing spiroimidates and their utility as α7 nicotinic acetylcholine
receptor (nAChR) partial agonists. A convergent synthetic route allowed for rapid SAR investigation and provided a diverse set
of fused 6,5-heteroaryl analogs. Two potent and selective α7 nAChR partial agonists, (1′S,3′R,4′S)-N-(7-bromopyrrolo[2,1-
f ][1,2,4]triazin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (20) and (1′S,3′R,4′S)-N-(7-chloropyrrolo[2,1-
f ][1,2,4]triazin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (21), were identified. Both agonists improved
cognition in a preclinical rodent model of learning and memory. Additionally, 5-HT3A receptor SAR suggested the presence of a
steric site that when engaged led to significant loss of affinity at that receptor.
KEYWORDS: α7 nAChR, schizophrenia, novel object recognition, quinuclidine
chizophrenia is a debilitating psychiatric disorder that
ties.12 The ability to affect biological functions such as memory
Saffects 1% of the general population. Related health care and sensory gating make the α7 nAChR an attractive target for
pharmaceutical manipulation, and such efforts could lead to
treatments for neurological disorders such as schizophrenia and
Alzheimer’s disease.13,14
costs are estimated to be in the tens of billions of dollars in the
US market alone. The chronic nature of this disease leads to a
decrease in life expectancy by approximately 10 years due to a
2−3-fold increased rate of all-cause mortality.1 Symptomatic
domains associated with schizophrenia are characterized as
positive, negative, or cognitive in nature. Existing therapies can
effectively alleviate positive symptoms; however, therapeutic
efficacy against negative and cognitive symptoms has remained
a challenge. Additionally, treatment has proven difficult as a
result of poor compliance due to extrapyramidal and metabolic
side effects of existing medications.
Preclinical and early clinical data suggest that α7 neuronal
nicotinic acetylcholine receptor (nAChR) agonists show
promise as treatments of cognitive and negative symptoms in
schizophrenia patients.2−6 The α7 nAChR is a homopentameric
ligand-gated ion channel that is centralized in the cortex,
hippocampus, and subcortical limbic areas, which is associated
with learning and memory.7−9 The role that α7 nAChR plays in
memory, sensory gating, and neuronal plasticity has inspired
both knockout animal and pharmaceutical studies to probe the
validity of this receptor as a target for improvements in learning
and memory.10,11 The outcomes of these studies show
enhancement in animal learning and memory function, reversal
of memory and sensory gating deficits, and anxiolitic proper-
Acetylcholine structural mimics are the predominant α7
nAChR ligands described in the literature, most of which arose
from AR-R17779, the first selective α7 nAChR agonist
identified.15 These molecules typically include three pharmaco-
phoric elements: a rigid basic amine, a central polar group with
a hydrogen-bond acceptor, and a lipophilic aryl/heteroaryl
group attached to the central region (Figure 1).16,17 In our
previous disclosure, we described a novel series of quinuclidine-
containing spirocyclic α7 nAChR partial agonists 1 built on
similar principles (Figure 1).18 In this chemotype, the
quinuclidine functioned as the rigid amine, and the spiroimidate
provided a centralized hydrogen-bond acceptor. Importantly,
this spiroimidate series 1 provided partial agonists, which are
expected to mitigate receptor desensitization associated with
full agonism.19,20 It should be noted that many earlier reported
α7 nAChR agonists also act as serotonergic 5-HT3A antagonists
due to high sequence homology between the two recep-
Received: November 19, 2016
Accepted: December 1, 2016
Published: December 1, 2016
© XXXX American Chemical Society
A
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Letter
geometry (Table 1). Specifically, unsubstituted heteroaryls
provided minimal selectivity over 5-HT3A inhibition (repre-
sentative compounds 10−12, 14, 16); however, the addition of
simple substituents often led to dramatic changes in potency at
the 5-HT3A receptor. For example, N-methylation of 7H-
pyrrolo[2,3-d]pyrimidine afforded highly selective spiroimidate
13, whereas similar unsubstituted analogs 10−12 were
unselective. This promising result suggested that the equivalent
elaboration of other fused 6,5-heteroaryls with the same ring
geometry could result in higher selectivity.
Subsequent SAR efforts expanded into 6,5-fused heteroaryl
groups with bridgehead nitrogen atoms (Table 1, compounds
14−20). Pyrrolo[1,2-a]pyrazine 16 was very potent in the α7
nAChR FLIPR assay, but was a potent 5-HT3A antagonist as
well. Considering the increased selectivity we observed with 7-
methyl-7H-pyrrolo[2,3-d]pyrimidine 13, 6-bromopyrrolo[1,2-
a]pyrazine 17 was prepared. Notably, installation of the C6
bromide provided a greater than 400-fold selectivity improve-
ment over the parent pyrrolo[1,2-a]pyrazine 16 via diminution
of the 5-HT3A receptor affinity. Methylation at C3 of the
pyrrolo[1,2-a]pyrazine ring led to the opposite result (e.g., 3-
methylpyrrolo[1,2-a]pyrazine 18). Subsequent synthesis of
pyrrolo[2,1-f ][1,2,4]triazines 19 and 20 provided spiroimidates
with equipotent activity at the α7 nAChR. Importantly, the 5-
HT3A receptor SAR trend was consistent with similar
heteroaryls and suggested there was a steric site in the 5-
HT3A receptor that when engaged led to significant loss of
affinity at that receptor (e.g., the 7-bromopyrrolo[2,1-f ][1,2,4]-
triazine 20 demonstrated a selectivity boost of more than 900-
fold over the des-bromo analog 19).
After weighing factors such as potential for selectivity against
5-HT3A, α7 nAChR potency, and metabolic stability,27 the
pyrrolo[2,1-f ][1,2,4]triazine bicycle was chosen for further SAR
studies. Several analogs were prepared in order to probe the
effects of substitution on potency and selectivity (21−27).
Relative to unsubstituted analog 19, chlorination and
fluorination at C7 led to losses in potency and selectivity
that, in conjunction with data generated for the bromo analog
20, appear to trend with substituent volume (compounds 21−
23). C7 methylation led to high potency and selectivity (23). A
C7 cyano substituent (24) was also reasonably potent, fitting
with the observation that large substituents at C7 were more
potent than smaller substituents. Bromination at C6 and C5
provided analogs 25 and 26 and led to an increase in 5-HT3A
receptor potency with a greater than 42-fold loss in selectivity
over 5-HT3A receptor antagonism (vs C7-bromo analog 20).
The potency/selectivity profile of 5,7-dibromopyrrolo[2,1-
f ][1,2,4]triazine 27 was also less attractive than monosub-
stituted compounds 20, 21, and 23.
Figure 1. Examples of known α7 nAChR ligands.
tors.21−24 Interestingly, we were previously able to build in
selectivity for the α7 nAChR with heteroaryl modifications and
changes to biaryl ring geometries (e.g., 2 vs 3).18
We have reported that potent α7 nAChR partial agonist 3
(Figure 1) was efficacious in the novel object recognition
(NOR) cognition assay: memory retention in mice was
observed at 0.1, 0.3, and 1.0 mg/kg, demonstrating its central
activity as an α7 nAChR agonist.18 Certain analogs with similar
concentration−response electrophysiology (EP) profiles and
pharmacokinetic properties had significantly different activity
profiles in behavioral assays. Translational considerations
prompted additional SAR studies to improve our understanding
of in vitro profiles and their predictive power with respect to in
vivo models used in our preclinical progression scheme.
Additionally, identification of a suitably selective molecule
with an acceptable off-target profile remained challenging for
the field.13,14,16,17 For example, certain analogs demonstrated
low micromolar inhibition of the hERG potassium channel, an
activity associated with cardiovascular liabilities.
Herein we report heteroaryl modifications to 1 that improve
selectivity over 5-HT3A antagonism and reduce potency at the
hERG channel, thus mitigating hERG-related cardiovascular
risks. Outside of preliminary work focused on establishing the
minimum pharmacophore, our previous efforts were largely
confined to unsubstituted 6,6-fused biaryls.18 In this study we
prepared 6,5-fused systems with varying substitution patterns to
further probe the hypothesized lipophilic pocket of the α7
nAChR. New spiroimidates were readily synthesized in
enantiopure form using an established route (Scheme 1).
Scheme 1. Synthetic Route to Spiroimidates 7
Select examples of pyrrolo[2,1-f ][1,2,4]triazine derivatives
with attractive α7 nAChR FLIPR profiles were progressed to
electrophysiology studies. Analogs were evaluated for potency
and efficacy (Ymax), as measured by patch clamp using HEK-293
cells that express rat α7 nAChR.27 Compounds 20 and 21 were
the two most potent pyrrolo[2,1-f][1,2,4]triazine-containing
analogs with selectivity over 5-HT3A (280 nM and 400 nM,
respectively). The area and peak Ymax values were consistent
with partial agonism (area/peak: 62%/26% and 73%/28%,
respectively).28
This protocol involved coupling and requisite cyclization of
amino alcohol 4 with a structurally diverse set of
isothiocyanates 5 and imidodithioates 6 to provide spiroimidate
products 7.
We screened for both α7 nAChR agonism and 5-HT3A
antagonism in Ca2+-based FLIPR (fluorescence image plate
reader) assays.18,25,26 The relationship between these two
values is reported for each compound as the FLIPR selectivity
ratio. Pyridine-, diazine-, and triazine-derived 6,5-fused bicycles
provided highly variable levels of α7 nAChR potency and
selectivity over 5-HT3A that appear to be independent of ring
The quinuclidine-containing spiroimidate core was shown to
be optimal in earlier series.18 In order to confirm these
observations, several modifications were made to the spirocycle
with 7-chloropyrrolo-[2,1-f ][1,2,4]triazine (Table 2). This
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Table 1. α7 nAChR and 5-HT3A FLIPR Data for Various Heteroaryl-Containing Spiroimidates
a
b
Number of determinations in parentheses. Ratio = 5-HT3A IC50/α7 EC50.
fused heterocycle was chosen because of its superior overall
profile, including α7 nAChR selectivity, EP potency, and hERG
profile (data not shown). The S-enantiomer 28 of spiroimidate
21 was prepared and exhibited only a slight loss in α7 nAChR
potency and 5-HT3A selectivity.18 Target potency dropped
considerably when the imidate heteroatoms were exchanged
(compound 29). Homologation of the imidate core provided
spirocycle 30, which was considerably weaker and failed to offer
any improvement over lead spiroimidate 21.18 Lastly, 2.2.1-
bicyclic amine analog 3129 was prepared, but was found to be
nonselective and provided no advantage over the quinuclidine
moiety.
reasonable potency in the FLIPR assays. We used the mouse
NOR behavioral assay that measures visual recognition
memory, which is an impaired cognitive domain in
schizophrenia patients.30 In this experiment, both drug-treated
and control mice are shown two identical objects followed by a
24 h delay, a time sufficient for natural forgetting. Upon
reintroduction of a familiar object with a novel object,
improved memory can be measured as time spent exploring
the novel object due to the innate tendency of mice to explore
unfamiliar objects. Both halo analogs (20 and 21) led to
significantly increased time spent exploring the novel object
over the familiar object. 7-Bromopyrrolo[2,1-f ][1,2,4]triazine
20 was active (p < 0.05) with an MED = 0.01 mg/kg and
plasma concentration = 7 nM (B/P = 4.9, Figure 2). 7-
Partial agonists 20 and 21 were chosen to advance into in
vivo efficacy models because of excellent selectivity and
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fraction levels were very high (50−75%), uncorrected plasma
exposures were used to calculate hERG margins. Plasma
exposures at the MED of bromo 20 and chloro 21 were 400-
fold and 170-fold31 lower, respectively, than the hERG IC50
values.
Table 2. α7 nAChR and 5-HT3A FLIPR Data for 7-
Chloropyrrolo-[2,1-f ][1,2,4]triazine Analogs
In summary, 6,5-fused bicyclic heteroaryls were appended to
a quinuclidine-containing spiroimidate core to provide novel,
potent α7 nAChR partial agonists. In the course of these
studies, we discovered a very steep SAR for 5-HT3A receptor
affinity driven by rigid steric interactions. The pyrrolo[2,1-
f ][1,2,4]triazine moiety emerged as a leading candidate for
additional elaboration due to attractive α7 nAChR FLIPR
potency and potential for increasing selectivity over 5-HT3A
antagonism. Pyrrolo[2,1-f ][1,2,4]triazines 20 and 21 signifi-
cantly improved memory retention in the NOR behavioral
model and were evaluated in a hERG patch clamp assay. These
results warranted follow-up in vivo studies, the results of which
will be reported in due course.
ASSOCIATED CONTENT
■
S
* Supporting Information
a
b
c
Number of determinations in parentheses. Racemic mixture. des-
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acsmedchem-
lett.6b00471.
d
Chloro analog. Ratio = 5-HT3A IC50/α7 EC50.
Chloropyrrolo[2,1-f][1,2,4]triazine 21 was similarly active (p <
0.01), with an MED = 0.03 mg/kg and plasma concentration =
18 nM (B/P = 1.9, Figure 2).
Both leads 20 and 21 were evaluated in the hERG patch
clamp assay to measure for potential cardiovascular toxicity.18
7-Bromopyrrolo[2,1-f][1,2,4]triazine 20 (hERG IC50 = 2.5
μM) and 7-chloropyrrolo[2,1-f ][1,2,4]triazine 21 (42% hERG
inhibition at 3.0 μM) were considered in the context of plasma
drug levels at respective MEDs. Since mouse plasma free
Experimental procedures and characterization data for
key compounds, and details of in vitro and in vivo assays
(PDF)
AUTHOR INFORMATION
Corresponding Author
■
*Tel: 1-203-677-7102. Fax: 1-203-677-7884. E-mail: matthew.
hill@bms.com.
ORCID
Matthew D. Hill: 0000-0002-5979-4592
James Cook: 0000-0002-1948-4039
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Bei Wang and Rulin Zhao for large-scale preparation
of compound 21.
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