Discovery of potent and selective histamine H3 receptor inverse agonists based on the 3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one scaffold

Article abstract of DOI:10.1016/j.bmcl.2010.08.009

A novel series of potent histamine H₃ receptor inverse agonists based on the 3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one scaffold has been discovered. Several compounds display high selectivity over other histamine receptor subtypes and have favo

Full text of DOI:10.1016/j.bmcl.2010.08.009

Bioorganic & Medicinal Chemistry Letters 20 (2010) 5713–5717
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of potent and selective histamine H3 receptor inverse agonists
based on the 3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one scaffold
H. G. F. Richter a, , C. Freichel a, J. Huwyler b, T. Nakagawa c, M. Nettekoven a, J.-M. Plancher a, S. Raab a,
⇑
O. Roche a, F. Schuler a, S. Taylor a, C. Ullmer a, R. Wiegand a
a F. Hoffmann-La Roche Ltd, Pharmaceutical Research, Grenzacherstrasse, CH-4070 Basel, Switzerland
b University of Applied Sciences Northwestern Switzerland, Institute of Pharma Technology, CH-4132 Muttenz, Switzerland
c Chugai Pharmaceutical Co. Ltd, 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel series of potent histamine H3 receptor inverse agonists based on the 3,4-dihydro-2H-pyrazi-
no[1,2-a]indol-1-one scaffold has been discovered. Several compounds display high selectivity over other
histamine receptor subtypes and have favorable physicochemical properties, low potential for CYP450
enzyme inhibition and high metabolic stability in microsomal preparations. (R)-2-Cyclopropylmethyl-
8-(1-isopropyl-piperidin-4-yloxy)-3-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (8t) showed
good in vivo efficacy after per os application in an acute rat dipsogenia model of water intake.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 21 June 2010
Revised 2 August 2010
Accepted 3 August 2010
Available online 6 August 2010
Keywords:
Histamine
Histamine H3 receptors
Histamine H3 inverse agonists
The neurotransmitter histamine exerts its physiological effects
through four distinct G-protein coupled histamine receptor sub-
types known as H1-, H2-, H3- and H4-R. Both histamine H1- and
H2 receptors have already proven to be excellent drug targets lead-
ing to the discovery of important therapeutic agents for the treat-
ment of allergic reactions (H1R antagonists, ‘antihistamines’)1 and
gastric ulcers (H2R antagonists),2 respectively.
P450 (CYP450) inhibition,9 lack of selectivity10 or suboptimal brain
penetration11 precluded further development of these compounds.
Over the last years focus was given to non-imidazole based his-
tamine H3 receptor antagonists in order to overcome the liabilities
O
NH
The H4 receptor, the youngest member of the histamine recep-
tor family, is less well studied but there is preclinical evidence for
its involvement in the immune response and inflammatory
processes.3
N
S
N
H
O
NH
N
Cl
NH
Ciproxifan
Clobenpropit
The histamine H3 receptor, cloned in 1999,4 is primarily located
in the central nervous system (CNS). It functions as a presynaptic
autoreceptor controlling the synthesis and release of histamine.
In addition, it serves as a heteroreceptor that upon activation
inhibits or stimulates the release of other neurotransmitters such
S
N
N
H
N
NH
as serotonin, dopamine, noradrenaline, acetylcholine or c-amino-
Thioperamide
butyric acid. These actions together with positive results from
pre-clinical animal studies make the histamine H3 receptor a
promising therapeutic target for the treatment of several CNS dis-
orders such as cognitive impairment, narcolepsy, attention-deficit
hyperactivity disorder (ADHD), Alzheimer’s disease and obesity.5
Early histamine H3R ligands such as ciproxifan,6 clobenpropit7
or thioperamide8 (Fig. 1) were based on the imidazole core present
in the endogenous substrate. However, issues like cytochrome
Figure 1. Selected examples of imidazole-based histamine H3-R antagonists.
O
Cl
NH
N
N
O
O
N
Pitolisant (BF2.649)
GSK 189254
⇑
Corresponding author. Tel.: +41 61 688 1330; fax: +41 61 688 6459.
E-mail address: hans.richter@roche.com (H.G.F. Richter).
Figure 2. Selected examples of non-imidazole histamine H3-R antagonists.
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.08.009

5714
H. G. F. Richter et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5713–5717
R3
O
indole-2-carboxamide analogues containing a tricyclic amide core
structure.
Based on the very good match with our recently published H3R
O
1
8
R1
pharmacophore model,16 we reasoned that incorporation of the
amide bond of 1 into 3,4-dihydro-2H-pyrazino[1,2-a]indol-1-ones
2 may provide such a new lead series. In order to extend the struc-
tural diversity and to further validate our pharmacophore model
we also investigated the constitutionally isomeric 2,3,4,9-tetrahy-
dro-beta-carbolin-1-ones 3 (Fig. 3).
N
O
R4
N
4
R2
N
F
6
F
n
Conformational
restriction
2
3
N
O
R3
O
R4
N
N
The synthesis of this new class of tricyclic amides was accom-
plished as outlined in Schemes 1 and 2. Alkylation of commercially
available 5-benzyloxy-1H-indole-2-carboxylic acid ethyl ester 4
with 2,2-dioxo[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl
esters (5, n = 1)17 proceeded in high yields. In case of chiral 5-
substituted sulfamidates the alkylation reaction proceeded under
inversion of configuration with an enantiomeric excess of more
than 98% ee.18 Removal of the Boc protective group under acidic
conditions and cyclization of the liberated amine onto the ester
group afforded the pyrazino-indolines 6. Cleavage of the benzyl
protective group by hydrogenolysis gave the phenol intermediate
7 that underwent Mitsunobu coupling with commercially available
1-isopropyl-piperidine-4-ol to the secondary amides 8. Alterna-
tively, alkylation of 7 with 1-bromo-3-chloro-propane and subse-
quent reaction with secondary amines afforded compounds 9.
R1
O
N
H
1
Figure 3. Conformational restriction around indole-2-carboxamide lead structure
1.
of the earlier ligands and several analogues such as Pitolisant
(BF2.649)12 or GSK18925413 have advanced into clinical trials
(Fig. 2).14
As a part of our lead optimization program around the indole
lead structure 115 we sought new chemical starting points for the
development of novel histamine H3 receptor inverse agonists.
Herein, we report the synthesis, structure–activity relationship
and evaluation of a novel series of conformationally constrained
O
O
O
N
O
S
O
R2
BnO
R1
HO
( )n
a, b
BnO
R1
O
O
O
O
5
c
R1
N
N
NH
( )n
N
NH
( )n
H
R2
R2
6
7
4
e, f
d
N
O
N
O
N
O
1
O
8
1
8
R1
R4
N
4
R1
R4
N
4
6
N
( )n
6
( )n
R2
R2
9 (R4 = H)
8 (R4 = H)
g
g
11 (R4 H)
10 (R4 H)
=
=
Scheme 1. Reagents and conditions: (a) 5, KOt-Bu, DMF, 0 °C to rt; (b) TFA, CH2Cl2, 0 °C to rt, then K2CO3, MeOH (45–70% over three steps); (c) H2, Pd/C, MeOH (70–100%); (d)
1-isopropyl-piperidine-4-ol, di-tert-butyl-azodicarboxylate, PPh3, THF, rt (20–45%); (e) 1-bromo-3-chloro-propane, K2CO3, 2-butanone (50–60%); (f) amine, K2CO3, KI, CH3CN
(16–75%); (g) R4-X, NaH, DMF, rt (5–100%).
N
O
N
O
O
O
O
O
O
c, d, e
O
a, b
N
N
R4
N
Br
Br
Br
N
H
H
12
13
14a (R4 = H)
14b (R4 = CH2c-Pr)
e
Scheme 2. Reagents and conditions: (a) BBr3, CH2Cl2, À78 °C to rt (79%); (b) 1-isopropyl-piperidine-4-ol, di-tert-butyl-azodicarboxylate, PPh3, THF, 0 °C to rt (76%); (c) 5 (5-S-
Me), KOt-Bu, DMF, 0 °C to rt (53%); (d) TFA, CH2Cl2, 0 °C to rt, then K2CO3, MeOH (31% over two steps); (f) c-PrCH2Br, NaH, DMF (55%).

H. G. F. Richter et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5713–5717
5715
O
Basic center
O
O
O
HN
HN
O
O
Electron rich
Aromatic
N
N
N
N
N
N
N
H
F
h-H3R Ki: 2 nM
h-H3R Ki: 25 nM
h-H3R: 35% inhib. at 3 µM
F
O
O
O
O
N
N
HN
N
N
HN
h-H3R Ki: 17 nM
h-H3R Ki: 6 nM
Figure 4. Docking of compound 1 (a), 8a (b), 3 (c), 8b (d), 8q (e) on pharmacophore model.
Table 1
Structure–activity relationship at human H3 receptor and selectivity over other histamine receptor sub-types
R3
O
O
1
8
R1
R4
N
N
6
4
R2
n
R1
R2 (config.)
R3
R4
Kia hH3-R
(nM)
EC50 hH3-R
Inhibitionc
hH1-R (%)
Inhibitiond
hH2-R (%)
Inhibitione
hH4-R (%)
b
Ex
n
(nM)
1
3
See Figure 3
See Figure 3 (R1 = R4 = H, R3 = Ni-Pr-piperidin-4-yl)
2
2
9
NT
1
À6
NT
À17
9
11
À2
6
7
NT
6
>3000
25
17
31
27
9
34
6
14
7
6
5
5
46
19
17
9
NTf
38
26
48
25
28
40
28
23
14
14
13
12
56
51
36
46
14
29
94
18
4
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
8m
8n
8o
8p
8q
8r
1
2
1
1
1
1
1
1
1
1
1
1
1
1
2
1
1
1
1
1
1
1
1
1
1
1
1
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Br
Br
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Ni-Pr-piperidin-4-yl
–//–
–//–
–//–
–//–
–//–
–//–
–//–
–//–
–//–
–//–
–//–
–//–
–//–
–//–
–//–
H
H
Me
i-Pr
CH2c-Pr
CH2CF3
CH2-(o-F-Ph)
CH2-(m-F-Ph)
CH2-(p-F-Ph)
CH2-(o-Py)
CH2-(m-Py)
CH2-(p-Py)
CH2CH2OH
CH2CH2OMe
CH2c-Pr
H
3
À3
À4
À6
À15
À1
16
24
17
6
3
4
À1
À26
5
0
À6
7
À6
À4
6
1
21
À3
4
4
1
À3
3
3
À14
14
6
15
13
26
10
9
3
À5
0
À7
7
15
9
10
12
À10
1
3-Me (R)
3-Me (S)
4-Me (R)
4-Me (S)
3-Me (R)
4-Me (S)
4-Me (S)
H
H
H
H
H
2
–//–
–//–
–//–
–//–
–//–
–//–
H
H
H
6
À2
À4
11
3
À16
10
À4
33
11
13
16
26
42
5
4
2
129
18
21
7
8s
8t
CH2c-Pr
H
CH2c-Pr
H
H
H
H
H
8
14a
14b
8u
9a
9b
9c
9d
18
À3
9
45
10
4
2
1-Cyclopropylmethyl-piperidin-4-yl
(Piperidin-1-yl)-propyl
((S)-2-Me-pyrrolidin-1-yl)-propyl
((R)-2-Me-pyrrolidin-1-yl)-propyl
((2S,5S)-2,5-Dimethyl-pyrrolidin-1-yl)-propyl
N.d.f
74
140
4
3
8
4
À4
11
24
17
6
a
b
c
d
e
f
Radioligand displacement of [3H]-RAMH (n = 1).
GTP 35S binding to human recombinant H3 receptor (inverse agonist) (n = 1).
Radioligand displacement of [3H]-mepyramine (n = 1).
Radioligand displacement of [3H]-tiotidine (n = 1).
Radioligand displacement of [3H]-histamine (n = 1).
Not determined.
c

5716
H. G. F. Richter et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5713–5717
Alkylation of the secondary amide function in 8 and 9 furnished
the N-alkylated products 10 and 11, respectively.
respectively. All compounds were tested in a functional GTPcS as-
say and were characterized as potent full inverse agonists at the
human H3 receptor (Table 1) with comparable potency at the rat
H3 receptor (data not shown).
With the exception of 8h, 9a and 9d that showed residual activ-
ity at hH1 and hH2 receptor subtypes and 8q that showed some
moderate activity against hH2 and hH4 receptors, all compounds
were highly selective against the other histamine receptor sub-
types (Table 1).
Several representative compounds were tested for their physi-
cochemical properties and were characterized by low to moderate
lipophilicity (log D À0.25 to 2.32) and high aqueous solubility
(Table 2).
In rat liver microsomes, compounds generally tended to be less
metabolically stable than in human microsomes where they were
characterized by low and comparable clearance values. With the
exception of 8m that showed sub-micromolar inhibition of CYP
2D6, compounds displayed no significant CYP450 inhibition (Table
2) indicating a low drug–drug interaction potential.
2,3,4,5-Tetrahydro-[1,4]diazepino[1,2-a]indol-1-ones (8–11, n =
2) could be synthesized using the 2,2-dioxo[1,2,3]-oxathiazinane-
3-carboxylic acid tert-butyl ester (5, n = 2, R1 = H).19 Following the
same protocol, the 7-bromo analogues 14a and 14b (from 6-bro-
mo-5-methoxy-1H-indole-2-carboxylic acid ethyl ester 12,20
Scheme 2) and 2,3,4,9-tetrahydro-beta-carbolin-1-ones 3 (from 6-
hydroxy-2,3,4,9-tetrahydro-beta-carbolin-1-one21) were obtained.
In accordance with our pharmacophore model, the 2,3-annu-
lated analogue 3 was much less active than its 1,2-annulated
counterpart 8a. The loss of activity can be rationalized by the
sub-optimal positioning of the carbonyl acceptor (Figs. 4b and c).
The ring size of the lactam ring (8a/8b and 8e/8o, respectively)
did not have a significant impact on the binding affinity, likely
due to the comparable space filling properties of the six and seven
membered ring (Fig. 4d). Alkylation at the lactam nitrogen espe-
cially with cyclopropylmethyl (8e) or pyridylmethyl substituents
(8j–8l) led to a 3–5-fold increase in binding affinity as compared
to 8a. As a next step we examined the effects of substitutions at
the lactam ring of 8a on binding affinity. Whereas the introduction
of a methyl group in the 4-position of 8a did not significantly alter
binding affinity (8r, 8s), the introduction of a methyl group in the
3-position of 8a led to a three and fourfold increase in binding
affinity for the R and S enantiomer 8p and 8q, respectively. The
highest activity resided with the 3-Me (S) analogue 8q (Fig. 4e),
although the higher potency is difficult to rationalize based on
the pharmacophore model which indicates a significant distance
of the chiral methyl group at either position 3 or 4 to the basic
and aromatic pharmacophoric features, respectively.
Based on the promising data obtained so far for this compound
class we investigated the effects of 8t (Ki rat H3R 12 nM, EC50 rat
H3R 18 nM) in a rat dipsogenia model measuring reversal of a
selective H3R agonist ((R)-a-methyl histamine)-induced increased
water intake.22 In addition, the animals were observed during
one hour and potential behavioral side-effects were recorded
according to a modified Irwin protocol. In this paradigm, com-
pound 8t did not lead to notable side-effects and significantly
inhibited the water intake by 64% at a dose of 10 mg/kg after oral
dosing, without affecting water intake when given alone. This re-
sult indicates functional antagonism of 8t at brain H3 receptors.
In summary, we identified a novel and conformationally rigid
series of potent histamine H3 inverse agonists derived from our in-
dole lead structure 1. Several compounds from this new series dis-
played high selectivity over other histamine receptor sub-types,
low CYP450 inhibition potential and were endowed with excellent
physicochemical properties. Following oral administration com-
pound 8t reduced water intake in a dipsogenia model after oral
administration, indicating good absorption and brain penetration.
The impact of different amine side-chains at the indole core on
binding affinity (8u, 9a–9d) was also investigated. From these ana-
logues, the (R)-1-(3-methoxy-propyl)-2-methyl-pyrrolidine deriv-
ative 9c exhibited the highest binding affinity. Finally we
introduced a bulky bromo substituent in the so far unexplored
position-7 of the indole core. This variation led to a further sub-
stantial increase of binding affinity resulting in the identification
of the most potent compounds from this series 14a and 14b,
Table 2
Solubility, lipophilicity, CYP450 inhibition and microsomal clearance for selected 3,4-dihydro-2H-pyrazino[1,2-a]indol-1-ones
R3
O
O
1
8
R1
R4
N
N
6
4
R2
n
Ex.
n
R1
R2 (config.)
R3
R4
Solubilitya
(l
g/mL)
log Db
CYP IC50
3A4, 2D6, 2C9
(
l
M)
Clint (h/r)c
(( L/min)/mg)
l
1
See Figure 3
>589
>436
>455
>455
>508
382
>456
>406
284
>455
>455
345
>441
>526
506
1.67
À0.05
0.07
0.13
1.09
2.06
0.64
À0.25
0.28
0.23
0.23
0.28
1.4
>50, 5, >50
>50, 4, >50
4/12
1/70
0/28
1/23
14/9
5/17
8/27
9/11
7/10
3/0
0/29
4/0
6/10
1/12
7/20
0/37
8a
8b
8c
8e
8i
1
2
1
1
1
1
1
1
1
1
1
1
1
1
1
H
H
H
H
H
H
H
H
H
H
H
H
Br
Br
H
H
H
H
H
H
H
H
Ni-Pr-piperidin-4-yl
–//–
–//–
–//–
–//–
–//–
–//–
–//–
–//–
–//–
–//–
–//–
–//–
–//–
H
H
>50, >50, >50
>50, 15, >50
>50, >50, >50
>50, 35, >50
6, >50, >50
>50, 0.9, >50
>50, >50, >50
>50, >50, >50
>50, 22, >50
26, >50, >50
>50, >50, >50
>50, >50, >50
>50, >50, >50
>50, >50, >50
Me
CH2c-Pr
CH2-(p-F-Ph)
CH2-(p-Py)
CH2CH2OH
H
H
H
8l
8m
8p
8q
8r
8s
8t
14a
14b
9c
3-Me (R)
3-Me (S)
4-Me (R)
4-Me (S)
3-Me (R)
4-Me (R)
4-Me (R)
H
H
CH2c-Pr
H
CH2c-Pr
H
1.13
2.32
0.13
((R)-2-Me-pyrrolidin-1-yl)-propyl
>436
a
b
c
Aqueous solubility in phosphate buffer at pH 6.5 in 0.05 M phosphate buffer.
pH 7.4.
Intrinsic clearance in human (h) and rat (r) liver microsomes.

H. G. F. Richter et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5713–5717
5717
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Jones, D. N. C.; Lacroix, L. P.; Martyn, A.; Ociepka, S.; Ray, A.; Regan, C. M.;
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Conformational restriction did not lead to a further improvement
of potency or in vitro ADME properties compared to the indole lead
structure 1.
Acknowledgements
The work of Martin Ritter and Kersten Klar is gratefully
acknowledged.
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