Challenges in the development of an M4 PAM preclinical candidate: The discovery, SAR, and biological characterization of a series of azetidine-derived tertiary amides

Article abstract of DOI:10.1016/j.bmcl.2017.10.053

Herein we describe the continued optimization of M₄ positive allosteric modulators (PAMs) within the 5-amino-thieno[2,3-c]pyridazine series of compounds. In this letter, we disclose our studies on tertiary amides derived from substituted azetidines. This series provided excellent CNS penetration, which had been challenging to consistently achieve in other amide series. Efforts to mitigate high clearance, aided by metabolic softspot analysis, were unsuccessful and precluded this series from further consideration as a preclinical candidate. In the course of this study, we found that potassium tetrafluoroborate salts could be engaged in a tosyl hydrazone reductive cross coupling reaction, a previously unreported transformation, which expands the synthetic utility of the methodology.

Full text of DOI:10.1016/j.bmcl.2017.10.053

Accepted Manuscript
Challenges in the development of an M4 PAM preclinical candidate: The dis-
covery, SAR, and biological characterization of a series of azetidine-derived
tertiary amides
James C. Tarr, Michael R. Wood, Meredith J. Noetzel, Bruce J. Melancon, Atin
Lamsal, Vincent B. Luscombe, Alice L. Rodriguez, Frank W. Byers, Sichen
Chang, Hyekyung P. Cho, Darren W. Engers, Carrie K. Jones, Colleen M.
Niswender, Michael W. Wood, Nicholas J. Brandon, Mark E. Duggan, P. Jeffrey
Conn, Thomas M. Bridges, Craig W. Lindsley
PII:
S0960-894X(17)31052-1
https://doi.org/10.1016/j.bmcl.2017.10.053
BMCL 25382
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
5 June 2017
18 October 2017
22 October 2017
Please cite this article as: Tarr, J.C., Wood, M.R., Noetzel, M.J., Melancon, B.J., Lamsal, A., Luscombe, V.B.,
Rodriguez, A.L., Byers, F.W., Chang, S., Cho, H.P., Engers, D.W., Jones, C.K., Niswender, C.M., Wood, M.W.,
Brandon, N.J., Duggan, M.E., Jeffrey Conn, P., Bridges, T.M., Lindsley, C.W., Challenges in the development of
an M4 PAM preclinical candidate: The discovery, SAR, and biological characterization of a series of azetidine-
derived tertiary amides, Bioorganic & Medicinal Chemistry Letters (2017), doi: https://doi.org/10.1016/j.bmcl.
2017.10.053
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Challenges in the development of an M4
PAM preclinical candidate: The discovery,
SAR, and biological characterization of a
series of azetidine-derived tertiary amides
Leave this area blank for abstract info.
James C. Tarr, Michael R. Wood, Meredith J. Noetzel, Bruce J. Melancon, Atin Lamsal, Vincent B. Luscombe,
Alice L. Rodriguez, Frank W. Byers, Sichen Chang, Hyekyung P. Cho, Darren W. Engers, Carrie K. Jones
Colleen M. Niswender, Michael W. Wood, Nicholas J. Brandon, Mark E. Duggan, P. Jeffrey Conn, Thomas M.
Bridges, and Craig W. Lindsley

Bioorganic & Medicinal Chemistry Letters
journal homepage: www.els evier.com
Challenges in the development of an M4 PAM preclinical candidate: The
discovery, SAR, and biological characterization of a series of azetidine-derived
tertiary amides
James C. Tarr,a Michael R. Wood,a,c Meredith J. Noetzel,a,b Bruce J. Melancon,a Atin Lamsal,a,b Vincent B.
Luscombe,a Alice L. Rodriguez,a Frank W. Byers,a Sichen Chang,a Hyekyung P. Cho,a Darren W. Engers,a
Carrie K. Jones a,b Colleen M. Niswender,a,b,e Michael W. Wood,d Nicholas J. Brandon,d Mark E. Duggan,d
P. Jeffrey Conn,a,b,e Thomas M. Bridges a,b* and Craig W. Lindsleya,b,c*
aVanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
bDepartment of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
cDepartment of Chemistry, Vanderbilt University, Nashville, TN 37232, USA
dNeuroscience Innovative Medicines, Astra Zeneca, 141 Portland Street, Cambridge, MA 02139, USA
eVanderbilt Kennedy Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
ARTICLE INFO
ABSTRACT
Article history:
Received
Herein we describe the continued optimization of M4 positive allosteric modulators (PAMs)
within the 5-amino-thieno[2,3-c]pyridazine series of compounds. In this letter, we disclose our
studies on tertiary amides derived from substituted azetidines. This series provided excellent
CNS penetration, which had been challenging to consistently achieve in other amide series.
Efforts to mitigate high clearance, aided by metabolic softspot analysis, were unsuccessful and
precluded this series from further consideration as a preclinical candidate. In the course of this
study, we found that potassium tetrafluoroborate salts could be engaged in a tosyl hydrazone
reductive cross coupling reaction, a previously unreported transformation, which expands the
synthetic utility of the methodology.
Revised
Accepted
Available online
Keywords:
M4
Muscarinic acetylcholine receptor
Positive Allosteric modulator (PAM)
Schizophrenia
2009 Elsevier Ltd. All rights reserved.
Azetidine
Following demonstration of clinical efficacy by xanomeline, a
pan muscarinic acetylcholine receptor (mAChR) agonist, to treat
multiple symptom clusters of schizophrenia,1-3 selective
activation of the mAChR subtype M4 has emerged as a promising
approach for the treatment of numerous CNS disorders.4-26 While
a)
flexible linker allows analogs
to adopt pi-stacking conformation,
potential metabolic hotspot
b)
NH2
O
NH2
O
N
N
S
HN
4, VU0467485
N
N
Ar
S
N
Y = CH, N
n = 1-2
m = 1-3
liability for solubility,
efflux transporter
Y
Figure 1. Structures of previously reported M4 PAMs
R
Figure 2. a) X-ray diffraction of 5 b) rationale for tertiary amide design

achieving mAChR subtype selectivity at the highly conserved
orthosteric acetylcholine binding site has remained challenging,
an alternative strategy of targeting an allosteric site with less
evolutionary pressure towards conservation via positive allosteric
modulators (PAMs) has met with success. This allosteric
We initially examined a variety of 4, 5, and 6-membered cyclic
amines and diamines to assess the feasibility of this strategy.
Despite finding numerous potent and efficacious secondary
exocyclic amides representing a variety of ring sizes and
substitution patterns, the majority of endocyclic tertiary amides
examined were either inactive or only weakly active (Figure 3).
Fortunately, in our screen we found that substitution at the 3-
position of the azetidine amides provided a substantial boost in
potency. In order to synthesize 3-aryl substituted azetidines, we
relied on either a Negishi reaction28 starting from commercially
available 1-Boc-3-iodoazetidine or a metal-free reductive cross
coupling between a tosyl hydrazone and boronic acid (Scheme
1).29,30 The operational simplicity (air and moisture stable
intermediates amenable to isolation, purification, and storage)
and substrate tolerance of the reductive cross coupling allowed us
to rapidly and efficiently explore the SAR of this series. In the
course of coupling tosyl hydrazone azetidine with boronic acid
partners, we sought to investigate the ability of the azetidine tosyl
hydrazones to engage BF3K salts (Table 1). In a small screen of
BF3K salts, we found that four out of five examined provided the
desired coupled product. While the simple allyl trifluoroborate
salt failed to couple, substituted vinyl, aryl, and heteroatom
containing BF3K salts afforded the desired product. Although the
yields were modest, we were able to obtain them with no
modification or optimization of the original protocol,
approach has not only proven to be
a mechanism to
potentiate the response of the M4 receptor to acetylcholine, but
also to obtain excellent selectivity across the mAChR subtypes.
Our group and others have reported a number of potent, selective
M4 PAMs which have shown efficacy in preclinical animal
models of schizophrenia (Figure 1).4-7,11,14,22-26
Recently, our group reported the discovery of VU0476406
(5),25 which displayed excellent potency (hM4 EC50 = 91 nM,
AChMax = 74+3%), clean ancillary pharmacology (including high
mAChR subtype selectivity), and an early DMPK profile suitable
for evaluation as a preclinical candidate (CLp = 1.6 mL/min/kg,
t = 2.7 h, Kp = 0.11, Kp,uu = 1.2). One of the key setbacks found
½
during the characterization of VU0476406, which precluded its
advancement into IND-enabling studies, was its low solubility
(<0.5 µM at pH 7.4) and solubility-limited oral absorption in dog
(%F = 4.7 as HCl salt). An x-ray crystal structure of 5 showed
extensive hydrogen bonding and π-stacking between neighboring
Scheme 1. Synthesis of tertiary azetidine analogs
NH2
O
a
d
BocN
b, c
BocN
N
S
N
N
Ar
I
10
Ar
9
8
NH2
e
b, c
O
N
BocN
BocN
BocN
N
S
R
N
N
O
HN
Ts
R
11
12
Conditions: a) Zn, TMSCl, 1,2-dibromoethane, ArX, Pd(PPh3)4 b) TFA,
DCM, r.t c) 5-amino-3,4-dimethylthieno[2,3-c]pyridazine-6-carboxylic acid,
HATU, DIPEA, DMF, r.t d) TsNHNH2, 1,4-dioxane, 80 °C e) RB(OH)2,
K2CO3, 1,4-dioxane, 110 °C.
demonstrating the general utility of this reaction. To the best of
our knowledge, this represents the first reported example
whereby a BF3K salt has been used to engage the tosyl hydrazone
in a reductive cross coupling, allowing for the preparation of
analogs for which the boronic acid may not be stable.
Figure 3. Cyclic tertiary amides generated on thieno-[2,3-c]pyridazine
core. Majority of examples hM4 EC50 > 2 µM.
molecules in the lattice, which likely contributed to the
compound’s poor aqueous solubility. We hypothesized that
disruption of both the hydrogen bonding and π-stacking would be
beneficial. Replacement of the benzyl linker with a saturated
cyclic moiety would impart additional sp3 character and could
disrupt the planarity of the compounds which may impede π-
stacking. Additionally, removal of the amide N-H could also
disrupt the hydrogen bonding network, which may improve the
solubility and absorption, as well as possibly mitigate P-gp efflux
which had limited CNS exposure in some 5-amino-thieno[2,3-
c]pyridazine analogs. Unfortunately, in examples across several
different amide series, replacement of the amide NH with a
methyl group resulted in a dramatic loss of human M4 (hM4)
potency (data not shown). However, given our success in
employing small, cyclic diamine linkers at the amide portion of
our compounds,24 we turned our attention to examining cyclic
amines linked through an endocyclic amine to the thieno[2,3-
c]pyridazine core to furnish a library of tertiary amides.
Table 1. Reductive cross coupling with trifluoroboronate salts
Entry
RBF3K
Yield (%)
NDP
1
2
3
4
31
29
25

5
57
10k
10l
28
7.24+0.20
6.82+0.13
[83+9]
151
[80+7]
The 3-position of the azetidine tolerated aryl (10a, 10d-10l),
aliphatic (10b), and heteraryl (10c) substitution (Table 2). One
of the most potent analogs prepared was unsubstituted phenyl
group 10a (hM4 EC50 = 72 nM, AChMax = 65+3%). As frequently
observed with PAM SAR, substitution on the aryl ring could
result in dramatic and unpredictable differences in potency.
Introduction of a methyl group at either the 2-, 3-, or 4-position
(10d-10f) resulted in a fairly uniform loss of potency (4-7-fold);
however, a methoxy substituent at the 4-postion (10i) resulted in
a modest ~3.5-fold loss in potency while the meta-substituted
analog gave >100-fold loss in potency (10h). As we have
previously observed in M4 PAM SAR, fluoro substituents were
well tolerated, especially the 3- and 4-position (10k and 10l).
Replacement of the fluorine with other halogens resulted in a
complete loss of hM4 activity (10m, 10n). Saturation of the
phenyl ring (10b) led to a modest decrease in potency (hM4 EC50
= 178 nM, AChMax = 54 + 12), as did heteroaryl substitution
(10c) (hM4 EC50 = 200 nM, AChMax = 78 + 7).
F
>10,000
[N.D.]
10m
10n
N.D.
N.D.
>10,000
[N.D.]
aCalcium mobilization assays with hM4/Gqi5-CHO cells performed in the
presence of an EC20 fixed concentration of acetylcholine; values represent
means from three (n=3) independent experiments performed in triplicate.31
In order to further evaluate this new amide series, 10a, 10b,
10k and 10l were evaluated for mAChR subtype selectivity and
in vitro DMPK assays. Compound 10a was subjected to full
subtype selectivity screening and found to possess excellent
selectivity for hM4 over other subtypes (hM1-3,5 EC50 > 10 µM).
Compound 10k and 10l were counter screened against hM2, and
10l was found to be inactive. While 10k was active at hM2 (EC50
= 2.10 µM), it only weakly potentiated the ACh response
(AChMax = 38%). In contrast to a number of other series with the
thieno[2,3-c]pyridazine core, 10a was ~2-fold more potent at
hM4 compared to rat M4 (rM4; data not shown). When assessed
for CNS penetration, all four compounds were found to have
high brain distribution in rat (10a Kp = 2.6, Kp,uu = 2.1; 10b Kp =
Table 2. Analogs derived from 3-substituted azetidines
8.46, Kp,uu = 0.71; 10k Kp = 2.1, Kp,uu = 0.92, 10l Kp = 2.3, Kp,uu
=
hM4
1.3). As a class, the tertiary azetidines appear to address one of
the major challenges associated with the previously reported
secondary azetidine series, which suffered from P-gp efflux and
low CNS exposure, requiring an extensive SAR campaign to
address these parameters. Unfortunately, all four compounds
exhibited high predicted clearance in both rat and human (10a
CLhep = 64 (r), 20 (h) mL/min/kg; 10b CLhep = 65 (r), 20 (h)
mL/min/kg; 10k CLhep = 56 (r), 19 (h) mL/min/kg; 10l CLhep = 56
(r), 19 (h) mL/min/kg) based on hepatic microsomal CLint data
using the well-stirred model (binding terms excluded).
EC50 (nM)a
[% ACh Max
SEM]
hM4 pEC50
( SEM)
Cmpd
R
72
10a
10b
10c
7.14+0.18
6.75+0.16
6.70+0.13
[65+3]
178
[54+12]
200
[78+7]
To address the putative high clearance in this series of
compounds, metabolic softspot analysis was performed using rat
hepatic microsomal incubations, which identified NADPH-
dependent hydroxylation of the azetidine ring as the principle
pathway of metabolism (data not shown). Based on this finding,
we sought to improve the metabolic stability by blocking the
benzylic site on the azetidine ring. Synthesis of these compounds
was accomplished by addition of the appropriate Grignard or
organolithium reagent into 1-Boc azetidinone, followed by
alkylation with MeI or fluorination of the resultant alcohol with
DAST (Scheme 2). The Boc group was then cleaved with TFA
and the azetidine connected to the core via a HATU coupling,
analogous to the route described in Scheme 1. In general, the
introduction of geminal substituents at the 3-position resulted in a
loss of potency, with -OH (11a) and -OMe (11b) resulting in a
~10-fold and ~6-fold loss of potency, respectively. Both of these
substitutions also resulted in a marked decline in the compounds’
efficacy in potentiation of the ACh response. Replacement of the
benzylic hydrogen with fluorine was better tolerated (11c-f),
especially with regards to AChMax; however, the EC50s obtained
from these compounds were still ~5-fold weaker than the best
457
10d
[72+7]
6.34+0.04
6.07+0.06
851
10e
10f
[83+6]
1096
5.96+0.11
5.64+0.15
[82+4]
2290
10g
[54+7]
>10,000
[N.D.]
10h
10i
N.D.
331
6.48+0.12
[94+7]
407
10j
analogs bearing
a
hydrogen at the benzylic position.
6.39+0.03
[75+8]
Additionally, all compounds tested in which the benzyl site was
blocked were still found to possess predicted rat and human
clearance near or at hepatic blood flow rates. Ultimately,

hM4
metabolite identification efforts found that the primary pathway
for metabolism was oxidation on the azetidine ring irrespective
of the fluorine atom at the benzylic site.
EC50 (nM)a
[% ACh Max
SEM]
hM4 pEC50
( SEM)
Cmpd
R
X
With these data in hand, additional strategies were also
examined for minimizing the clearance of the 3-aryl azetidine
analogs. We examined introduction of a methyl group at the 2-
position of the azetidine, which we hoped may reduce oxidation
on the azetidine ring. Starting from commercially available tert-
butyl 2-methyl-3-oxoazetidine-1-carboxylate and following the
synthetic route described in Scheme 1, analogs 12a and 12b were
prepared. Both compounds suffered from weaker potency (EC50
= 1510, 1455 nM, respectively), but also an impaired ability to
reach full potentiation of the hM4 receptor (AChMax = ~45%).
Introduction of a spiro-pyrroldine ring to the azetidine amide
afforded analogs 13a and 13b. This substitution also led to a
decrease in hM4 potency relative to 10a (EC50 = 324 and 500 nM,
respectively). Furthermore, both analogs still suffered from high
predicted clearance (CLhep = 49 and 56 mL/min/kg, respectively).
After being unable to identify substitutions to either the 3-
position substituent or the azetidine ring that would allow us to
address the high clearance associated with this class of
compounds yet still maintain reasonable potency, 10a was
evaluated in a rat amphetamine-induced hyperlocomotion (AHL)
model of antipsychotic efficacy. Despite its high predicted
clearance, at a 30 mg/kg oral dose 10a was still able to achieve
32% reversal of AHL.
1047
11a
11b
OH
OMe
F
5.98+0.04
[30+4]
417
[36+2]
6.38+0.08
6.35+0.18
447
11c
11d
[67+3]
2240
F
5.65+0.23
[78+1]
316
[85+12]
363
11e
11f
F
F
6.50+0.23
6.44+0.07
-Me
[98+12]
aCalcium mobilization assays with hM4/Gqi5-CHO cells performed in the
presence of an EC20 fixed concentration of acetylcholine; values represent
means from three (n=3) independent experiments performed in triplicate.
Table 4. Azetidine analogs to address high clearance
In summary, we have described the synthesis and biological
evaluation of a novel series of tertiary azetidine amides within
the 5-amino-thieno[2,3-c]pyridazine class of M4 PAMs. In the
synthesis of these compounds, we were able to utilize a reductive
cross coupling between azetidinyl tosyl hydrazones and boronic
acids, and found that this methodology could be extended to
trifluoroboronate salts as well. This new series of azetidine
amides was promising because its members generally provided
excellent CNS exposure and possessed a preference for activity at
hM4 over rM4, two trends that had been challenging to overcome
in other series studied. Despite suffering from high predicted
clearance, which we were unable to alleviate with substitutions at
either the 3-position substituent or the azetidine ring itself,
compound 10a was able to achieve 32% reversal in a rodent AHL
model. Future studies aimed at achieving potent molecules with
a suitable disposition are currently underway and will be reported
in due course.
hM4
EC50 (nM)a
[% ACh Max
SEM]
hM4 pEC50
( SEM)
Cmpd
R
1510
12a
12b
13a
5.82+0.24
5.84+0.15
6.49+0.07
[45+3]
1455
[45+2]
324
[57+0]
500
13b
6.39+0.22
[53+1]
aCalcium mobilization assays with hM4/Gqi5-CHO cells performed in the
presence of an EC20 fixed concentration of acetylcholine; values represent
means from three (n=3) independent experiments performed in triplicate.
Scheme 2. Synthesis of azetidines with benzylic hydrogen removed
Acknowledgments
The authors would like to thank NIH (U01MH087965,
Vanderbilt, NCDDG). We also thank William K. Warren, Jr. and
the William K. Warren Foundation who funded the William K
Warren, Jr. Chair in Medicine (to C.W.L.).
◦
Conditions: a) RMgBr or RLi, THF, 0 C b) MeI, K2CO3, DMF c) DAST,
DCE
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