Discovery of N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide as an agonist of the α7 nicotinic acetylcholine receptor: In vitro and in vivo activity

Article abstract of DOI:10.1016/j.bmcl.2008.04.070

A novel α7 nAChR agonist, N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide (3a, PHA-709829), has been identified for the potential treatment of cognitive deficits in schizophrenia. The compound shows potent and selective α7 in vitro activity, excellent brain penetration, good rat oral bioavailability and robust in vivo efficacy in a rat auditory sensory gating model.

Full text of DOI:10.1016/j.bmcl.2008.04.070

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry Letters 18 (2008) 3611–3615
Discovery of N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]furo-
[2,3-c]pyridine-5-carboxamide as an agonist of the a7 nicotinic
acetylcholine receptor: In vitro and in vivo activity
Brad A. Acker, E. Jon Jacobsen, Bruce N. Rogers, Donn G. Wishka, Steven C. Reitz,
David W. Piotrowski, Jason K. Myers, Mark L. Wolfe, Vincent E. Groppi,
Bruce A. Thornburgh, Paula M. Tinholt, Rodney R. Walters, Barbara A. Olson,
Laura Fitzgerald, Brian A. Staton, Thomas J. Raub, Michael Krause, Kai S. Li,
William E. Hoffmann, Mihaly Hajos, Raymond S. Hurst and Daniel P. Walker*
Neuroscience Research, Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA
Received 9 April 2008; revised 25 April 2008; accepted 28 April 2008
Available online 1 May 2008
Abstract—A novel a7 nAChR agonist, N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide (3a, PHA-709829),
has been identified for the potential treatment of cognitive deficits in schizophrenia. The compound shows potent and selective a7
in vitro activity, excellent brain penetration, good rat oral bioavailability and robust in vivo efficacy in a rat auditory sensory gating
model.
ꢀ 2008 Elsevier Ltd. All rights reserved.
Due in large part to the significant unmet medical need
for treating the cognitive deficits in schizophrenia,1 the
a7 nicotinic acetylcholine receptor (nAChR) has
emerged as a pharmacological target of considerable
interest in neuroscience research.2 Physiological,3 phar-
macological,4 and human genetic studies5 have strongly
established the a7 nAChR as a viable target for treating
the cognitive deficits of schizophrenia. Several a7
nAChR agonists have recently entered human clinical
trials,6 and the search for novel ligands with improved
safety profiles is desirable.
dihydrochloride (1) and demonstrated that the corre-
sponding para-chlorophenyl benzamide 2 possesses
equal activity in the a7-5HT3 chimera assay to the po-
tent a7 nAChR agonist, PNU-282987.8 Herein we detail
the synthesis, SAR and in vivo activity of an expanded
set of amides derived from amine 1.
N
N
O
O
N
N
H
H
N
O
Cl
PNU-282987
PHA-543613
As part of an on-going a7 nAChR drug discovery pro-
gram, we have been interested in the synthesis and bio-
logical profiling of novel azabicyclic aryl amides as a7
nAChR agonists.7 Our program objective was to iden-
tify novel, potent and orally bioavailable a7 nAChR
agonists with an equal or better in vitro and in vivo pro-
file to that of PHA-543613.7b Recently, we disclosed the
synthesis of (3R,5R)-1-azabicyclo[3.2.1]octane-3-amine
N
N
O
5
N
H
H2N
2HCl
3
H
H
Cl
2
1
Amides of type 3 were prepared in a single step by
HATU-mediated coupling of enantiomerically pure
amine 1 with various aryl carboxylic acids (Scheme
1).8 The custom aryl carboxylic acids utilized in this
study were either available from a commercial vendor
or prepared according to literature procedures.7b,c Prior
Keywords: Azabicyclic; a7; Nicotinic; nAChR; Schizophrenia; PHA-
543613; PHA-709829.
*
Corresponding author. Tel.: +1 636 247 1192; fax: +1 636 247
2086; e-mail: daniel.p.walker@pfizer.com
0960-894X/$ - see front matter ꢀ 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.04.070

3612
B. A. Acker et al. / Bioorg. Med. Chem. Lett. 18 (2008) 3611–3615
N
shows very similar activity in the a7-5HT3 chimera func-
a, b
O
tional assay and similar affinity in the a7 binding assay.
Compound 3a also shows comparable stability in RLM
to that of PHA-543613. With the exception of benzodi-
oxane 3f, which did not meet our potency criteria in the
functional assay, all the remaining compounds in Table
1 show similar binding and functional activity to that of
PHA-543613. This was not unexpected given the potent
a7 activity displayed by these heterocycles in the corre-
sponding quinuclidine amide series.7b,c Because our pri-
mary in vivo efficacy studies were performed in rat (vide
infra), achieving reasonable stability in RLM was an
important aspect of our screening funnel. Thus, thieno-
pyridine 3d and pyrrolopyrimidine 3e were removed
from further consideration due to their low stability in
RLM.
+
1
ArCO2H
Ar
N
H
H
58-87%
HCl
3a-f
Scheme 1. General synthetic route for the preparation of type 3
amides. Reagents and conditions: (a) HATU, i-Pr2NEt, DMF, 0ꢁ ! rt,
24 h; (b) HCl, MeOH.
SAR studies by our lab had established that there is
good modularity between the azabicyclic amine and
the aryl fragment within this class of compounds.7c
Hence, the primary interest of this study was to prepare
and profile amide 3a, which possesses the same furopyri-
dine heterocycle found in our earlier clinical candidate,
PHA-543613. However, to ensure that we did not over-
look any fortuitous benefits of amine 1, we prepared a
variety of other type 3 amides possessing aryl carboxylic
acids that showed promising in vitro activity in the cor-
responding quinuclidine series.
Compounds 3a–3c were profiled in a brain delivery
assessment (BDA) screen, which measures a com-
pound’s ability to penetrate the blood–brain barrier
(BBB) (Table 2).10 The screen consists of three assays,
a mouse brain uptake assay (MBUA), a Maden Darby
Canine Kidney (MDCK) cell permeability assay and a
multidrug resistant (MDR) P-glycoprotein (Pgp) assay.
Furopyridine 3a shows excellent CNS penetration in
the BDA screen, displaying a profile very similar to
PHA-543613. Benzofuran 3b shows reasonable BBB
penetration in this model; however, the compound also
shows brain accumulation. Given the a7 nAChR’s
Newly prepared compounds, along with a7-5HT3 chi-
mera functional potency, a7 nAChR Ki and stability
in rat liver microsomes (RLM), are detailed in Table
1; PHA-543613, PNU-282987, and chlorobenzamide 2
are shown for comparative purposes. We were pleased
to see that furopyridine 3a,9 which is structurally the
most similar analog in Table 1 to that of PHA-543613,
Table 1. 3-Amino-1-azabicyclo[3.2.1]octane aryl amides
a
Compound
Ar
a7-5HT3 chimera EC50 (nM)
a7 Kib (nM)
In vitro RLMc Eh
PHA-543613
PNU-282987
65 11 (n = 11)
128 31 (n = 16)
9.0 1.0 (n = 13)
24 8 (n = 13)
0.56
<0.27
2
190, 350
46
18, 26
2.9, 3.9
6.2, 4.7
21, 28
7.0, 6.1
14, 15
29, 32
0.37
Cl
O
3a
3b
3c
3d
3e
3f
0.51
N
81
<0.27
<0.27
0.71
O
S
182
70
N
S
N
N
129
430
0.86
N
O
0.74
O
a Cell-based FLIPR assay using SH-EP1 cells expressing the a7-5HT3 chimera. Numbers indicate EC50 values generated from individual 7-point
concentration–response relationships in triplicate; when >3 measurements were made, mean SEM is reported.
b [3H]MLA rat brain homogenate binding assay. Numbers indicate individual Ki values; when >3 measurements were made, mean SEM is
reported.
c RLM, rat liver microsomes; in vitro compound stability (Eh) is reported as the fraction of compound remaining after 30 min. as compared with the
concentration at t0.

B. A. Acker et al. / Bioorg. Med. Chem. Lett. 18 (2008) 3611–3615
3613
Table 2. BDA for compounds 3a–3c
Compound
for the potent 5-HT3 receptor antagonist Ondense-
tron.13 Compound 3a shows minimal cross reactivity
against a panel of human muscarinic receptors M1,
M2, and M3.14 Finally, the affinity of furopyridine 3a
for the human. a7 nAChR is very similar to the rat a7
nAChR, which was not unexpected given the 94% ami-
no acid sequence identity between rat and human a7
nAChR subunits.15
MDCK (A > B)a MBUAb brain/
Pgpc
Papp · 10ꢀ6 cm/s plasma at 5, 60 min substrate
PHA-543613 34
1.5, 1.5
No
No
No
Yes
3a
3b
3c
21
1.52, 1.88
0.27, 1.15
0.02, 0.33
3.8
0.2
a Madin Darby canine kidney cell permeability assay, apical to basel
(A > B) permeability expressed as Papp
.
b MBUA, mouse brain uptake assay, brain to plasma = concentration
in brain divided by concentration in plasma following a 10 mg/kg
dose.
c Assessment based on compound’s performance in a multidrug-resis-
tant P-glycoprotein assay. Compounds possessing efflux ratios
(B > A)/(A > B) >3 were labeled as Pgp substrates.
In vitro cardiovascular safety was assessed in a patch-
clamp hERG K+ channel assay (Table 3).16 Com-
pound 3a shows 25% inhibition of the hERG channel
at a concentration of 20 lM.17 This level of inhibition
was very encouraging as it is comparable to that ob-
served for PHA-543613 (29% at 20 lM).7b In order
to further understand the cardiovascular profile of
3a and establish a therapeutic index (TI), an in vivo
cardiovascular safety study was performed using an
acute dog ECG model. The ‘No observable adverse ef-
fects level’ or NOAEL for 3a was established at a
dose of 40 mg/kg (Cmax = 22 lM), which is fivefold
known desensitization profile,11 brain accumulation was
not a desirable attribute. Benzothiazole 3c shows limited
brain penetration, which is likely due to the fact that the
compound shows significant efflux in the MDR Pgp as-
say. Based on these data, 3a clearly emerged as the best
compound among this small group of related azabicyclic
amides.
higher
than
the
NOAEL
for
PHA-543613
(Cmax = 3.8 lM).
Furopyridine 3a is expected to possess low plasma pro-
tein binding (PPB) based on the measured PPB value for
PHA-543613 and its similarity in structure and logD to
that of PHA-543613 (Table 4). Compound 3a shows im-
proved stability in human liver microsomes compared to
rat. This was not unexpected given that the same trend
was seen for other azabicyclic amides, including PHA-
543613; however, the data do suggest that RLM is
potentially underestimating compound stability in hu-
mans for this class of compounds.
Compound 3a was evaluated in a set of ligand-gated ion
channel selectivity screens, including the 5-hydroxy-
trypamine 3 (5-HT3) receptor, the predominant gangli-
onic nAChR (a3b4), the neuromuscular nAChR
(a1b1kd), and the a4b2 nAChR (Table 3). Compound
3a shows high selectivity against all these receptors
except 5-HT3, where the selectivity was ca. 100-fold.
Further work demonstrated that compound 3a is a weak
5-HT3 antagonist. This weak off-target activity was
expected to carry minimal risk based on clinical data
Table 3. In vitro selectivity screens and hERG data
Compound
Rat 5-HT3
Ki (nM)
Nicotinic selectivity data
Human M1,
M2, M3e % inhib
hERGf %
inhib
Human a7
Kig (nM)
a3b4a,b IC50 (lM)
a1b1cd
IC50 (lM)
a4b2d % inhib
a,c
PHA-543613
3a
630
350
>100
>100
>100
>100
13
<1
16, 23, 33
16, 25, 15
29
25
7
9
a FLIPR cell-based functional assay; numbers indicate EC50 values generated from individual 7-point concentration–response relationships.
b SH-SY5Y cells expressing a3b4.
c TE671 cells, native a1b1cd.
d Rat brain homogenate binding assay, [3H]cytosine, % block at 1 lM.
e Human muscarinic receptor in transfected CHO cells using [3H]pirenzepine (M1), [3H]AF-DX 384 (M2) or [3H]DAMP (M3) as a radio ligand,
%block at 10 lM.
f In vitro effect on hERG current (IKr), HEK cells expressed as percent inhibition at a concentration of 20 lM.
g IMR32 human cells, [3H]MLA.
Table 4. ADME and pharmacokinetic data
Compound
Human PPBa fu
HLMc Eh
HLM t1/2 (min)
Rat in vivo pharmacokinetic propertiesd
CL (ml/min/kg)
33
72 25
Half-life (min)
Vss (L/kg)
%F
PHA-543613
3a
0.83 0.041
Est. 0.75–0.85b
<0.26
<0.26
>120
>120
5
36 6.0
48 0.0
1.8 0.2
2.4 0.3
65 23
40 16
a In vivo human plasma protein binding, expressed as fraction unbound (fu), determined at a drug concentration of 0.100 lg/mL.
b Estimation based on similar logD and structure to PHA-543613.
c HLM, human liver microsomes; in vitro extraction ratios (Eh) are reported as the fraction of compound remaining as compared with the
concentration at t0.
d Pharmacokinetic data generated following a single 5.0 mg/kg dose (Ref. 12) in Sprague–Dawley rats.

3614
B. A. Acker et al. / Bioorg. Med. Chem. Lett. 18 (2008) 3611–3615
Figure 1. Effect of compound 3a (PHA-709829) (0.01–1.0 mg/kg) on
the auditory gating deficit in amphetamine treated rats.22,19 Auditory
gating was measured as the ratio of ‘conditioning’ and ‘test’ field
potentials (EEG) evoked by paired auditory tones delivered at 0.5 Hz.
Subsequent to disrupting the normal auditory gating with amphet-
amine (1 mg/kg, iv), PHA-709829 (sc) was administered and gating was
monitored for 30 min. Results are expressed as a % Reversal of the
amphetamine-induced deficit.
Figure 2. Chronic dosing studies of PHA-709829: Vehicle (0.9% saline,
sc, n = 8) or PHA-709829 (1 mg/kg, sc, n = 8) administered twice daily
for 6 days. PHA-709829 (1 mg/kg, sc) was tested for the ability to
reverse the amphetamine-induced gating deficit on the seventh day.
both in brain (5.3 0.3 nM) and in plasma
(12 3.6 nM). Brain/plasma ratios varied from
0.81 0.09 to 2.7 0.51 in these auditory gating
in vivo electrophysiological experiments.
The pharmacokinetics of compound 3a were determined
in rat following a single oral dose administration of the
compound (Table 4). The clearance (CL) of compound
3a is higher than that of PHA-543613, which was not
predicted by the RLM stability assay. However, com-
pound 3a has a longer half-life than PHA-543613, which
is attributed to the compound’s higher volume of distri-
bution. Also, the higher in vivo rat clearance of 3a was
less concerning based on its high in vitro stability in
HLM. The bioavailability for 3a was somewhat lower
than for PHA-543613 but still within an acceptable
range.
The ability of PHA-709829 to reverse amphetamine-in-
duced gating deficit was also demonstrated after its re-
peated administration (Fig. 2). In these studies, PHA-
709829 (1 mg/kg, n = 8) or vehicle (0.9% saline, n = 8)
was administered subcutaneously twice a day for six
days, then PHA-709829 was tested for the ability to re-
verse the amphetamine-induced gating deficit on the sev-
enth day. Thus, administration of PHA-709829 (1 mg/
kg, sc) on the seventh day reversed the gating deficit in-
duced by amphetamine in both vehicle and PHA-709829
treated rats with the same potency. Acute administra-
tion of PHA-709829 resulted in very similar brain and
plasma exposures in rats chronically treated with vehicle
(brain: 350 48 nM, plasma: 550 48 nM) and PHA-
709829 (brain: 350 36 nM, plasma: 490 45 nM).
Thus, chronic administration of PHA-709829 does not
affect its ability to reverse amphetamine-induced audi-
tory gating deficits when given acutely.
The in vivo pharmacological activity of compound 3a
(PHA-709829) was tested in a rat model of impaired
auditory gating.18 It has been shown previously that
amphetamine-induced auditory gating deficit in rats is
restored by nicotine, and partial or full a7 nAChR ago-
nists, including PNU-282987 and PHA-543,613.18,19,7b
In the present study, a dose-dependent, significant rever-
sal of amphetamine-induced gating deficit by PHA-
709829 (0.01–1.0 mg/kg, sc, n = 6–9)12 was demon-
strated (Fig. 1). The minimum effective dose was
0.1 mg/kg (sc, n = 9), which resulted in a 60 4.3 nM,
and a 47 4 nM plasma and brain exposure, respec-
tively, determined at 37 3 min after drug administra-
tion. The minimum effective dose for PHA-543613 in
the same assay was 0.24 mg/kg (IV, n = 6),20 which re-
sulted in a plasma concentration of 130 38 nM at
30 min. Thus, PHA-709829 is twofold more potent in
this assay than PHA-543613, which is consistent with
the lower rat Ki of PHA-709829 (3.4 nM) versus PHA-
543613 (9.0 nM).21 The highest tested effective dose,
1 mg/kg (sc, n = 7) for PHA-709829 resulted in signifi-
cantly higher brain (1200 300 nM) and plasma
(1100 110 nM) exposures, while the highest ineffective
dose (0.01 mg/kg, sc, n = 6) reached only low exposures
In summary, several aryl amides derived from azabicy-
clic amine 1 were prepared as a7 nAChR agonists. In
general these compounds show potent a7 activity in
both the functional and binding assays, suggesting that
amine 1 is an effective isostere of (3R)-3-amino-quinucli-
dine for this receptor subtype. Furopyridine 3a (PHA-
709829), possessing the same aryl fragment as our earlier
clinical candidate, PHA-543613, demonstrated the best
overall profile among type 3 analogs. Compound 3a is
a potent a7 nAChR agonist with good to excellent selec-
tivity against a variety of related CNS receptors. The
compound exhibits excellent CNS penetration and good
oral bioavailability in a rat pharmacokinetic model. In a
dog ECG cardiovascular model, the NOAEL for PHA-
709829 was established at a dose fivefold higher than
that of PHA-543613. In vivo efficacy profiling in an

B. A. Acker et al. / Bioorg. Med. Chem. Lett. 18 (2008) 3611–3615
3615
Hanchar, A. J.; Thornburgh, B. A.; Cortes-Burgos, L.
A.; Wong, E. H.; Staton, B. A.; Raub, T. J.; Higdon, N.
R.; Wall, T. M.; Hurst, R. S.; Walters, R. R.; Hoffman,
W. E.; Hajos, M.; Franklin, S.; Carey, G.; Gold, L. H.;
Cook, K. K.; Sands, S. B.; Zhao, S. X.; Soglia, J. R.;
Kalgutkar, A. S.; Arneric, S. P.; Rogers, B. N. J. Med.
Chem. 2006, 49, 4425; (c) Walker, D. P.; Wishka, D. G.;
Piotrowski, D. W.; Jia, S.; Reitz, S. C.; Yates, K. M.;
Myers, J. K.; Vetman, T. N.; Margolis, B. J.; Jacobsen,
E. J.; Acker, B. A.; Groppi, V. E.; Wolfe, M. L.;
Thornburgh, B. A.; Tinholt, P. M.; Cortes-Burgos, L. A.;
Walters, R. R.; Hester, M. R.; Seest, E. P.; Dolak, L. A.;
Han, F.; Olson, B. A.; Fitzgerald, L.; Staton, B. A.;
Raub, T. J.; Hajos, M.; Hoffmann, W. E.; Li, K. S.;
Higdon, N. R.; Wall, T. M.; Hurst, R. S.; Wong, H. F.;
Rogers, B. N. Bioorg. Med. Chem. 2006, 14, 8219.
8. Walker, D. P.; Acker, B. A.; Jacobsen, E. J.; Wishka, D.
G. J. Heterocycl. Chem. 2008, 45, 247.
amphetamine-induced gating model demonstrated that
PHA-709829 is twofold more potent than PHA-
543613, and it is efficacious over a range of doses (0.1–
1.0 mg/kg). Taken together, the efficacy and safety data
represent a 10-fold improvement in cardiovascular TI
for PHA-709829 compared to PHA-543613. Addition-
ally, it was shown that PHA-709829 remains efficacious
after chronic administration. Future plans include pro-
filing PHA-709829 in additional safety-related models,
which could identify other advantages relative to
PHA-543613.
Acknowledgments
We thank Tony Bahinski, Kipp Erickson, Ann Wiltse
and Dan Rudmann of the Kalamazoo Preclinical Toxi-
cology group for in vitro and in vivo cardiovascular
safety data, the Kalamazoo SAM-Chem group for ana-
lytical data, the ADME CoE group for in vitro ADME
data, and the Kalamazoo Pharmaceutics group for sol-
ubility data.
9. Characterization data for compound 3a (PHA-709829):
25
white solid, mp >300 ꢁC; ½aꢁD 9 (c 0.96, DMSO); IR
(diffuse reflectance) 3362, 3080, 2678, 2597, 2577, 2539,
1
2485, 1667, 1531, 1461, 1028, 895, 798, 787, 614 cmꢀ1; H
NMR (400 MHz, DMSO-d6) d 10.67 (br s, 1H), 9.02 (s,
1H), 8.85–8.75 (m, 1H), 8.43 (s, 1H), 8.38 (d, 1H,
J = 2.1 Hz), 7.23 (d, 1H, J = 2.1 Hz), 4.65–4.50 (m, 1H),
3.60–3.05 (m, 6H), 2.75–2.65 (m, 1H), 2.25–2.05 (m, 1H),
2.00–1.80 (m, 3H); high resolution MS (FAB) Calcd for
C15H18N3O2 [M+H] m/e 272.1399. Found: 272.1413.
%Water (KF): 2.37. Anal. Calcd for C15H17N3O2Æ1.25H-
ClÆ2.37%H2O: C, 55.50; H, 6.02; N, 12.95. Found: C,
55.76; H, 5.80; N, 12.85.
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E.; Yu, J. H.; Robinson, D. D.; Wall, T. M.; Higdon, N.
R.; Svensson, K. A.; Nichols, N. F.; Walters, R. R.;
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Dinh, D. M.; Groppi, V. E.; Hajos, M.; Higdon, N. R.;
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21. It is worth noting that since PHA-543613 and PHA-
709829 possess essentially equal affinity for the human a7
nAChR (7 nM vs. 9 nM), it is not known whether the
improved efficacy of PHA-709829 in the rat auditory
gating assay will translate to humans.
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22. Krause, M.; Hoffmann, W. E.; Hajos, M. Biol. Psychiatry
2003, 53, 244.