Further optimization of the M1PAM VU0453595: Discovery of novel heterobicyclic core motifs with improved CNS penetration

Article abstract of DOI:10.1016/j.bmcl.2016.04.083

This Letter describes the continued chemical optimization of the VU0453595 series of M₁positive allosteric modulators (PAMs). By surveying alternative 5,6- and 6,6-heterobicylic cores for the 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one core of

Full text of DOI:10.1016/j.bmcl.2016.04.083

Bioorganic & Medicinal Chemistry Letters xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Further optimization of the M1 PAM VU0453595: Discovery of novel
heterobicyclic core motifs with improved CNS penetration
Joseph D. Panarese a, Hykeyung P. Cho a, Jeffrey J. Adams a, Kellie D. Nance a,c, Pedro M. Garcia-Barrantes a,
Sichen Chang a, Ryan D. Morrison a, Anna L. Blobaum a,b, Colleen M. Niswender a,b,d, Shaun R. Stauffer a,b,c
,
P. Jeffrey Conn a,b,d, Craig W. Lindsley a,b,c,
⇑
a Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA
b Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
c Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA
d Vanderbilt Kennedy Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
This Letter describes the continued chemical optimization of the VU0453595 series of M1 positive
allosteric modulators (PAMs). By surveying alternative 5,6- and 6,6-heterobicylic cores for the 6,7-dihy-
dro-5H-pyrrolo[3,4-b]pyridine-5-one core of VU453595, we found new cores that engendered not only
comparable or improved M1 PAM potency, but significantly improved CNS distribution (Kps 0.3–3.1).
Moreover, this campaign provided fundamentally distinct M1 PAM chemotypes, greatly expanding the
available structural diversity for this valuable CNS target, devoid of hydrogen-bond donors.
Ó 2016 Elsevier Ltd. All rights reserved.
Received 22 April 2016
Revised 27 April 2016
Accepted 28 April 2016
Available online xxxx
Keywords:
M1
Muscarinic acetylcholine receptor
Positive allosteric modulator (PAM)
CNS penetration
Structure–activity relationship (SAR)
Positive allosteric modulators (PAMs) of the muscarinic acetyl-
choline receptor subtype 1 (M1) have garnered a great deal of atten-
tion as a novel therapeutic approach for the treatment of the
cognitive and negative symptom domains of schizophrenia, espe-
cially targeting NMDA receptor hypofunction.1–8 Moreover, M1
PAMs are also of interest in general cognition enhancement and
Alzheimer’s disease.1–4,9–12 Since we reported on the discovery of
the first M1 PAM, BQCA,13,14 numerous M1 PAMs have been
reported in the primary and patent literature (most by scaffold hop-
ping VU and Merck series) with many conserved moieties that con-
sistently engender low CNS penetration (Kps < 0.3).15–25 Our latest
entry into M1 PAMs was the result of three distinct high-throughput
screening campaigns,26 which resulted in novel indole-, azaindole-
and isatin-based M1 PAM scaffolds.25,27–29 Of these, the isatin
VU0119498 (1) was a unique PAM in that it potentiated all of the
Gq-coupled mAChRs (M1, M3 and M5) with equivalent potency
and efficacy.27 Subsequent optimization efforts identified ‘molecu-
lar switches’ that gave rise to a series of highly selective M5
PAMs,30–32 as well as ML137 (2), a highly selective M1 PAM by
virtue of the fluorophenyl pyrazole moiety.28 Carbonyl deletion
provided lactam 3, and surveying regioisomeric lactams afforded
VU0451725 (4), with improved DMPK properties over 2 and 3.33
Finally, an aza-scan identified the the 6,7-dihydro-5H-pyrrolo[3,4-
b]pyridine-5-one core of VU0453595 (5), which proved a useful
in vitro and in vivo tool, demonstrating efficacy in rodent models
of pharmacologically-induced NMDA hypofunction (Fig. 1).33 In this
O
X
fluorination/
heterobiaryl
development
O
O
positional lactam
isomer
N
N
N
N
M1-selectivity
Br
F
2, X = O, ML137
, X = CH2, VU0448350
1, VU0119498
M1,3,5 PAM
3
this work -
alternate 5,5- and
5,6-heterobiaryl
cores and pyrrole
replacements
O
N
F
O
aza
scan
N
F
N
fluorine walk
N
N
N
N
4, VU0451725
5, VU0453595
Figure 1. Evolution of the development of the VU0119498 series of M1 PAMs,
culminating in VU0453595 (5), a moderately potent PAM (rM1 EC50 = 3.2 M, 75%
l
ACh Max and 3Â less potent on hM1) with modest CNS penetration (Kp = 0.3). In this
work, we survey alternative 5,6- and 6,6-heterobicyclic cores and pyrrole replace-
ments in an attempt to increase CNS penetration.
⇑
Corresponding author.
E-mail address: craig.lindsley@vanderbilt.edu (C.W. Lindsley).
http://dx.doi.org/10.1016/j.bmcl.2016.04.083
0960-894X/Ó 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Panarese, J. D.; et al. Bioorg. Med. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.bmcl.2016.04.083

2
J. D. Panarese et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
Table 1
Letter, we detail an optimization campaign surveying alternative
5,6- and 6,6-heterobicyclic cores, alternate moieties for the pyra-
zole, and walking additional fluorines around the central phenyl
ring to ultimately provide multiple novel M1 PAM scaffolds with
comparable or improved rat M1 PAM potencies and improved CNS
distribution (Kps 0.4–3.1).
Structures and activities of analogs 16
F
NMe
N
Het
F
The chemistry to access new analogs, if not commercially avail-
able, was straightforward (Scheme 1).34 The fluorinated hetero-
biaryl tail moities were readily prepared in two steps as either a
benzyl chloride 7 or a benzyl mesylate 8 from commercial benzyl
alcohols 6. Various 5,6- and 6,6-heterobiaryl systems were then
alkylated with either 7 or 8 to provide analogs 10. A subsequent
Suzuki coupling installed the heterobiaryl motif, delivering analogs
11. Quinolinone and naphthyridinone analogs 11 of 9, were made
in a single step from 12, and based on our previous work, cores
such as 15 were also accessed in a simple three step procedure.34
SAR was steep for the diverse analogs 11, with many compounds
devoid of M1 PAM activity on both human or rat M1, or displaying
species bias towards rat M1 PAM activity. In general, the 2,6-
difluoro analogs were active whereas mono-fluoro and des-fluoro
phenyl congeners were inactive as M1 PAMs. Representative SAR
is shown in Table 1 for a subset of analogs 16, possessing an
N-Me-indazole attached at the 4-position to the 2,6-difluorophenyl
ring. While only rat M1 data is shown, analogs 16 were uniformly
16
M)a [% ACh
Compd Het
rM1 EC50
(l
rM1 pEC50
( SEM)
Rat Kp
b
Max SEM]
(Kp,uu
)
O
N
0.79
(0.32)
N
16a
4.7 [45 4%]
5.32 0.10
O
0.77
(0.60)
N
16b
4.7 [73 5%]
4.9 [67 3%]
4.3 [52 4%]
1.7 [50 5%]
5.32 0.08
5.31 0.02
5.37 0.07
5.77 0.04
N
N
N
2.16
(0.77)
16c
N
O
O
0.52
(0.49)
N
N
16d
N
2- to 3-fold less potent on human M1 (with many >10
various 6,6-hetrobicyclic ring systems were comparably active
(rM1 EC50 4.3–4.9 M) across quinazolin-4(3H)-ones (16a),
lM). Here,
O
0.35
(0.30)
N
16e
s
l
N
pyrido[3,4-d]pyrimidin-4(3H)-ones (16b), quinoxalin-2(1H)-ones
(16c) and naphthyridin-5(6H)-ones (16d). These analogs possessed
favorable in vitro DMPK profiles (rat and human fus of 0.01–0.04)
and moderate predicted hepatic clearance (CLheps of
40–44 mL/min/kg). However, they were superior to the lead 5 in
terms of brain distribution (Kp), wherein 16a–d displayed Kps (rat
brain:plasma ratios) of 0.35–2.16, and when corrected for fraction
a
Calcium mobilization assays with rM1-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.
b
Total and calculated unbound brain:plasma partition coefficients determined at
0.25 h post-administration of an IV cassette dose (0.20–0.25 mg/kg) to male, SD rat
(n = 1), in conjunction with in vitro rat plasma protein and brain homogenate
binding assay data.
unbound in plasma and brain homogenate binding, the Kpuu
s
ranged from 0.3 to 0.77—a major advance in the context of M1
PAMs. Notably, 16c (VU0478436) afforded a >6-fold increase in
CNS penetration over 5. The 5,6-congener 16e (VU0486691), based
improved in vitro DMPK profile (rat and human fus of 0.08 and
0.04, respectively and moderate rat predicted hepatic clearance
(CLhep = 40 mL/min/kg)). Moreover, 16e demonstrated a rat Kp of
0.35 and a Kpuu of 0.3. This finding led us to explore additional
5,6-heterobicyclic cores.
on
a dihydroimidazol[1,2-c]pyrimidin-5(3H)-one core, showed
enhanced M1 PAM potency (rM1 EC50 = 1.7
lM, 50% ACh Max),
SAR proved steep as additional 5,6-hetrobicyclic cores were
prepared and evaluated, with the vast majority devoid of M1
PAM activity. During this effort, it was also shown that
regioisomeric N-Me indazoles had a profound effect on M1 PAM
activity (Fig. 2). Interestingly, the 4-positional isomer 17 was
devoid of M1 PAM activity, while in contrast, the 5-positional
H (F)
H (F)
H (F)
b
a
Cl
MsO
(F) H
HO
(F) H
(F) H
Br
Br
Br
isomer 18 was a potent M1 PAM (EC50 = 1.7 lM, 50% ACh Max,
7
6
8
pEC50 = 5.76 + 0.02) with very attractive in vitro DMPK properties
(rat and human fus of 0.06 and 0.05, respectively, low rat hepatic
clearance (CLhep = 29 mL/min/kg) and a large free fraction in rat
O
O
O
c
N
H (F)
Br
Het
d
N
H (F)
Het1
Het
NH
Het
brain
homogenate
binding,
fu = 0.098).
Moreover,
18
(F) H
(F) H
(VU0484061) possessed a rat brain:plasma ratio (Kp) of 0.40 and
a Kpuu of 0.70. Once again, and in comparison to the known M1
PAMs with low Kps and Kpuus, both 16c and 18 truly stand out. It
9
10
11
9
Cores
Y
O
O
F
O
F
H
N
CO2Et
NH
NH2
NH2
O
NH
e
Y
X
f-h
NMe
N
N
N
N
X
N
N
5
4
N
N
N
W
W
N
N
F
F
NMe
N
12
13
14
15
17
, VU0478499
rM1 EC50 >10 µM
18
, VU0484061
Scheme 1. Reagents and conditions: (a) Ghosez’s reagent or SOCl2, DCM, rt, 65–78%;
(b) MsCl, Et3N, DCM, 0 °C, 75–88%; (c) 7 or 8, Cs2CO3, MeCN, 70 °C, 52–80%; (d) Het-
rM1 EC50 = 1.7 µM
p = 0.4, Kpuu = 0.7
K
B(OH)2, Pd(dppf)Cl2, Cs2CO3, THF:H20 (10:1),
lw 140 °C, 22–69%; (e) ethyl
glyoxylate, 51–68%; (f) Br(CH2)2NHBoc, Cs2CO3, DMF, rt, 16 h, 98%; (g) HCl, 1,4-
dioxane, rt, 1.5 h, 90%; (h) Na2CO3, 1,4-dioxane/H20, rt 3 h, 90%.
Figure 2. The impact of positional isomers of the N-Me indazole in the context of
dihydropyrazolo[1,5-a]pyrazin-4-(5H)-ones 17 and 18.
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J. D. Panarese et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
3
N
F
N
O
N
F
O
N
F
N
O
N
N
N
N
N
N
F
F
N
F
N
N
19, VU0486384
rM1 EC50 = 2.8
Kp = 1.64, Kpuu = 1.1
20, VU0483225
rM1 EC50 = 6.1
Kp = 3.1, Kpuu = 2.7
21, VU0483232
rM1 EC50 = 5.3
Kp and Kpuu = BLQ
µ
µ
µ
M
M
M
Figure 3. Additional M1 PAMs 19–21 based on 6,6-heterobicyclic cores with a diverse range of pharmacological and DMPK properties.
is important to point out that the majority of M1 PAMs possess two
or more hydrogen bond donors (typically a trans-2-hydroxy cyclo-
hexyl amide moiety) that likely engenders the poor CNS penetra-
tion due to P-gp efflux or low permeability.13–25
candidates, the improved disposition of these new chemotypes
represent fundamentally new starting points for further chemical
optimization. Additional refinements are in progress and will be
reported in due course.
Prior to leaving this unique sub-series of M1 PAMs, one last
library of analogs was prepared with more diverse tail pieces within
the 16b and 16c 6,6-heterobicyclic cores. Again, SAR was steep, and
few active M1 PAM resulted. However, this last campaign afforded
three M1 PAMs 19–21 with diverse profiles (Fig. 3). Here, the
pyrido[2,3-b]pyrazin-2(1H)-one 19 (VU0486384) was a potent
Acknowledgments
We thank the NIH for funding via the National Institute of
Mental Health (2RO1MH082867, 5R01MH073676, 1U19MH10
6839 and 1U01MH087965). 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.). P.MG. would like to
acknowledge the VISP program for its support.
and efficacious rat M1 PAM (EC50 = 2.8 lM, 80 1% ACh Max,
pEC50 = 5.56 0.12), with a favorable fraction unbound in plasma
(rat and human fus of 0.04), high predicted hepatic clearance
(CLhep = 60 mL/min/kg), yet excellent CNS penetration (Kp = 1.64
and Kpuu = 1.1). The nature of the heterobiaryl moiety played a key
role in analogous pyrido[3,4-d]pyrimidin-4-(3H)-one congeners
20 and 21. The isoquinoline analog 20 was a weak rat M1 PAM
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(EC50 = 6.1 lM, 42 3% ACh Max, pEC50 = 5.21 0.11) with equiva-
lent plasma fraction unbound (fus of 0.03) for rat and human, and
the best Kp to date for an M1 PAM of 3.1 (and a Kpuu of 2.7). In
sharp contrast, the more basic N-Me benzimidazole congener 21
was of comparable potency (EC50 = 5.3 lM, 65 4% ACh Max,
pEC50 = 5.28 0.14), good plasma fraction unbound (rat and human
fus of 0.04 and 0.06, respectively), but no detectable CNS penetration
(brain levels below the level of quantitation, BLQ). These data show
that subtle pKa modulation can dramatically impact Kp.
Finally, the concept of divergent signal bias, mediated by stabi-
lization of unique conformers of the GPCR by the allosteric ligand,
has emerged, and in many instances is critical for avoiding adverse
effect liabilites.1–4,35–38 Thus, our lab surveys the propensity of new
M1 PAM ligands to display signal bias.38-41 For VU0453595 (5),
DiscoverRX assessed activities of the M1 PAM against human M1
in a calcium flux assay, as well on b-arrestin recruitment and inter-
nalization.39 PAM 5 was shown to be a modest human M1 PAM
(EC50 = 1.9
ization (EC50 >10
(EC50 = 2.6 M, 57% Max). New M1 PAM 16b was evaluated simi-
larly, and was found to be a modest human M1 PAM (EC50 = 5.3 M,
65% ACh Max) with no effect on receptor internalization
(EC50 >10 M), yet a submicromolar effect on b-arrestin recruit-
l
M, 79% ACh Max) with no effect on receptor internal-
l
M) and modest effect on b-arrestin recruitment
l
l
l
ment (EC50 = 980 nM, 33% Max). At this point, the in vivo ramifica-
tion of these profiles across signal transduction pathways are
unclear, but we are tracking and noting differences between M1
PAMs and plan to investigate more thoroughly once a collection
of M1 PAM ligands with diverse profiles (and comparable PK) are
accumulated.
In summary, we report on the further optimization of the
in vivo tool M1 PAM, VU0453595 (5). A diverse array of 5,6- and
6,6-heterobicyclic cores were developed as novel M1 PAMs with
unprecedented levels of CNS penetration (Kps 0.3–3.1 and Kpuu
s
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motifs. While these M1 PAMs are too weak to advance as clinical
Please cite this article in press as: Panarese, J. D.; et al. Bioorg. Med. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.bmcl.2016.04.083

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Please cite this article in press as: Panarese, J. D.; et al. Bioorg. Med. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.bmcl.2016.04.083