Development of novel 2-[4-(aminoalkoxy)phenyl]-4(3H)-quinazolinone derivatives as potent and selective histamine H3 receptor inverse agonists

Article abstract of DOI:10.1016/j.bmcl.2008.10.034

Novel 2-[4-(aminoalkoxy)phenyl]-4(3H)-quinazolinone derivatives were identified as potent human H₃ receptor inverse agonists. After systematic modification of lead 5a, the potent and selective analog 5r was identified. Elimination of hERG K⁺ channel and human α_1A-adrenoceptor activities is the main focus of the present study.

Full text of DOI:10.1016/j.bmcl.2008.10.034

Bioorganic & Medicinal Chemistry Letters 18 (2008) 6041–6045
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Development of novel 2-[4-(aminoalkoxy)phenyl]-4(3H)-quinazolinone
derivatives as potent and selective histamine H3 receptor inverse agonists
Takashi Mizutani, Tsuyoshi Nagase, Sayaka Ito, Yasuhisa Miyamoto, Takeshi Tanaka,
*
Norihiro Takenaga, Shigeru Tokita, Nagaaki Sato
Tsukuba Research Institute, Merck Research Laboratories, Banyu Pharmaceutical Co., Ltd., 3 Okubo, Tsukuba, Ibaraki 300-2611, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel 2-[4-(aminoalkoxy)phenyl]-4(3H)-quinazolinone derivatives were identified as potent human H3
receptor inverse agonists. After systematic modification of lead 5a, the potent and selective analog 5r
Received 14 July 2008
Revised 25 August 2008
Accepted 8 October 2008
Available online 11 October 2008
was identified. Elimination of hERG K+ channel and human
of the present study.
a
1A-adrenoceptor activities is the main focus
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Histamine H3 receptor inverse agonists
hERG K+ channel
a1A-Adrenoceptor
Quinazolinone
Histamine release assay
The histamine H3 receptor was pharmacologically discovered in
1983,1 and genetically identified in 1999.2 The genetic identifica-
tion of the H3 receptor generated significant interest, and shifted
both the detailed pharmacological characterization of the receptor
and associated drug discovery efforts from academia and pharma-
ceutical industries.3 Signaling through the H3 receptor activates
G-proteins that inhibit adenylate cyclase activity and reduce intra-
cellular cAMP level.2,4 The H3 receptor, which is predominantly
expressed in the CNS, is localized on the presynaptic membrane
as an autoreceptor, and negatively regulates the release and syn-
thesis of histamine.1 In addition, the H3 receptor is known to mod-
ulate the release of other neurotransmitters such as
norepinephrine, dopamine, acetylcholine, serotonin, and GABA.5
Due to the effects of H3 signaling on multiple neuronal transmit-
ters, it has been suggested that H3 antagonists/inverse agonists
could be effective therapeutic agents for several CNS-related disor-
ders.6 In animal models, H3 receptor antagonists/inverse agonists
have been shown to enhance wakefulness, attentive and cognitive
behaviors, and to reduce feeding and body weight.7,8 Since the
identification of the H3 receptor genes, various classes of non-imid-
azole H3 receptor antagonists have been developed to target the
CNS H3 receptor.3,7,10 Among them, 1 (BF2.649),9,11 2 (ABT-239)12
and 3 (GSK189254)13 have entered clinical trials for treatment of
CNS disorders such as excessive daytime sleepiness, schizophrenia,
and cognitive dysfunctions (Fig. 1).
We previously reported a series of novel quinazolinone H3 in-
verse agonists.14 Representative quinazolinone lead 4 is shown in
Figure 2. Based on structure–activity relationships (SAR) developed
by modification of lead 4, we designed and synthesized regioiso-
meric quinazolinone 5a in order to further extend structural diver-
sity. The regioisomeric quinazolinone derivative 5a was found to
have 2-fold more potent human H3 (hH3) activity than the original
quinazolinone 4; however, 5a displayed relatively potent affinity
for both the human ether-a-go-go-related gene (hERG) K+ channel
and human a1F-adrenoceptor (ha1A) (Fig. 2). The main focus of this
communication is SAR development aimed at eliminating these
off-target activities while potentiating the hH3 activity.
The synthetic route for these quinazolinone derivatives re-
ported herein is illustrated in Scheme 1. Commercially available
anthranilic acids 6 or 3-amino-2-methoxyisonicotinic acid (13)
were converted to the corresponding amide 7. The amide was ther-
mally condensed with 4-aminoalkoxy benzaldehyde 8 or 9 in the
presence of a catalytic amount of p-toluenesulfonic acid, followed
by oxidation with 2,3-dichloro-5,6-dicyanobenzoquinone to fur-
nish the desired product 5aꢀr. Compound 13 was prepared by lith-
iation and carboxylation of the corresponding tert-butoxycarbonyl
(Boc)-protected aminopyridine, as shown in Scheme 2. Commer-
cially available aminopyridine 10 was protected with a Boc group
to give 11, which was treated with n-BuLi in the presence of
N,N,N0,N0-tetramethylethylenediamine, followed by addition of so-
lid CO2 to give carboxylic acid 12. Removal of the Boc group was
effected by trifluoroacetic acid to give the desired 3-amino-2-
methoxyisonicotinic acid (13).
* Corresponding author. Tel.: +81 29 877 2004; fax: +81 29 877 2029.
E-mail address: nagaaki_sato@merck.com (N. Sato).
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.10.034

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T. Mizutani et al. / Bioorg. Med. Chem. Lett. 18 (2008) 6041–6045
NC
N
O
N
Cl
O
1
2
O
H
N
N
N
O
3
Figure 1. Histamine H3 antagonists/inverse agonists in clinical trials.
N
O
O
N
N
N
O
N
N
5a
4
O
hH3 IC50 = 3.1 nM
hERG IC50 = 7.9 μM
hα1A IC50 = 6.5 μM
hH3 IC50 = 1.2 nM
hERG IC50 = 2.8 μM
hα1A IC50 = 2.9 μM
Figure 2. Structures of quinazolinone 4 and regioisomer 5a.
R3
N
O
R4
NH2
NH2
b
a
N
O
X
X
H
X
N
R2
R3
N
N
CO2H
R1
R1
R2
R1
O
O
R4
6 (X=CH)
13 (X=N)
7
5a−g
H
8
O
O
R5
b
N
O
N
X
N
R6
R2
O
R1
H
N
R5
5h−r
9
O
R6
Scheme 1. Reagents and conditions: (a) 1,1-carbonyldiimidazole, DMF, 40 °C, 1–24 h, then R2NH2, rt, 0.5ꢀ12 h, 68ꢀ99%; (b) 4-aminoalkoxy benzaldehyde 8 or 9,
p-toluenesulfonic acid, 1,4-dioxane, 120 °C, 3ꢀ15 h, then 2,3-dichloro-5,6-dicyanobenzoquinone, rt, 8ꢀ42 h, 24ꢀ72%.
CH3O
N
CH3O
N
CH3O
N
CH3O
N
a
c
b
NHBoc
CO2H
NH2
NH2
NHBoc
CO2H
10
11
12
13
Scheme 2. Reagents and conditions: (a) (Boc)2O, 1,4-dioxane, reflux, 24 h, 100%; (b) n-BuLi, N,N,N0,N0-tetramethylethylenediamine, Et2O, ꢀ78 °C, 1 h, then CO2, 30 min, 70%;
(c) trifluoroacetic acid, MeOH, CHCl3, rt, 8 h, 88%.
Synthesis of the right hand aldehyde units 8 and 9 is illustrated
in Schemes 3 and 4. Compound 8 was prepared from 4-hydroxy-
benzaldehyde (14) by alkylation with 3-bromochloropropane, fol-
lowed by displacement with the desired amine (Scheme 3).
Synthesis of aldehyde 9 was started from the Mitsunobu condensa-
tion15 of methyl 4-hydroxybenzoate (15) and tert-butyl 4-hydroxy-

T. Mizutani et al. / Bioorg. Med. Chem. Lett. 18 (2008) 6041–6045
6043
Table 1
R3
SAR of compounds 5aꢀf.
OH
O
N
a
R4
OHC
OHC
O
N
8
5
1
14
8
N
7
6
Scheme 3. Reagents and conditions: (a) 3-bromochloropropane, K2CO3, DMF, 60 °C,
4 h, then R3R4NH, KI, DMF, 60 °C, 10ꢀ20 h, 54ꢀ60%.
3
R
N
O
a
c
1-piperidinecarboxylate. Removal of the Boc group from 16 fol-
lowed by reductive alkylation with the desired ketone afforded
17. Ester 17 was reduced with DIBAL to give the corresponding
alcohol, which was oxidized with MnO2 to give aldehyde 9
(Scheme 4).
Compound
R
hH3 IC50 (nM)
hERGb IC50
(lM)
ha1A IC50 (lM)
5a
5b
5c
5d
5e
5f
Methyl
Ethyl
n-Propyl
i-Propyl
Benzyl
Phenyl
1.2
2.8
1.7
1.8
3.0
0.17
0.46
2.9
1.3
1.8
1.1
7.2
2.4
0.87
0.47
0.87
0.31
1.6
A series of regioisomeric quinazolinone derivatives were tested
in the [35S]GTP S binding assay.16 All the compounds reduced
c
Inhibition of R-a cS to human H3
-methylhistamine-induced binding of [35S]GTP
receptor. Values are means of at least two independent experiments. The maximum
a
basal GTP
Inhibitory activity for hERG K+ channel was evaluated using the
35S]N-[(4R)-10-[(2R)-6-cyano-1,2,3,4-tetrahydro-2-naphthalenyl]-
cS binding, indicating that they are inverse agonists.
variability of each assay in this series was 3-fold.
[
b
Inhibition of [35S]MK-499 binding to hERG K+ channel in HEK293 cells.
3,4-dihydro-4-hydroxyspiro[2H-1-benzopyran-2,40-piperidin]-6-
yl]methanesulfonamide ([35S]MK-499) binding assay17 to assess
cardiac QTc prolongation liability. Binding activity for ha1A was
evaluated using the [3H]prazosin binding assay18 to assess the
potential risks of hypertension and agitation.
Inhibition of [3H]Prazosin binding to human 1A-adrenoceptor in LMtkꢀ cells.
a
c
Importantly, 8-methoxy derivative 5m was found to be devoid of
both hERG and h 1A activity. Encouraged by the binding profile
a
of 5m, we introduced several substituents at the 8-position of
the quinazolinone ring (5nꢀq). The 8-methyl and 8-chloro deriva-
tives 5n and 5o were slightly more potent than 5h, yet their hERG
inhibitory activities were greater than desired. The 8-trifluoro-
methyl derivative 5p showed reduced hH3 activity with very po-
tent hERG inhibitory activity. The binding profile of the 8-fluoro
derivative 5q was similar to that of the parent 5h. Incorporation
of a nitrogen atom into the 7-position of 5m led to the more potent
derivative 5r, which retained good selectivity against hERG and
Variation of the 3-substituent on the quinazolinone ring of 5
was investigated first (Table 1). Substituted methyl derivatives
5bꢀd displayed improved hH3 activities compared to the parent,
5a. The benzyl derivative 5e was 4-fold more potent
(IC50 = 0.31 nM), whereas the phenyl derivative 5f was less potent
than 5a. Potent hERG inhibitory activities of the benzyl and phenyl
derivatives, 5e and 5f, were observed, and no improvements were
observed for the alkyl derivatives 5bꢀd. A reduced ha1A activity
was observed in 5e. Although the potent hH3 activities of 5c and
5e were attractive, 3-methyl derivative 5a was selected as a tem-
ha1A. In addition, compound 5r was selective over other histamine
receptor subtypes (hH1, hH2, and hH4; IC50 > 10 M).
l
plate for further SAR studies based on its hERG and ha1A activities.
Compound 5r was assessed in in vivo studies. Brain exposure
and pharmacokinetics of 5r were evaluated in Sprague–Dawley
(SD) rats. Brain and plasma levels 2 h after 10 mg/kg oral dosing
with 5r were 2.96 nmol/g and 2.08 lM, respectively. Compound
5r exhibited a suitable pharmacokinetic profile, as summarized
Next, the right hand piperidinopropoxy portion was optimized
(Table 2). Pyrrolidine derivative 5g showed enhanced hH3 activity,
but its off-target activities were not improved. The structurally ri-
gid cycloalkyl piperidine derivatives 5h and 5i were found to pos-
sess potent hH3 activities. The activity of cyclobutyl derivative 5h
was noticeable (IC50 = 0.22 nM), 5-fold improvement over the par-
ent 5a. In addition to its enhanced potency, 5h exhibited reduced
in Table 4.
Having demonstrated excellent potency, selectivity, pharmaco-
kinetic profile and brain penetration, 5r was tested for brain hista-
mine release activity in SD rats.19 In our histamine release assay,20
an inverse agonist (po), pargyline and a monoamine oxidase inhibi-
tor (ip), were co-dosed in SD rats. After 2 h the whole brain was rap-
idly removed, and the concentration of tele-methylhistamine, a
major extracellular metabolite of histamine, was measured.
hERG (IC50 = 5.6 lM) and ha1A (IC50 = 6.3 lM) activities.
Further optimization of 5h by modification of the quinazolinone
part is summarized in Table 3. The effect of introducing a methoxy
group was examined first. Although substitution with a methoxy
group had no influence on hH3 activity, the 5- and 7-methoxy
derivatives 5j and 5l showed improved off-target selectivity.
OH
a
O
b, c
NBoc
MeO2C
MeO2C
MeO2C
15
16
O
O
d, e
N
R5
R6
N
R5
R6
OHC
17
9
Scheme 4. Reagents and conditions: (a) tert-butyl 4-hydroxy-1-piperidinecarboxylate, diisopropyl azodicarboxylate, PPh3, THF, rt, 24 h, 62%; (b) trifluoroacetic acid, rt, 3 h;
(c) R5R6C@O, NaBH3CN, ZnCl2, MeOH, rt, 16ꢀ20 h; (d) DIBAL, toluene, 0 °C, 1ꢀ3 h; (e) MnO2, CH2Cl2, rt, 40ꢀ50 h, 45ꢀ49% over 4 steps from 16.

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T. Mizutani et al. / Bioorg. Med. Chem. Lett. 18 (2008) 6041–6045
Table 2
Table 4
SAR of compounds 5g–i; variation of the basic amine unit.
Pharmacokinetic parameters of 5r in SD rats.a
Compound
Iv (1 mg/kg)
Po (3 mg/kg)
O
CLp
(mL/min/
kg)
Vdss
(L/
kg)
t1/2
(h)
Cmax
M)
AUC0–1
Fb
(%)
h
R
(
l
(
lM h)
N
N
O
5r
29
4.8
2.0
0.57
2.1
48
a
Values represent the means, n = 3.
Based on AUC0–1 values after iv and po dosing.
b
h
Compound
R
hH3 IC50
(nM)
hERGb IC50
M)
h
a1A IC50
a
c
(
l
(l
M)
300
250
200
150
100
50
**
5a
5g
1.2
2.8
2.9
2.9
2.2
∗
N
N
*
0.68
∗
∗
5h
0.22
0.74
5.6
2.9
6.3
N
∗
5i
6.2
N
0
Vehicle
1
3
10
a
-methylhistamine-induced binding of [35S]GTP
c
S to human H3
Compound 5r (mg/kg)
Inhibition of R-
a
receptor. Values are means of at least two independent experiments. The maximum
variability of each assay in this series was 3-fold.
Figure 3. Brain tele-methylhistamine levels in SD rats after oral administration of
compound 5r. Values are means SE, determined from five experiments. *P < 0.05,
**P < 0.01 (ANOVA Dunnett) compared with the vehicle control.
b
Inhibition of [35S]MK-499 binding to hERG K+ channel in HEK293 cells.
c
Inhibition of [3H]Prazosin binding to human 1A-adrenoceptor in LMtkꢀ cells.
a
proportional elevation of tele-methylhistamine was observed in
rat brain after oral administration of 5r. Further evaluation of this
class of compounds is currently underway.
Table 3
SAR of compounds 5j–r; variation of the quinazolinone core.
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8-Me
8-Cl
8-CF3
8-F
CH 0.10
CH 0.18
CH 0.70
CH 0.25
8-OMe
N
0.31
>10
Inhibition of R-a cS to human H3
-methylhistamine-induced binding of [35S]GTP
receptor. Values are means of at least two independent experiments. The maximum
a
variability of each assay in this series was 3-fold.
Inhibition of [35S]MK-499 binding to hERG K+ channel in HEK293 cells.
b
Inhibition of [3H]Prazosin binding to human 1A-adrenoceptor in LMtk– cells.
a
c
Significantand dose-proportional elevation of tele-methylhistamine
was observed in rat brain after oral administration of 5r (Fig. 3).
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derivatives which had potent H3 receptor inverse agonist activity.
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