Identification of pyridazin-3-one derivatives as potent, selective histamine H3 receptor inverse agonists with robust wake activity

Article abstract of DOI:10.1016/j.bmcl.2011.06.108

H₃R structure-activity relationships on a novel class of pyridazin-3-one H₃R antagonists/inverse agonists are disclosed. Modifications of the pyridazinone core, central phenyl ring and linker led to the identification of molecules wi

Full text of DOI:10.1016/j.bmcl.2011.06.108

Bioorganic & Medicinal Chemistry Letters 21 (2011) 5493–5497
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Identification of pyridazin-3-one derivatives as potent, selective histamine
H3 receptor inverse agonists with robust wake activity
⇑
Robert L. Hudkins , Lisa D. Aimone, Thomas R. Bailey, Robert J. Bendesky, Reddeppa reddy Dandu,
Derek Dunn, John A. Gruner, Kurt A. Josef, Yin-Guo Lin, Jacquelyn Lyons, Val R. Marcy, Joanne R. Mathiasen,
Babu G. Sundar, Ming Tao, Allison L. Zulli, Rita Raddatz, Edward R. Bacon
Discovery Research, Cephalon, Inc., 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:
H3R structure–activity relationships on a novel class of pyridazin-3-one H3R antagonists/inverse agonists
are disclosed. Modifications of the pyridazinone core, central phenyl ring and linker led to the identifica-
tion of molecules with excellent target potency, selectivity and pharmacokinetic properties. Compounds
13 and 21 displayed potent functional H3R antagonism in vivo in the rat dipsogenia model and demon-
strated robust wake activity in the rat EEG/EMG model.
Received 26 May 2011
Revised 23 June 2011
Accepted 24 June 2011
Available online 30 June 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Histamine H3
H3 inverse agonist
CEP-26401
Pyridazin-3-one
Sleep–wake
Histamine elicits physiological responses mediated by four G-
protein coupled receptors (H1R–H4R) and exerts a variety of func-
tions in the central nervous system (CNS).1 H1 and H2 receptors in
the periphery are involved in the allergic response and gastric acid
secretion, respectively, and have been some of the more successful
drug target classes over the past 50 years. The H4 receptor is ex-
pressed mainly in mast cells, eosinophils, and tissues involved in
the immune response, and may play a role in inflammation and
pain.2 The H3 receptor (H3R) in the brain is primarily localized pre-
synaptically, where it functions both as an autoreceptor to modu-
late histamine release and as an inhibitory heteroreceptor
regulating the release of multiple neurotransmitters, including
acetylcholine (ACh), dopamine (DA), norepinephrine (NE) and
serotonin (5-HT).1 While activation of the H3R results in the inhibi-
tion of neurotransmitter release, blockade of H3R by selective
antagonists or inverse agonists can reverse the histamine-medi-
ated inhibition of neurotransmitter release, leading to enhanced
release. H3Rs by virtue of their localization and function regulate
a variety of neurotransmitters that are thought to be involved in
attention, sleep and cognition.1c–i The discovery of H3R antagonists
are of current interest, with potential utility in addressing a variety
of CNS disorders associated with attention and cognitive deficits,
including deficits in wakefulness, attention–deficit hyperactivity
disorder (ADHD), Alzheimer’s disease (AD), mild cognitive
impairment, and schizophrenia. Several clinical candidates (Ia–Ie)
have advanced into trials (Fig. 1).1g–m
We identified a novel class of pyridazin-3-one H3R antagonists/
inverse agonists with exceptional drug properties, safety and
in vivo profiles.3 The preliminary structure–activity relationships
(SAR) and characterization of 1 (CEP-26401, irdabisant) and N-
methyl 2 were recently disclosed.4 In this paper we report SAR
around the pyridazinone core, central phenyl ring and the linker
leading to the identification of molecules with excellent target
N
Me
N
O
H
N
N
N
Me
CF3
O
O
O
N
Ia GSK-189254
Ib MK-0249
O
F
O
N
Et
N
N
H
Cl
F
Ic BF2.649
Id PF03654746
H
N
O
N
O
N
O
Me
N
N
O
N
Ie JNJ-31001074
1 CEP-26401
⇑
Corresponding author. Tel.: +1 610 738 6283.
E-mail address: rhudkins@cephalon.com (R.L. Hudkins).
Figure 1. Structures of clinical H3R antagonists.
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.06.108

5494
R. L. Hudkins et al. / Bioorg. Med. Chem. Lett. 21 (2011) 5493–5497
O
potency and selectivity, pharmacokinetic properties and potent
in vivo wake-promoting activity in the rat.
O
a
b
The N2-substituted targets (e.g. 3–8) were synthesized using
our previously described method outlined in Scheme 1.3,4 Cyclo-
condensation of 4-(4-methoxyphenyl)-4-oxobutyric acid 23 (or es-
ter) with (N-substituted)hydrazine,5a oxidation of the resulting
4,5-dihydropyridazinone 24 (MnO2, CuCl2 or SeO2/HOAc) to 25,5b
followed by O-demethylation produced phenol intermediates 26
in very good yield and purity. Alkylation of 26 with 3-bromo-1-
chloropropane provided chloroalkyl intermediates that were re-
acted with R-2-methylpyrrolidine to produce targets 3–8. In an
analogous manner, ring substituted analogues (e.g. 13–18) were
synthesized starting with a phenyl substituted keto-acid or ester
23. An alternative approached was employed for 3-cyano 19 using
a previously described Suzuki coupling. 5-Boranyl-2-[3-((R)-2-
methyl-pyrrolidin-1-yl)-propoxy]-benzonitrile with 3,6-dichloro-
pyridazine and hydrolysis of the intermediate chloropyridazine
gave 19.4 The S- and R-methyl linker isomers 21 and 22 were syn-
thesized by alkylation of 26 (R2 = Me, R1 = H) with R- and S-3-bro-
mo-2-methyl-propanol to provide 27, conversion to the mesylate
then (R)-2-methylpyrrolidine alkylation (Scheme 1). Synthesis of
the central ring 3-pyridyl 20 was produced by ethyl 4-(6-chloro-
pyridin-3-yl)-4-oxo-butyrate 28 and hydrazine hydrate cyclization
to the 4,5-dihydro-2H-pyridazinone 29, followed by alkylation
with 3-(R-2-methylpyrrolidin-1-yl)propan-1-ol using DMSO and
base to directly produce aromatized target 20 (Scheme 2). The 4-
methyl analogue 9 was synthesized by the procedure outlined in
Scheme 1, starting with 4-(4-methoxyphenyl)-3-methyl-4-oxobu-
tyric acid.
OH
O
Cl
30
H
N
H
O
O
N
N
N
c
Me
O
Cl
O
N
11
31
Scheme 3. Reagents and conditions: (a) Br(CH2)3Cl, K2CO3, acetone, 80 °C. 65%;
(b) (i.) HC(O)COOHÁH2O, 85 °C; (ii.) NH2NH2ÁH2O, ethanol, 85 °C. two steps 35%; (c)
R-2-methylpyrrolidine, K2CO3, CH3CN; 67%.
O
O
Br
a, b
c, d
OH
O
Cl
32
OEt
O
O
N
e, f
Me
10
O
N
34
Scheme 4. Reagents and conditions: (a) K2CO3, Br(CH2)3Cl, acetone, 80 °C, 70%; (b)
CuBr, EtOAc, CHCl3, reflux, 70%; (c) ethyl 2-pyridylacetate, NaH, DMF, 72% ? 33;
(d) (R)-2-methylpyrrolidine, NaI, K2CO3, CH3CN 80 °C; (e) NH2NH2ÁH2O; ethanol,
HOAc, 46%; (f) DMSO, K2CO3, 80 °C, 75%.
Additional approaches to selectively modify either the 4- or 5-
position are shown in Schemes 3–5. The 5-methyl analogue 11
was produced using a modification of our previously described
EtO2C
EtO2C
Me
a, b,
c
OH
O
N
R2
35
37
O
EtO
O
N
R1
O
O
O
N
N
a
R1
HO2C
24 single bond
25 double bond
b
Me
Me
d
e, f
OMe
12
23
OMe
N
O
N
O
N
R2
N
R2
N
38
39
O
O
N
N
R1
d, e
R1
c
Scheme 5. Reagents and conditions: (a) K2CO3, Br(CH2)3Cl, acetone, 80 °C, 89% ?
36; (b) (R)-2-methylpyrrolidine, NaI, K2CO3, CH3CN 80 °C, 96%; (c) LiHMDS, THF, 2-
methylpyridine, 0 ? 45 °C, 70–80%; (d) NaH, BrCH2CO2Et, DMSO, toluene, 52%; (e)
NH2NH2ÁH2O; ethanol, 25%; (f) NaOH, water, EtOH, Na 3-nitrobenzenesulfonic acid,
35%.
Me
N
OH
O
26
3-8, 13-18
f
Me
N
Me
O
O
N
N
N
g, e
Me
Aldol/hydrazine cyclocondensation sequence to construct the
pyridazinone ring4,6 (Scheme 3).
O
OH
O
N
Me
Me
Chloro 30 was condensed with glyoxalic acid monohydrate in
acetic acid at 135 °C, followed by hydrazine cyclocondensation of
the resulting Aldol adduct to give the 4,5-dihydro-2H-pyridazin-
3-one 31 in low yield. Incorporation of (R)-2-methylpyrrolidine
gave 11. The critical step toward the synthesis of the 4-pyridyl
10 (Scheme 4) was alkylation of 2-bromo-1-[4-(3-chloroprop-
oxy)phenyl]ethanone 32 with ethyl 2-pyridinyl acetate to produce
27
21, 22
Scheme 1. Reagents and conditions: (a) R2NHNH2, 2-propanol, reflux, 80–95%; (b)
MnO2, xylenes, 155 °C, SeO2/HOAc or Cu(II)Cl2, CH3CN, reflux, 50–85%; (c) BBr3,
DCM, 5 °C ? rt, 70–95%; (d) K2CO3, Br(CH2)3Cl, acetone, 65 °C; (e) (R)-2-methyl-
pyrrolidine, NaI, K2CO3, CH3CN 80 °C, 35–60% two steps; (f) R or S 3-bromo-2-
methylpropanol, K2CO3, CH3CN 80 °C, 50–75%; (g) (i.) MsCl, TEA, DCM; (ii.)
(R)-2-methylpyrrolidine, NaI, K2CO3, CH3CN 80 °C, 40–60% two steps.
H
O
N
H
O
N
O
N
N
OEt
a
b
N
Me
N
O
Cl
N
O
N
Cl
28
29
20
Scheme 2. Reagents and conditions: (a) H2NNH2ÁH2O, ethanol, 80 °C, 87%; (b) 1 M KtOBu, t-BuOH, 3-(R-2-methylpyrrolidin-1-yl)propan-1-ol, DMSO, 100 °C, 8%.

R. L. Hudkins et al. / Bioorg. Med. Chem. Lett. 21 (2011) 5493–5497
5495
Table 2
33 (72% yield). Installation of (R)-2-methylpyrrolidine (34), hydra-
Pyridazin-3-one central ring and linker H3R binding dataa
zine cyclization, followed by DMSO oxidation produced 10 in 30%
yield. The 5-(2-pyridyl) 12 synthesis commenced with ethyl 4-
hydroxybenzoate 35 (Scheme 5), installation of the amine side
chain (36 ? 37), and 2-methylpyridine addition to ketone 38, fol-
lowed by subsequent alkylation with ethyl bromoacetate to pro-
duce the keto-ester intermediate 39. Hydrazine condensation and
oxidation of the 4,5-dihydropyridazinone using sodium 3-nitro-
benzenesulfonate produced 12.
R2
R1
Me
N
2
N
3
O
X
N
R3
O
6
5
Entry
R1
R2
X
R3
hH3 (Ki, nM)
rH3 (Ki, nM)
27
69 24
13
14
15
16
17
18
19
20
21
22
3-F
2-F
Me
H
Me
Me
H
H
H
H
C
CH
C
C
C
CH
C
N
H
H
H
H
H
H
H
H
5.8 1.2
7
The pyridazinone analogues were tested using in vitro binding
assays by displacement of [3H]NAMH in membranes isolated from
CHO cells transfected with cloned human H3 or rat H3 receptors as
shown in Table 1 and Table 2.3,4 The (R)-2-methylpyrrolidine
amine was previously established to be optimum4 and was fixed
for comparison while exploring further SAR. Also previously dis-
closed was substitution at the N2 position could accommodate sig-
nificant steric bulk without affecting H3R binding affinity, although
increasing the size of the R2 group greater than methyl (2) resulted
in compounds with log P values greater than 3. This negatively af-
fected molecular weight and decreased the ligand efficiency (LE)
and the ligand lipophilic efficiency (LLE).7 Amphiphilic, high log P
compounds have been shown to enhance hERG activity and drive
high tissue distribution inducting phospholipidosis.8 Motivated to
synthesize compounds with lower c log P, the fluorinated ethyl (3
and 4) and polar N-ethanol 5 were designed. Similar to other sim-
ple alkyl derivatives (e.g. 2)4 compounds 3, 4 and 5 also had high
affinity for both human and rat H3R. Further discovery flow profil-
ing with these analogues however showed poor oral bioavailability
in the rat (F < 10%). Lowering the c log P also was the motivation for
replacement of the lipophilic R2 phenyl 6 with more polar 2-pyri-
dyl 7 and 2-pyrimidinyl 8 heteroaryls. The 2-Pym 8 showed bal-
anced and slightly higher affinity compared with 7 for both
human and rat H3Rs (hH3R Ki = 1.4 nM, rH3R Ki = 7.9 nM) with low-
er lipophilicity (calculated c log P = 1.8 by the Tripos method).
Compound 8 had acceptable in vitro metabolic stability across spe-
16
4.4 0.5
11
2
3-Cl
3,5-F
3,5-F
2-OMe
3-CN
H
14
41
40
2
5
4
3
7.1 1.4
152 19
38 12
229 65
111 17
70 15
35 14
H
H
Me
Me
CH
CH
S-Me
R-Me
2.4 0.4
4.6
52
1
5
15
2
a
Ki values nM SEM.
able i.v. intrinsic pharmacokinetic properties (t = 1.5 h, CL =
½
29 mL/min/kg, Vd = 3.9 L/kg) and oral bioavailability (F = 56%).
However, the brain exposure was low (brain/plasma ratio (B/
P) = 0.5) for potential CNS indications, and this compound was
not further advanced. Subsequently, the 4- and 5-positions were
probed with methyl and 2-Pyr substitution. Methyl substitutions
(9 and 11) were equally tolerated at both positions, while the 5-
Pyr 12 had 4-fold and 7-fold lower affinity for hH3R and rH3R,
respectively, compared to the 4-Pyr 10. Compounds 10 and 12
showed acceptable in vitro metabolic stability, but did not show
improvement in oral bioavailability (F < 10%) and/or brain expo-
sure (B/P << 1) compared to 1 or 2.
Data in Table 2 reveals the effect of varying the substitution on
the central phenyl ring. Substitution in the 3-position with fluorine
(13), chlorine (15) or with 3,5-difluoro (16, and 17) were tolerated
for H3R binding affinity, while 2-substitution showed significantly
reduced H3R affinity (e.g. 14 and 18). Replacing the central phenyl
ring with 3-pyridyl 20 led to a P 10-fold decrease in human and
rat H3R affinity. The effect of incorporating a chiral methyl group
on the propyl linker was also investigated with S-21 and R-22.
The S-isomer 21 retained hH3R (Ki = 2.4 nM) and rH3R (Ki = 4.6 nM)
affinity equivalent to 2, while R-22 had 6- and 11-fold weaker
affinity for hH3R and rH3R.
cies in liver microsomes (t > 40 min in mouse, rat, dog, monkey
½
and human) and IC50 values > 30 lM for inhibition of cytochrome
P450 enzymes CYP1A2, 2C9, 2C19, 2D6 and 3A4, indicating mini-
mal potential for drug–drug interactions. In a hERG patch–express
assay 8 had an IC50 value >10
lent selectivity (>1000-fold) for hH1, hH2, and hH4 receptor sub-
types and against panel of 70 GPCRs, ion channels and
lM. Compound 8 also showed excel-
a
enzymes. In a rat pharmacokinetic experiment 8 showed accept-
Based on target affinity and physical property data (pH2 and
pH7.4 solubility >0.25 mg/mL, c log P = 3.3 and 3.0) S-methyl 21
and 3-fluoro 13 were further profiled for selectivity against hH1,
hH2, and hH4 receptor subtypes and against a panel of 70 GPCRs,
ion channels and enzymes (MDS Pharma Services, LeadProfiler).
Compound 13 showed <30% inhibition against hH1, hH2, and hH4
Table 1
Pyridazin-3-one H3R binding dataa,b
R2
N
Me
O
N
subtypes at 10
nephrine transporter (NET) by greater than 70% at 10
l
M concentration, and inhibited only the norepi-
N
R4
O
R5
lM concen-
trations in the broader screening panel. Compound 21 also showed
excellent selectivity (> 1000-fold) for hH1, hH2, and hH4 subtypes
and displayed <30% inhibition at 10 lM concentration in the
MDS panel of 70 targets, including NET (19% inh.). Functionally,
Entry
R2
R4
R5
hH3 (Ki nM)
rH3 (Ki nM)
c log P
1
2
3
4
5
6
7
8
H
Me
CH2CH2F
CH2CF3
CH2CH2OH
Ph
2-Pyr
2-Pym
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
2-Pyr
2.0 0.4
1.4 0.1
3.4 0.5
5.7 0.8
3.0 0.1
2.5 0.9
7.2 0.4
6.3 1.1
11 0.5
11 0.5
9.5 0.7
7.9 1.6
2.3
2.8
2.6
2.7
1.5
4.3
2.8
1.9
2.8
3.1
2.5
2.3
13 and 21 showed potent antagonist activity and displayed full
inverse agonist activity in the [35S]GTP S hH3R binding assay.3,4
c
3-Fluoro 13 and S-Methyl 21 decreased basal activity with EC50
values of 1.3 0.1 nM and 2.1 0.1 nM, respectively.
10
2
22
3
1.4 0.1
3.4 0.1
3.1 0.03
2.9 0.1
7.9 0.8
8.7 1.0
10 1.0
12 0.1
Based on the target H3R affinity, selectivity, in vitro metabolic
9
Me
2-Pyr
H
stability in liver microsomes (t > 40 min across species) and CYP
10
11
12
H
H
H
½
inhibition selectivity (IC50 > 30 lM), 21 and 13 were further
H
12
1
70
1
evaluated for pharmacokinetic properties in the rat (Table 3) in
comparison with 2.4 Compound 13 showed an i.v. t of 1.2 h, clear-
a
Ki values nM SEM.
½
b
Pyr = 2-pyridine; 2-Pym = 2-pyrimidine.
ance of 38 mL/min/kg, and oral bioavailability of 42% based on 6 h

5496
R. L. Hudkins et al. / Bioorg. Med. Chem. Lett. 21 (2011) 5493–5497
AUC data with good brain exposure (B/P = 3.4). S-Me 21 had similar
oral bioavailability (%F = 37 based on 6 h AUC) with good brain
exposure in the rat (B/P = 2.5) (Table 3).
The rat dipsogenia model was used in the project as an in vivo
surrogate measure of H3R functional inhibition in the brain follow-
ing peripheral administration. Histamine and the H3-selective ago-
240
180
120
60
*
*
nist, R-a-methylhistamine (RAMH), induce water drinking in the
0
rat when administered either peripherally or centrally, an effect
that is blocked by H3R antagonists.1h,9 In this model both 13 and
21 potently and dose-dependently inhibited RAMH-induced dipso-
genia with ED50 values of 0.13 (0.02–0.91) mg/kg i.p. and 0.02
(0.005–0.07) mg/kg i.p., respectively. Following the demonstration
of potent in vivo H3R functional activity in the brain, 13 and 21
were further evaluated for wake promoting activity in the rat.10
Histamine-producing neurons are an important part of the mono-
aminergic arousal system and H3R antagonists have been docu-
mented to increase wakefulness in a number of species, although
at doses and cortical H3R occupancy levels much higher than those
producing activity in the dipsogenia model or efficacy in cognition
models.11 Wake promoting activity was measured as previously
described using male Sprague Dawley rats surgically implanted
for chronic recording of EEG (electroencephalographic) and EMG
(electromyographic) signals.12 The cumulative wake time at 4 h
after dosing was evaluated during the normal quiet period of the
Vehicle
3
10
30
Dose mg/kg (i.p.)
Figure 3. Compound 13-induced wake promotion; administered i.p. to male rats
chronically implanted with electrodes for recording EEG and EMG activity.
Cumulative wake 4 h AUC values shown for each dose (mean + SEM, n = 7–8/
group). ⁄p < 0.05, Dunnett’s post hoc versus vehicle.
maximal cumulative wake surplus was 196 min reached at 7 h.
EEG activity, behavior and body temperature were all normal at
the 3 or 10 mg/kg doses. At 10 mg/kg, 21 demonstrated robust
wake promotion, with the treated animals being awake 96% of
the time up to 4 h post dose and averaging a 62% increase in wake
time over the vehicle treated animals (Fig. 2). Compound 13 in-
creased wake activity in
a
dose-related manner at 10
(157 9 min) and 30 mg/kg (184 15 min) by 4 h AUC values
(P < 0.001 ANOVA) (Fig. 3). Compound 13 showed less robust wake
activity compared to 21, consistent with weaker potency in the
dipsogenia model.
rat. Compound 21 increased waking at
3 (166 6 min) and
10 mg/kg i.p. (231 6 min) by 4 h AUC values (P < 0.001 ANOVA).
In summary, H3R structure-activity relationships were disclosed
on the pyridazin-3-one phenoxypropyl amine core leading to the
identification of new molecules displaying excellent H3R target po-
tency, selectivity and rat pharmacokinetic properties. Compounds
13 and 21 were profiled in greater detail and advanced into
in vivo evaluations. Both compounds displayed potent H3R antag-
onist activity in the brain using the rat dipsogenia model as a func-
tional H3R readout and demonstrated potent wake-promoting
activity in the rat EEG/EMG model.
At 10 mg/kg, waking was enhanced out to 5.5 h post dosing, and
Table 3
Pharmacokinetic properties in rata
2b
13b
21c
i.v.
p.o
t1/2/(h)
Vd (L/kg)
CL (mL/min/kg)
1.6 0.3
6.5 2.9
45 11
1.2 0.3
4.5 1.4
0.8 0.2
2.5 1.0
38
7
37
8
References and notes
AUC (ng h/mL)
Cmax (ng/mL)
t1/2/(h)
538 75
936 166
284 34
1.6
892 198
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123
2.3
28
6
146
4.3
38
9
F (%)
4
42
7
8
B/Pd
3.5 0.4
3.4 0.3
2.5 0.1
a
Administration at 1 mg/mg i.v. and 5 mg/kg p.o.; data calculated from 6 h AUC
values.
b
i.v. formulation (3% DMSO, 30% solutol, 67% phosphate buffered saline) oral
formulation (saline).
c
i.v. formulation (3% DMSO, 30% solutol, 67% phosphate buffered saline) oral
formulation (50% Tween 80, 40% propylene carbonate and 10% propylene glycol).
d
B/P = brain to plasma ratio.
*
240
*
180
120
60
0
Vehicle
3
10
Dose mg/kg (i.p.)
Figure 2. Compound 21-induced wake promotion; administered i.p. to male rats
chronically implanted with electrodes for recording EEG and EMG activity.
Cumulative wake 4 h AUC values shown for each dose (mean + SEM, n = 7–8/
group). ⁄p < 0.05 Dunnett’s post hoc versus vehicle.

R. L. Hudkins et al. / Bioorg. Med. Chem. Lett. 21 (2011) 5493–5497
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