Discovery of (1R,6S)-5-[4-(1-cyclobutyl-piperidin-4-yloxy)-phenyl]-3,4- diaza-bicyclo[4.1.0]hept-4-en-2-one (R,S-4a): Histamine H3 receptor inverse agonist demonstrating potent cognitive enhancing and wake promoting activity

Article abstract of DOI:10.1016/j.bmcl.2014.01.061

A series of fused cyclopropyl-4,5-dihydropyridazin-3-one (3,4-diaza-bicyclo[4.1.0]hept-4-en-2-one) phenoxypiperidine analogs was designed and synthesized, leading to the identification of (1R,6S)-5-[4-(1-cyclobutyl- piperidin-4-yloxy)-phenyl]-3,4-diaza-bicyclo[4.1.0]hept-4-en-2-one (R,S-4a) as a second-generation pyridazin-3-one H₃R antagonist. Compound R,S-4a was a potent H₃R functional antagonist in vivo in the rat dipsogenia model, demonstrated potent wake activity in the rat EEG/EMG model, and enhanced short-term memory in the rat social recognition memory model at doses as low as 0.03-0.3 mg/kg po.

Full text of DOI:10.1016/j.bmcl.2014.01.061

Bioorganic & Medicinal Chemistry Letters 24 (2014) 1303–1306
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of (1R,6S)-5-[4-(1-cyclobutyl-piperidin-4-yloxy)-phenyl]-
3,4-diaza-bicyclo[4.1.0]hept-4-en-2-one (R,S-4a): Histamine H3
receptor inverse agonist demonstrating potent cognitive enhancing
and wake promoting activity
⇑
Robert L. Hudkins , Kurt A. Josef, Nadine C. Becknell, Lisa D. Aimone, Jacquelyn A. Lyons,
Joanne R. Mathiasen, John A. Gruner, Rita Raddatz
Discovery and Product Development, Teva Pharmaceutical Global R&D, 145 Brandywine Parkway, West Chester, PA 19380, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of fused cyclopropyl-4,5-dihydropyridazin-3-one (3,4-diaza-bicyclo[4.1.0]hept-4-en-2-one)
Received 10 October 2013
Revised 16 January 2014
Accepted 21 January 2014
Available online 30 January 2014
phenoxypiperidine analogs was designed and synthesized, leading to the identification of (1R,6S)-5-
[4-(1-cyclobutyl-piperidin-4-yloxy)-phenyl]-3,4-diaza-bicyclo[4.1.0]hept-4-en-2-one (R,S-4a) as a second-
generation pyridazin-3-one H R antagonist. Compound R,S-4a was a potent H R functional antagonist
3
3
in vivo in the rat dipsogenia model, demonstrated potent wake activity in the rat EEG/EMG model,
and enhanced short-term memory in the rat social recognition memory model at doses as low as
Keywords:
0.03–0.3 mg/kg po.
3
Histamine H receptor
Ó 2014 Elsevier Ltd. All rights reserved.
H
3
inverse agonist
CEP-26401
Pyridazin-3-one
Sleep–wake
Cognition
The histamine H
3
receptor (H
3
R) in the brain functions as both
excessive daytime sleepiness in PD and schizophrenia are on going.
1
n,o
an autoreceptor to modulate histamine release and as an inhibitory
heteroreceptor to regulate the release of multiple neurotransmit-
ters, including acetylcholine, dopamine, norepinephrine and sero-
3
We disclosed a novel class of pyridazin-3-one H R antagonists/
inverse agonists including the clinical compound 1 (CEP-26401,
2
irdabisant, Fig. 1), and a subsequent series of publications out-
tonin, that are thought to be involved in attention, sleep and
lined the structure–activity relationships (SAR) on the pyridazin-
1
3-one and the 4,5-dihydropyridazin-3-one subseries.3 The SAR
cognition. H
mitter release, while H
3
R activation results in the inhibition of neurotrans-
R blockade by selective antagonists or in-
verse agonists reverses histamine-mediated inhibition and
enhances neurotransmitter release. H R antagonists remain of
3
3
for the identification of second-generation pyridazinone H R
antagonists to irdabisant was explored by replacement of the
phenoxypropylamine fragment with the conformationally re-
stricted 4-phenoxypiperidine and change of the aromatic pyridaz-
3
interest as a potential treatment for multiple CNS disorders associ-
ated with attention and cognitive deficits, including sleep/wake
activity, attention-deficit hyperactivity disorder (ADHD), Alzhei-
mer’s disease (AD), mild cognitive impairment, and the cognitive
3
f,g
inone to the 4,5-dihydropyridazin-3-one.
However, a key issue
with the 4,5-dihydropyridazin-3-one scaffold was in vivo metabo-
3
f
lism to the aromatized system. Detailed SAR and metabolite
investigations (MetID) determined that installing a chiral S-5-
methyl (Fig. 1, compound S-2) blocked in vivo aromatic metabolite
formation, while the R-isomer was extensively metabolized in both
deficits in schizophrenia.1 While about 20 H
antagonists have
entered clinical evaluation in various CNS indications, most were
3
1
h,i
3
terminated. Several H antagonists such as GSK239512 (GSK),
1
j
1k-m
3g
and bavisant (JNJ) and MK-0249 (Merck)
failed to show
rat and dog. Fully profiling both isomers revealed comparable
efficacy in late-stage clinical studies in cognition or attention. Only
pitolisant (Bioprojet) showed positive results in a phase III study in
narcolepsy and data analysis in two other phase III studies evaluating
3
H R binding affinity and functional activity, selectivity and
rat pharmacokinetics. Subsequently, further modification at the
4-position produced a potent lead wake promoting agent, 6-[4-
(
1-cyclobutyl-piperidin-4-yloxy)-phenyl]-4,4-dimethyl-4,5-dihy-
3
g
dro-2H-pyridazin-3-one 3. Motivated by the compelling in vitro
and in vivo profile of S-2, a novel sub-series was designed by
⇑
Corresponding author. Tel.: +1 610 738 6283; fax: +1 610 738 6558.
E-mail address: robert.hudkins@tevapharm.com (R.L. Hudkins).
http://dx.doi.org/10.1016/j.bmcl.2014.01.061
960-894X/Ó 2014 Elsevier Ltd. All rights reserved.
0

1
304
R. L. Hudkins et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1303–1306
2
D
4
24
D
H
N
½
aꢁ
+213 (c 0.1, MeOH) and peak 2 (1S,6R(ꢂ)-4b) ½
a
ꢁ
ꢂ195 (c
H
N
O
N
O
N
0.1, MeOH). The 6-S stereochemistry in 4a corresponds to 4S-2
N
(Fig. 1).
O
N
The cyclopropyl-dihydropyridazinone analogs were tested
in vitro by displacement of [ H]NAMH binding to membranes iso-
O
3
1
3
hH R K = nM
rH R K = nM
hH R K = 2.7 nM
rH R K = 4.4 nM
lated from CHO cells transfected with cloned human H
receptors, as shown in Table 1. The fused cyclopropyl 4 with an
or rat H3
3
i
3
i
3
2
3
i
3
i
2
R
cyclobutyl had high affinity for both hH
3 i
R (K = 4.7 nM) and
H
H
O
N
O
N
N
N
rH
3
R (K = 8.4 nM) and the individual enantiomers 4a and 4b also
i
N
R
N
had comparable affinity. Substitution at the pyridazinone N-R1 po-
sition with alkyl (9–11) or aryl (12) groups was well tolerated
showing equally high affinity, consistent with our previous find-
S
S
O
O
S-2
R,S-4a
R antagonists.
2
a,3a,f,g
2
ings.
The SAR at the piperidine R position with compounds
Figure 1. Structures of clinical H
3
13–17 showed that a cyclobutyl (4) or cyclopentyl (16–17) group
was optimal. A large decrease in binding affinity was observed
for the N-ethyl 13, while N-isopropyl (14 and 15) retained affinity
cyclizing the S-methyl to a fused cyclopropyl scaffold that retained
chirality at the 4-position, with blockade of both the 4- and 5-posi-
tions (Fig. 1). Disclosed here is the SAR around a set of 4,5-cyclo-
propyl fused dihydropyridazines, and the profile and selection of
comparable to N-cyclobutyl 4. Comparing 15 to 14 showed the R2
3
methyl had 3-fold higher affinity for the rH R. Substitution on the
central phenyl ring with methyl substitution was tolerated, while
fluoro showed weak affinity compared to 4 (data not shown).
In the discovery flow, compounds meeting binding affinity cri-
(
(1R,6S)-5-[4-(1-cyclobutyl-piperidin-4-yloxy)-phenyl]-3,4-diaza-
bicyclo[4.1.0]hept-4-en-2-one (R,S-4a) as a second-generation
wake-promoting H R antagonist.
teria were prioritized and screened for selectivity against hH
1
,
3
hH , and hH receptor subtypes, for aqueous solubility (pH 2 and
2
4
The piperidin-4-yloxy-phenyl-3,4-diaza-bicyclo[4.1.0]hept-4-
en-2-ones 4, 9–20 were synthesized by the sequence outlined in
Scheme 1. Mitsunobu reaction with phenol 5 and 4-hydroxy-1-
pH 7.4), in vitro liver microsomal stability (rat, mouse, dog, and hu-
man), and inhibition of CYP isoforms (1A2, 2C9, 2C19, 2D6, and
3
A4). The selectivity profiles of compounds meeting criteria were
4
boc-piperidine gave boc-4-phenoxypiperidine 6. Boc deprotection
further assessed for activity against GPCRs, ion channels, and en-
zymes. Compounds of interest were then screened in rat pharma-
cokinetic (PK) experiments designed to evaluate the intrinsic
(
TFA, DCM) to the piperidine intermediate, followed by reductive
amination with an appropriate ketone or aldehyde, afforded 7. Tar-
get inhibitors 4 and 9–17 were synthesized from 4-phenoxypiperi-
dines 7 using a one-pot sequence. Friedel–Crafts acylation with 7
and 3-oxa-bicyclo[3.1.0]hexane-2,4-dione produced the crude
piperidin-4-yloxy-benzoyl-cyclopropanecarboxylic acid interme-
diates 8. After reacting 0.5–1 h at 70 °C, the mixture was concen-
intravenous (iv) PK parameters (t
and brain partitioning. Compounds 9–12 and 14–17 showed excel-
lent selectivity (>1000-fold) for hH , hH , and hH subtypes. Profil-
½ d
, CL, V ), oral (po) bioavailability
1
2
4
ing of the pyridazinone-N-substituted series (9–12) revealed that
N-methyl 9 showed acceptable metabolic stability but poor
in vivo rat PK (%F = 6), while 10 and 11 showed unacceptable met-
abolic stability. Compound 12 was not profiled further due to the
4
trated, and crude acid 8 dissolved in aqueous NH OH was
immediately treated with hydrazine or N-substituted hydrazine
at reflux to produce racemic targets 4 and 9–20. Racemic 4 was
separated using chiral supercritical fluid chromatography (SCF) to
give both isomers in >99% ee. The structure of the first eluting iso-
mer 4aꢀHCl salt was solved by single crystal X-ray crystallography
and the stereochemistry assigned as the 1R,6S(+)-5-[4-(1-cyclobu-
tyl-piperidin-4-yloxy)-phenyl]-3,4-diaza-bicyclo[4.1.0]hept-4-en-
2a
high clogP (3.4). Compounds 14 and 16 also showed acceptable
in vitro metabolic stability and selectivity for inhibition of cyto-
chrome P450 enzymes but did not advance further due to unac-
ceptable rat PK.
Isomers R,S-4a and S,R-4b were profiled in a series of discovery
flow activities to identify their developability potential. In addition
2
-one isomer. The specific rotation of peak 1 (1R,6S(+)-4a) was
2
Boc
R
Table 1
4
b, c
a
N
N
R binding dataa
,5-Cyclopropyl fused pyridazin-3-one phenoxypiperidine H
3
OH
O
O
1
R
N
5
O
6
7
N
1
2
R
N
R
O
N
O
N
HO C
2
d
2
e
N
R
N
2
O
R
N
O
Entry
R1
R2
hH
3
R
3
rH R
O
N
8
4
, 9-17
1
4
—
H
H
H
Me
Et
iPr
4-F-Ph
H
H
Me
H
—
2.0 ± 0.4
4.7 ± 0.2
3.8 ± 0.5
6.8 ± 0.6
4.0 ± 0.1
4.5 ± 0.7
6.9 ± 1.5
3.5 ± 0.5
173 ± 44
9.1 ± 0.9
4.0 ± 0.2
3.7 ± 0.1
3.6 ± 0.4
7.2 ± 0.4
8.4 ± 1.0
7.3 ± 0.9
12 ± 2
6.9 ± 0.2
8.0 ± 2.1
5.6 ± 1.8
6.7 ± 0.9
228 ± 102
51 ± 19
cButyl
cButyl
cButyl
cButyl
cButyl
cButyl
cButyl
Et
H
N
H
N
f
O
O
R,S(+)-4a
S,R(ꢂ)-4b
9
N
N
1
1
0
1
O
O
4
a
4b
12
13
Scheme 1. Reagents and conditions: (a) 4-hydroxy-1-Boc-piperidine, P(Ph)
DEAD, rt, 68–80%; (b) TFA, DCM, 25 °C, 100%; (c) R -ketone or aldehyde, NaCNBH
DMF, MeOH, AcOH, 60 °C, 60–80%; (d) 3-oxa-bicyclo[3.1.0]hexane-2,4-dione, AlCl
DCE, 0 °C ? 70 °C; (e) R NHNH
3
, THF,
14
15
16
17
iPr
iPr
2
3
,
,
17 ± 2
8.1 ± 1.8
5.7 ± 1.6
3
cPentyl
cPentyl
1
2
, 2-propanol, 110 °C, 65–70% 2 steps; (f) chiral SFC
, 100 bar,
Me
separation, chiralpak AS-H (2 ꢃ 25 cm), 40% methanol (0.2%DEA)/CO
2
a
6
0 mL/min, 220.
Human H
3
R (hH
3
3 3 i
R), rat H R binding (rH R); K values in nM ± SEM.

R. L. Hudkins et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1303–1306
1305
to nanomolar binding affinity, both isomers were full inverse ago-
3
5
180
*
*
3
nists in the [ S]GTPcS hH R functional binding assay (EC50 = 0.4 nM
*
2
and 0.5 nM, respectively). Compounds R,S-4a and S,R-4b showed
acceptable in vitro metabolic stability across species in liver micro-
1
20
somes (t
IC50 values >30
CYP1A2, 2C9, 2C19, 2D6 and 3A4), indicating low potential for
drug–drug interactions. Both isomers had excellent selectivity for
hH over hH , hH2, and hH receptor subtypes (<10% inhibition
at 10 M) and against a panel of 172 GPCRs, ion channels, trans-
porters and enzymes. S,R-4b only inhibited the dopamine trans-
porter (DAT, 63%) at a final concentration of 10 M (MDS Pharma
Services, LeadProfile and Spectrum screen). In the hERG patch
clamp assay, the IC50 value for R,S-4a was 14 M, while the IC50
value for S,R-4b was 6 M. Based on the hERG and DAT activity
½
>40 min in mouse, rat, dog, monkey and human) and
lM for inhibition of cytochrome P450 enzymes
6
0
(
0
3
1
4
Vehicle
1
3
10
30
l
Compound R,S-4a (mg/kg po)
l
Figure 2. Cumulative time awake for 4 h (4 h AUC) following administration of
vehicle or compound R,S-4a in chronically implanted rats. Mean + SEM, n = 8–14/
group. ( ) p <0.05, Dunnett’s post hoc test versus vehicle.
l
⁄
l
observed for S,R-4b, R,S-4a was selected for detailed preclinical
and in vivo profiling. R,S-4a displayed acceptable drug-like proper-
(10 mg/kg). At 10 mg/kg, over 90% percent time awake was main-
tained for the first 1.5 h after dosing. Wake in the 30 mg/kg group
was increased to 217 ± 5 at 4 h (equivalent to 90% time awake for
4 h). At 30 mg/kg, maximal cumulative wake surplus (excess wake
time compared to the vehicle group) was 174 min at 7.5 h post
dosing, which was maintained up to 18 h. No evidence of abnormal
behavioral or EEG activity was observed at any dose tested and
sleep rebound was not observed in any of the treatment groups.
Take together 4a demonstrated very potent wake promotion in
the rat at doses as low as 1 mg/kg ip and robust wake at higher
doses with no adverse events.
ties of low lipophilicity (clogP = 1.2), high permeability (Caco-2
ꢂ6
P
app = 16.4 ꢃ 10 cm/s with no evidence of P-gp efflux), moderate
plasma protein binding for rat, dog, and human (77–82%) and
water solubility (pH 2 > 1 mg/mL and pH 7.4 = 0.8 mg/mL). The
pharmacokinetic properties of R,S-4a were studied in rat, dog,
and monkey, with a comparison to isomer S,R-4b in the rat
(Table 2). Compound R,S-4a showed high oral bioavailability
across species (%F >90) with an iv terminal half-life of 2.6 h in
rat, 3 h in dog, and 8.6 h in monkey, with moderate clearance.
The measured brain to plasma ratio was 3.6 in rat and 5.1 in dog.
Compound R,S-4a was evaluated in vivo using the rat dipsoge-
nia model and the rat EEG/EMG sleep–wake model. The rat dipso-
3
Following the demonstration of potent in vivo H R functional
activity in the brain, R,S-4a was further evaluated for enhancement
of short-term memory using the rat social recognition (SR) mem-
ory model, which tests the ability of agents to improve the reten-
genia model was used as a surrogate measure of in vivo H
functional inhibition in the brain following peripheral administra-
tion. Histamine and the H R-selective agonist, R- -methylhista-
3
R
2
,3,9
3
a
tion of encounters between animals.
In this model, an adult
mine (RAMH), induce drinking in the rat when administered
rat is allowed to explore a juvenile rat for a short period of social
investigation and then, after a 2 h separation, is reintroduced to
the juvenile for a second investigation period. Social memory
was quantified by determining the investigation ratio (RID), which
is the ratio of the time the adult rat spends investigating the juve-
nile in the second encounter divided by the time the adult spends
investigating the juvenile during the first encounter. An agent that
enhances memory will reduce the exploration time of the second
encounter relative to the first and lower the investigation ratio.
In this model R,S-4a produced a significant decrease in the inves-
tigation ratio at doses as low as 0.03–0.3 mg/kg po, suggesting an
enhancement of short-term memory (Fig. 3).
either peripherally or centrally, an effect that is blocked by H3R
2
,5
antagonists.
inhibited RAMH-induced dipsogenia with an ED50 value of
.14 mg/kg ip. H R antagonists, including irdabisant and its ana-
logs, demonstrate wake promoting activity in the rat.
Compound 4a potently and dose-dependently
0
3
2
b,3a,d,f,g,6
Wake-promoting activity of 4a in the rat was measured from 1
to 30 mg/kg ip as previously described using rats surgically im-
planted for chronic recording of EEG (electroencephalographic)
and EMG (electromyographic) signals enabling wake, slow-wave
sleep, and rapid eye-movement sleep as scored by standard crite-
2
b,7,8
ria.
The cumulative wake time at 4 h after dosing (5 h after
lights on) was evaluated during the normal quiet period of the
rat. Compound 4a significantly and dose-dependently increased
wake at doses from 1 up to 30 mg/kg ip by 4 h AUC values (ANOVA,
P <0.001; Fig. 2). Doses of 1–10 mg/kg increased wake 40–120%
above the vehicle value, from 86 ± 7 min (vehicle group) to
In summary, a series of fused cyclopropyl-4,5-dihydropyri-
dazin-3-one phenoxypiperidine analogs was designed and
synthesized, leading to the identification of ((1R,6S)-5-[4-(1-cyclo-
butyl-piperidin-4-yloxy)-phenyl]-3,4-diaza-bicyclo[4.1.0]hept-4-
en-2-one (R,S-4a) as a second-generation pyridazin-3-one H
3
R
1
21 ± 12 (1 mg/kg), 129 ± 6 min (3 mg/kg), and 189 ± 5 min
antagonist. Compound R,S-4a met all discovery criteria, including
Table 2
a
Pharmacokinetic properties in rat
R,S-4a Rata
S,R-4b Rata
R,S-4a Dogb
R,S-4a Monkeyb
iv t
½
(h)
2.6 ± 0.4
3.7 ± 0.5
17 ± 0.5
1.6 ± 0.4
3.0 ± 0.4
22 ± 3
3.0 ± 0.3
4.1 ± 0.5
16 ± 2
8.6 ± 0.4
6.0 ± 0.5
8 ± 1
V
d
(L/kg)
CL (mL/min/kg)
po AUC (ng h/mL)
8320 ± 624
888 ± 85
92 ± 3
5144 ± 599
649 ± 78
66 ± 4
2955 ± 116
502 ± 24
94 ± 12
7187 ± 792
645 ± 29
114 ± 4
Cmax (ng/mL)
F (%)
B/Pc
3.6 ± 0.3
i
5.0 ± 0.2i
5.1 ± 1.1
ii
ND
d
a
b
c
Administration at 1 mg/mg iv and 5 mg/kg po; iv formulation (3% DMSO, 30% solutol, 67% phosphate buffered saline) oral formulation (water pH 2).
Administration at 1 mg/mg iv and 3 mg/kg p.o.
(
i) B/P = brain to plasma ratio measured 6 h post 10 mg/kg ip dose (ii) 4 h post 5 mg/kg po dose.
d
ND = not determined.

1
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Figure 3. Vehicle or R,S-4a was administered 120 min prior to trial 2 in the rat
⁄
3. (a) Hudkins, R. L.; Aimone, L. D.; Bailey, T. R.; Bendesky, R. J.; Dandu, R.; Dunn, D.;
Gruner, J. A.; Josef, K. A.; Lin, Y.-G.; Lyons, J.; Marcy, V. R.; Mathiasen, J. R.;
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2
b
(
mean ± SEM, n = 16–52/group).
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3
demonstration of potent H R functional antagonism in vivo in the
2
1, 6126; (d) Dandu, R.; Gruner, J. A.; Mathiasen, J. R.; Aimone, L. D.; Hosteller,
rat dipsogenia model, potent wake activity in the rat EEG/EMG
model at doses as low as 3 mg/kg ip and enhancement of short-
term memory using the rat social recognition memory model at
doses as low as 0.03–0.3 mg/kg po.
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A.; Huang, Z.; Josef, K. A.; Lyons, J.; Mathiasen, J. R.; Tao, M.; Zulli, A. L.; Raddatz,
R. Bioorg. Med. Chem. Lett. 2012, 22, 194; (g) Hudkins, R. L.; Zulli, A. L.; Dandu, R.;
Tao, M.; Josef, K. A.; Aimone, L. D.; Haltiwanger, R. C.; Huang, Z.; Lyons, J.;
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Acknowledgments
(
h) Josef, K. A.; Aimone, L. D.; Lyons, J.; Raddatz, R.; Hudkins, R. L. Bioorg. Med.
The authors acknowledge Ed Bacon, Mike Marino, Mark Ator,
Emily Kordwitz, Mark Olsen, Gilbert Moachon, Nicole Lepallec, Isa-
belle Kanmacher, Véronique Agathon, Mehran Yazdanian, Ed Hell-
riegel, Phil Robertson, Curtis Haltiwanger, Yinguo Lin, Val Marcy,
Amy DiCamillo and Bob Bendesky for their contributions, assis-
tance and support on this project.
Chem. Lett. 2012, 22, 4198; (i) Becknell, N. C.; Lyons, J.; Aimone, L. D.; Huang, Z.;
Gruner, J. A.; Raddatz, R.; Hudkins, R. L. Bioorg. Med. Chem. 2012, 20, 3880; (j)
Tao, M.; Aimone, L. D.; Gruner, J. A.; Mathiasen, J. R.; Huang, Z.; Lyons, J.;
Raddatz, R.; Hudkins, R. L. Bioorg. Med. Chem. Lett. 2012, 22, 1073; (k) Tao, M.;
Raddatz, R.; Aimone, L. D.; Hudkins, R. L. Bioorg. Med. Chem. Lett. 2011, 21, 6126;
(l) Tao, M.; Aimone, L. D.; Huang, Z.; Mathiasen, J.; Raddatz, R.; Lyons, J.;
Hudkins, R. L. J. Med. Chem. 2012, 55, 414.
4
5
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.
Becknell, N. C.; Dunn, D.; Hudkins, R. L.; Josef, K. A.; Knutsen, L.; Tao, M.; Zulli, A.
L. US 8,207, 168 (2012).
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