Challenges in the development of an M4 PAM preclinical candidate: The discovery, SAR, and in vivo characterization of a series of 3-aminoazetidine-derived amides

Article abstract of DOI:10.1016/j.bmcl.2017.05.014

This letter details the continued chemical optimization of a novel series of M₄ positive allosteric modulators (PAMs) based on a 5-amino-thieno[2,3-c]pyridazine core by incorporating a 3-amino azetidine amide moiety. The analogs described within this work represent the most potent M₄ PAMs reported for this series to date. The SAR to address potency, clearance, subtype selectivity, CNS exposure, and P-gp efflux are described. This work culminated in the discovery of VU6000918, which demonstrated robust efficacy in a rat amphetamine-induced hyperlocomotion reversal model at a minimum efficacious dose of 0.3?mg/kg.

Full text of DOI:10.1016/j.bmcl.2017.05.014

Accepted Manuscript
Challenges in the development of an M4 PAM preclinical candidate: The dis-
covery, SAR, and in vivo characterization of a series of 3-aminoazetidine-
derived amides
James C. Tarr, Michael R. Wood, Meredith J. Noetzel, Jeanette Bertron,
Rebecca L. Weiner, Alice L. Rodriguez, Atin Lamsal, Frank W. Byers, Sichen
Chang, Hyekyung P. Cho, 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)30490-0
DOI:
http://dx.doi.org/10.1016/j.bmcl.2017.05.014
BMCL 24959
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
17 April 2017
2 May 2017
3 May 2017
Please cite this article as: Tarr, J.C., Wood, M.R., Noetzel, M.J., Bertron, J., Weiner, R.L., Rodriguez, A.L., Lamsal,
A., Byers, F.W., Chang, S., Cho, H.P., Jones, C.K., Niswender, C.M., Wood, M.W., Brandon, N.J., Duggan, M.E.,
Conn, P.J., Bridges, T.M., Lindsley, C.W., Challenges in the development of an M4 PAM preclinical candidate: The
discovery, SAR, and in vivo characterization of a series of 3-aminoazetidine-derived amides, Bioorganic &
Medicinal Chemistry Letters (2017), doi: http://dx.doi.org/10.1016/j.bmcl.2017.05.014
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Challenges in development of an M4 PAM
preclinical candidate: The discovery, SAR,
and in vivo characterization of a series of 3-
aminoazetidine-derived amides
James C. Tarr, Michael R. Wood, Meredith J. Noetzel, Jeanette Bertron, Rebecca L. Weiner, Alice L.
Rodriguez, Atin Lamsal, Frank W. Byers, Sichen Chang, Hyekyung P. Cho, Carrie K. Jones, Colleen M.
Niswender, Michael W. Wood, Nicholas J. Brandon, Mark E. Duggan, P. Jeffrey Conn, Thomas M. Bridges,
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 in vivo characterization of a series of 3-aminoazetidine-
derived amides
James C. Tarr,a Michael R. Wood,a,c Meredith J. Noetzel,a,b Jeanette Bertron,a Rebecca L. Weiner,a,a Alice
L. Rodriguez,a Atin Lamsal,a Frank W. Byers,a,b Sichen Chang,a,b Hyekyung P. Cho,a Carrie K. Jones a,b,e
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
*To whom correspondence should be addressed: thomas.m.bridges@vanderbilt.edu and craig.lindsley@vanderbilt.edu
ARTICLE INFO
ABSTRACT
Article history:
Received
This letter details the continued chemical optimization of a novel series of M4 positive allosteric
modulators (PAMs) based on a 5-amino-thieno[2,3-c]pyridazine core by incorporating a 3-
amino azetidine amide moiety. The analogs described within this work represent the most
potent M4 PAMs reported for this series to date. The SAR to address potency, clearance,
subtype selectivity, CNS exposure, and P-gp efflux are described. This work culminated in the
discovery of VU6000918, which demonstrated robust efficacy in a rat amphetamine-induced
hyperlocomotion reversal model at a minimum efficacious dose of 0.3 mg/kg.
Revised
Accepted
Available online
Keywords:
M4
2009 Elsevier Ltd. All rights reserved
.
Muscarinic acetylcholine receptor
Positive allosteric modulator (PAM)
Schizophrenia
Azetidine
Me
N
Me
N
Positive allosteric modulators (PAMs) of the muscarinic
acetylcholine receptor (M4) (1-4) have emerged as an exciting
potential strategy for the treatment of numerous CNS disorders,
including schizophrenia,1-20 Huntington’s disease,21 and
Alzheimer’s disease.22 Previous reports from our laboratory have
described the discovery and characterization of VU0152100
(ML108, 1), an in vivo tool compound which demonstrated
efficacy in rodent models of anti-psychotic efficacy.3,4 We
subsequently reported related congener VU0467154 (2), based on
a 5-amino-thieno[2,3-c]pyridazine core, which, despite its robust
in vivo activity in multiple preclinical rodent models and a
favorable pharmacokinetic (PK) profile, suffered from
considerably lower potency at the human M4 receptor as
compared to rat.11,19 In the course of our medicinal chemistry
campaign to identify a compound with improved potency at the
human M4 receptor while maintaining suitable DMPK properties
for a clinical candidate, we encountered steep SAR not only in
potency at M4, but in multiple DMPK properties as well.13,14,19,20
Herein, we describe our efforts to replace the benzylic linker
present in compounds 1-4 with substituted 3-amino azetidines.
NH2
NH2
Me
O
O
N
S
HN
S
HN
Me
OMe
SO2CF3
2,
1, VU0152100 (ML108)
VU0467154
Me
Me
N
NH2
NH2
Me
Me
O
HN
O
N
N
S
S
HN
N
F
F
OMe
4,
3
VU0476406
, VU0467485
(AZ13713945)
N
Figure 1. Structures of representative M4 PAMs 1-4, highlighting the
optimized rodent in vivo tool M4 PAM, VU0467154 (2), the clinical candidate
VU0467485/AZ13713945 (3) and the non-human primate in vivo tool

VU0476406 (4).
Observing that small cyclic amides afforded potent analogs in
both Eli Lilly’s and our M4 PAM programs, we wished to
examine the introduction of a cyclic linker between the 5-amino-
thieno[2,3-c]pyridazine amide core and the appended aryl ring.
Such a change may serve to decrease the planarity of the
molecule, thus reducing its ability to form pi-stacking
interactions and thereby improve solubility, restrict the
conformations available for the aryl ring to adopt, and remove the
benzylic methylene as a potential metabolic soft spot. Diamine
linkers would provide a convenient synthetic handle by which to
introduce substituents on the cyclic linker. Several potential
linkers were examined, including monocyclic and bicyclic
diamines; however, 3-amino substituted azetidines yielded the
Encouraged by our initial results within this series, we sought
to further improve the azetidine amides by examining N-aryl
azetidines. Initial efforts sought to mimic the carbamate
functionality by incorporating 1,3-heteroaryl substituents (16a-c).
Compound 16c maintained reasonable hM4 potency (EC50 = 106
nM), exhibited moderate in vitro clearance (predicted rat and
human CLhep = 41 and 12 mL/min/kg, respectively, based on
hepatic microsomal CLint), and achieved moderate CNS exposure
(rat brain:plasma Kp = 0.17, Kp,uu = 1.3). Despite lacking mAChR
subtype selectivity (hM2 EC50 = 220 nM), 16c was advanced to a
rat amphetamine hyperlocomotion (AHL) reversal study where it
exhibited marginal efficacy (16% reversal following 10 mg/kg
PO) but provided initial proof-of-concept for the azetidine amide
class of compounds. Broadening our scope of N-heteroaryl
azetidines led us to identify numerous potent analogs (16d-q). A
wide variety of heterocycles was tolerated, with pyridyl,
pyrimidyl, and pyrazinyl substituents providing EC50s < 100 nM.
Substitution of the heteroaryl ring proved capable of imparting
dramatic shifts in potency. While the parent 4-pyridyl azetidine
analog possessed micromolar PAM activity (data not shown),
introduction of halogen substituents on the 4-pyridyl ring
provided exquisitely potent analogs (16p, 16q). Substitution at
the meta-position was also tolerated on 3-pyridyl analogs, with
methoxy (16l) and fluorine (16m) providing analogs of
comparable potency to 16e.
most potent analogs (Figure 2).
Figure 1. Structures of previously reported M4 PAMs from Eli Lilly (1)
and Vanderbilt University (2-4)
Figure 2. Cyclic diamines examined as alternative amide linkers to
thieno[2,3-c]pyridazine core.
Table 1. Structures and activities for M4 PAM analogs 6.
Analogs were readily prepared following functionalization of
commercially available 3-(Boc-amino)-azetidine via nucleophilic
substitution or Buchwald-Hartwig23,24 cross-coupling reactions,
followed by Boc deprotection and amide coupling to the
thieno[2,3-c]pyridazine core (Scheme 1). Our initial library
examined the effect of tertiary carbamates, sulfonamides, and
amides (Table 1). Basic tertiary azetidine amines were poorly
tolerated and led to a sharp decrease in human M4 (hM4) potency
(data not shown). Carbamates proved to be the most potent
compounds in this class, with analog 6b displaying an EC50 of 23
nM. However, upon further profiling, 6b was found to have weak
activity at human M2 (hM2, EC50 = 2.65 µM) and a short
elimination half-life in vivo in rat (t1/2 < 30 min) due to facile
hydrolysis of the carbamate, which proved to be the case in
general for the carbamate series and thus precluded their
advancement. Azetidine sulfonamides (6e), ureas (6d), and
amides (6f-h) were also tolerated, albeit with lower potency as
compared to the carbamates. Compound 6h was selected for
further assessment, which gratifyingly found an improved profile
compared to the carbamate series with reduced activity at hM2
(EC50 > 10 µM) and low in vivo clearance (rat CLp = 3.1
mL/min/kg). Unfortunately, 6h was found to have low CNS
exposure (rat brain:plasma Kp = 0.03, Kp,uu = 0.37 at 0.25 hr post-
IV cassette dose) likely due to P-gp efflux (MDCK-MDR1 ER =
96).
hM4
EC50 (nM)a
hM4 pEC50
Cmpd
R
( SEM)
7.62+0.19
7.65+0.03
7.23+0.17
6.66+0.03
6.58+0.07
6.22+0.25
6.25+0.03
6.75+0.03
[% ACh Max SEM]
30
6a
6b
6c
6d
6e
6f
CO2Bn
CO2Ph
[81+8]
23
[96+3]
67
CO2(3-Me)Ph
C(O)NHPh
SO2Ph
[85+9]
217
[89+6]
268
[70+8]
773
C(O)Ph
[85+6]
564
6g
6h
C(O)2-pyridyl
[91+5]
179
C(O)4-pyridyl
[85+7]
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 1. Synthesis of M4 PAM analogs 6, 16, 17. Reagents and
conditions: (a) R-X, DCM, DIPEA, rt. (b) R- Het-X, Cs2CO3, DMF,
heat (c) Ar-X, Pd2(dba)3, rac-BINAP, Cs2CO3, toluene, 100 ºC (d) TFA,
DCM, rt,
3 hr (e) 5-amino-3,4-dimethylthieno[2,3-c]pyridazine-6-
carboxylic acid, HATU, DIPEA, DMF, 2 hr.

While we were able to achieve excellent in vitro potencies
within this series, obtaining both reasonable CNS exposure and
metabolic stability proved more challenging. A number of
compounds (16e-h, 16l) failed to achieve acceptable CNS
exposure (rat brain:plasma Kp < 0.05) and/or were found to be
substrates for human P-gp efflux (16e, 16i, 16q,). Additionally,
rat in vivo PK studies revealed evidence for extrahepatic non-
CYP450 metabolism in certain cases (16o, 16p; possibly due to
aldehyde oxidase-mediated metabolism alpha to the 4-pyridyl
nitrogen). Increasing the lipophilicity of analogs by incorporation
of halogen atoms generally led to modest increases in rat CNS
exposure and reduced P-gp efflux. Compound 16j was selected
for further DMPK profiling, which revealed low predicted
clearance (human and rat predicted CLhep = 5.6 and 18
mL/min/kg, respectively, based on hepatic microsomal CLint) and
29
16i
16j
7.74+0.22
7.12+0.08
[82+5]
76
[75+6]
16k
16l
Inactive
Inactive
7.77+0.01
7.81+0.03
17
[88+11]
16
16m
[90+7]
low potential for CYP450 inhibition (3A4, 2D6, 2C9, 1A2 IC50
>
185
16n
16o
30 µM). In a rat (male, Sprague-Dawley; n = 2) in vivo PK
study, 16j demonstrated low clearance (CLp = 8.8 mL/min/kg)
with a small volume of distribution (Vss = 0.89 L/kg) and
moderate elimination half-life (t1/2 = 1.3 hr). Total and unbound
distribution of 16j to the brain was moderate in rat (brain:plasma
Kp = 0.12, Kp,uu = 0.33 at 0.25 hr post-IV cassette dose), and,
while it was still a substrate for human P-gp (ER = 8.5 in
MDCK-MDR1 cells), its efflux was attenuated compared to
related analogs. Given this favorable profile, it was advanced to a
dose-response amphetamine hyperlocomotion (AHL) study in rat
where it demonstrated robust reversal of AHL (Figure 3). An
oral dose of 1 mg/kg provided a 44% reversal of AHL, and a
maximal effect of 55% AHL reversal was achieved from 10 and
30 mg/kg dose levels. This level of in vivo efficacy was
encouraging for the series and comparable to that previously
reported for benchmark compounds 3 and 4. However, due to
16j’s P-gp liability and potentiation of hM2 (EC50 = 0.96 µM,
AChMax = 43%), it was deemed not suitable for further
development.
6.80+0.19
7.30+0.00
[87+4]
51
[86+6]
8
16p
8.09+0.05
[86+3]
11
16q
7.97+0.09
[84+5]
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 2. Structures and activities for M4 PAM analogs 16.
hM4
EC50 (nM)a
[% ACh Max
SEM]
hM4 pEC50
( SEM)
Cmpd
R
439
16a
16b
16c
6.36+0.04
6.45+0.19
7.04+0.16
[87+4]
419
[89+6]
106
[81+4]
124
16d
16e
6.99+0.18
7.48+0.09
7.13+0.11
[81+9]
Figure 3. Reversal of amphetamine-induced hyperlocomotion in rat (male,
Sprague Dawley, n = 6 per dose group) by 16j (VU0477806). M4 PAM or
vehicle (10% tween-80 90% water [v/v]) was administered orally 30 min
after habituation in the chamber, and then 0.75 mg/kg amphetamine was
administered subcutaneously 30 min later (t = 60 min). Total ambulations
were measured over the subsequent 1 hr interval (t = 60-120 min) and used to
calculate %reversal of AHL for each dose group. Data represent means
SEM.
34
[96+5]
78
16f
[80+11]
41
16g
16h
7.41+0.11
7.48+0.17
[89+11]
38
[83+10]
Expanding on the scope of azetidine analogs we had already
investigated, we synthesized a library of N-aryl analogs (Table

means from three (n=3) independent experiments performed in triplicate
.
3). Phenyl congener 17a retained the excellent hM4 potency that
could be attained with N-heteroaryl analogs. While 17a did suffer
from higher in vivo clearance (rat CLp = 45 mL/min/kg), a
consequence of phenyl hydroxylation based on in vitro metabolic
soft-spot experiments (data not shown), as well as moderately
potent potentiation of hM2 (EC50 = 1.78 µM, 58% AChMax), it
showed a promising divergence from the N-heteroaryl azetidine
SAR with improved CNS exposure (rat brain:plasma Kp = 0.57,
Kp,uu = 0.73). Fluorine substitution(s) on the phenyl ring (17b,
17h-j) generally maintained good hM4 potency and reduced in
vivo clearance (17i, 17j; rat CLp = 4.4 and 16 mL/min/kg,
respectively). Notably, the azetidine congeners (17f, 17g) of
benzylic-linked M4 PAMs previously reported by our group19,20
exhibited significantly weaker hM4 activity compared to that of
17j (~10-fold and 40-fold, respectively). In light of its favorable
potency and rat PK, compound 17j, bearing a 2,3-difluorophenyl
substituent, was selected for additional characterization.
Operational model parameters were determined for 17j from
ACh CRC fold-shift experiments (Ca2+ mobilization assays),
which revealed a rat M4 KB of 120 nM and αβ of 63, a
cynomolgus monkey M4 KB of 890 nM and αβ of 120, and a
human M4 KB of 2000 nM and αβ of 380. Gratifyingly, 17j
displayed broadly attractive properties including an absence of P-
gp efflux (MDCK-MDR1 ER = 1.3), acceptable selectivity
versus hM2 (~230-fold based on potency), and high brain
distribution (rat brain:plasma Kp = 0.77, Kp,uu = 0.86 at 0.25 hr
post-IV cassette dose).
Based on these findings, compound 17j was then evaluated in
a rat AHL dose response study (Figure 4) where it demonstrated
statistically significant AHL reversal (18%) from a low oral dose
of 0.03 mg/kg and reached maximal reversal (74%) from a 3
mg/kg dose, with a resulting in vivo plasma EC50 of 74 nM (0.66
nM unbound) based on terminal concentrations measured in the
study animals (1.5 hr post-administration of 17j).
Compound 17j was further studied to evaluate its suitability
for progression into IND-enabling studies. An Ames test found
no evidence of mutagenesis, a large secondary pharmacology
panel (Cerep) revealed a fairly clean profile (all IC50s/EC50s >25-
30 µM except for human DAT binding IC50 = 0.45 µM), and
CYP450 inhibition was acceptable (1A2 IC50 = 25 µM, 3A4 IC50
11 µM, 2D6 IC50 = 14 µM, 2C9 IC50 = 3.8 µM, 2C19 IC50 = 6.3
µM; with no evidence for time-dependent inhibition). IV and PO
=
Table 3. Structures and activities for M4 PAM analogs 17.
hM4
EC50 (nM)a
hM4 pEC50
Cmpd
R
( SEM)
[% ACh Max SEM]
25
17a
7.61+0.08
[85+8]
28
17b
7.56+0.03
[82+9]
282
17c
17d
17e
17f
17g
6.55+0.04
6.88+0.11
5.90+0.06
[77+8]
Figure 4. Reversal of amphetamine-induced hyperlocomotion in rat (male,
Sprague Dawley, n = 8-24 per dose group) by 17j (VU6000918). M4 PAM,
control M4 PAM (VU0467154) or vehicle (10% tween-80 90% water [v/v])
was administered orally 30 min after habituation in the chamber, and then
0.75 mg/kg amphetamine or vehicle (100% water) was administered
subcutaneously 30 min later (t = 60 min). Total ambulations were measured
over the subsequent 1 hr interval (t = 60-120 min) and used to calculate %
reversal of AHL for each dose group. Data represent means SEM.
141
[77+11]
1289
[81+8]
934
6.03+0.04
6.63+0.29
[86+1]
325
[75+13]
37
17h
17i
7.49+0.12
7.54+0.06
[94+9]
PK studies with 17j in rat (male, Sprague Dawley, n = 1-3) and
dog (female, mongrel, n = 1-2) found the compound to possess
low to moderate in vivo clearance (rat and dog CLp = 16 and 17
mL/min/kg, respectively) with a small to moderate volume of
distribution (rat and dog Vss = 0.67 and 1.6 L/kg, respectively),
and moderate oral bioavailability (rat and dog F = 38% and 20%,
respectively, from a 2-3 mg/kg solution dose). However, lower
oral bioavailability in dog was observed (11%) from a suspension
30
[84+5]
19
17j
7.73+0.06
[88+5]
aCalcium mobilization assays with hM4/Gqi5-CHO cells performed in the
presence of an EC20 fixed concentration of acetylcholine; values represent

Melancon, B.J.; Tarr, J.C.; Wess, J.; Duggan, M.E.; Brandon, N.J.;
Dunlop, J.; Wood, M.W.; Wood, M.R.; Lindsley, C.W.; Conn,
P.J.; Jones C.K. ACS Chem. Neurosci. 2014, 5, 920-942.
dose (2 mg/kg) in a low-excipient vehicle. These findings,
coupled with a low kinetic solubility (solubility in FaSSIF at pH
6.5 after 1 hr = 0.015 mg/mL; aqueous solubility at pH 7.4 = 1.8
µM), as well as suboptimal predicted human PK (~1-2 hr t1/2
based on moderate and small predicted CL and Vss, respectively)
led us to deprioritize 17j for further evaluation as a preclinical
candidate and focus efforts on overcoming the evident solubility-
limited absorption.
12. Smith, E.; Chase, P.; Niswender, C.M.; Conn, P.J.; Lindsley, C.W.;
Madoux, F.; Acosta, M.; Scampavia, L.; Spicer, T.; Hodder, P.
J. Biomol. Screening 2015, 20, 858-868.
13. Wood, M.R.; Noetzel, M.J.; Tarr, J.C.; Rodriguez, A.L.; Lamsal, A.;
In summary, substitution of the benzyl linker with a 3-
aminoazetidine moiety afforded facile entry into an extremely
potent series of M4 PAMs. By varying the substitution pattern of
N-aryl and N-heteroaryl groups, we were able to optimize
subtype selectivity, clearance, CNS exposure, and P-gp efflux.
Compound 17j demonstrated robust AHL reversal in a rodent
model; however, an unacceptably short projected human half-life
and low oral bioavailability (due in part to solubility-limited
absorption) precluded its advancement as a clinical candidate.
Further study and optimization within this series is ongoing, and
will be reported in due course.
Chang, S.; Foster, J.J.; Smith, E.; Hodder, P.S.; Engers, D.W.;
Niswender, C.M.; Brandon, N.J.; Wood, M.W.; Duggan, M.E.;
Conn, P.J.; Bridges, T.M.; Lindsley, C.W. Bioorg. Med. Chem. Lett.
2016, 26, 4282-4286.
14. Wood, M.R.; Noetzel, M.J.; Engers, J.L.; Bollinger, K.A.; Melancon,
B.J.; Tarr, J.C.; Han, C.; West, M.; Gregro, A.R.; Lamsal, A.; Chang,
S.; Ajmera, S.; Smith, E.; Chase, P.; Hodder, P.S.; Bubser, M.;
Jones, C.K.; Hopkins, C.R.; Emmitte, K.A.; Niswender, C.M.; Wood,
M.W.; Duggan, M.E.; Conn, P.J..; Bridges, T.M.; Lindsley, C.W.
Bioorg. Med. Chem. Lett. 2016, 26, 3029-3033.
Acknowledgments
15. Szabo, M.; Huynh, T.; Valant, C.; Lane, J.R.; Sexton, P.M.;
Christopoulos, A.; Capuano, B. MedChemComm. 2015, 6, 1998-
2003.
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.)
16. Huynh, T.; Valant, C.; Crosby, I.T.; Sexton, P.M.; Christopoulos,
A.; Capuano, B. ACS Chem. Neurosci. 2015, 6, 1592-1599.
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