Novel and highly potent histamine H3 receptor ligands. Part 2: Exploring the cyclohexylamine-based series

Article abstract of DOI:10.1016/j.bmcl.2011.06.102

Synthesis and biological evaluation of novel and potent cyclohexylamine-based histamine H3 receptor inverse agonists are described. Compounds in this newly identified series exhibited subnanomolar binding affinities for human receptor and no significant interaction with hERG channel. One derivative (10t) demonstrated enhanced in vivo efficiency and preferential brain distribution, both properties suitable for potential clinical evaluation.

Full text of DOI:10.1016/j.bmcl.2011.06.102

Bioorganic & Medicinal Chemistry Letters 21 (2011) 5384–5388
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Novel and highly potent histamine H3 receptor ligands. Part 2: Exploring
the cyclohexylamine-based series
⇑
Olivier Labeeuw , Nicolas Levoin, Olivia Poupardin-Olivier, Thierry Calmels, Xavier Ligneau,
Isabelle Berrebi-Bertrand, Philippe Robert, Jeanne-Marie Lecomte, Jean-Charles Schwartz, Marc Capet
Bioprojet-Biotech, 4 rue du Chesnay Beauregard, BP 96205, 35762 Saint-Grégoire, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Synthesis and biological evaluation of novel and potent cyclohexylamine-based histamine H3 receptor
inverse agonists are described. Compounds in this newly identified series exhibited subnanomolar bind-
ing affinities for human receptor and no significant interaction with hERG channel. One derivative (10t)
demonstrated enhanced in vivo efficiency and preferential brain distribution, both properties suitable for
potential clinical evaluation.
Received 20 May 2011
Revised 21 June 2011
Accepted 22 June 2011
Available online 28 June 2011
Ó 2011 Elsevier Ltd. All rights reserved.
In memory of Professor Walter Schunack
Keywords:
Histamine
Histamine H3 receptor
GPCR
hERG
Since its discovery in 1983 by Arrang et al.1 and its cloning in
1999 by Lovenberg et al.,2 the histamine H3 receptor (H3R) has
been widely studied and reviewed.3 This G-protein-coupled recep-
tor mainly controls histamine biosynthesis and release via a nega-
tive-feedback process. It also regulates the release of several other
neurotransmitters such as acetylcholine,4 GABA,5 norepinephrine,6
dopamine,7 and serotonin.8 This crucial role of H3R in brain led to
an intensive search for potent H3R antagonists. Such compounds
enhance brain histamine level and thus display waking and
pro-cognitive effects in several CNS-related disorders. More than
a dozen of chemical entities have already entered into clinical
trials. A selection of the most advanced H3 antagonists/inverse
agonists (for which chemical structures are available) are shown
in Figure 1. Our PitolisantINN (previously named BF2.649 or tiproli-
sant) is currently completing Phase III trials for the treatment of
narcolepsy, excessive daytime sleepiness in Parkinson’s disease
and obstructive sleep apnea.9 GSK-189254 has completed Phase
II clinical trial in narcolepsy,10 and was replaced by the back-up
GSK-239512 (structure undisclosed).11 JNJ-39220675 is developed
for allergic rhinitis (Phase II)12 whereas PF-03654746 (recently dis-
continued) was targeting Alzheimer’s disease, attention deficit
hyperactivity disorder (ADHD), schizophrenia, narcolepsy, and
allergic rhinitis.13
Here we report an extension of our previous work aiming at
discovering potent histamine H3 inverse agonists devoid of hERG
and CYP450 interactions with favorable CNS penetration and phar-
macokinetic profile.
The traditional pharmacophore model for H3R antagonists3b,f
consists of a basic amine coupled to an aromatic core via a linear
(usually a propyloxy chain) or structurally constrained linker.14
Introduction of a second amine moiety beyond the aromatic part
increases H3R binding affinity15 and concomitantly greatly reduces
hERG binding.16 One interesting compound, in our hands, is
JNJ-5207852 (Fig. 2)17 which is a very potent H3R inverse agonist
(Ki = 0.60 nM) at the human receptor. Nevertheless, its pharmaco-
kinetic profile presents some limitations such as a low brain/
plasma ratio of 1 and a delayed Tmax (time required to achieve
maximum concentration after administration) in brain.18
To overcome these drawbacks and improve brain penetration, a
new series of conformationally restricted diamines with
cyclohexyl ring was designed.
a
The synthesis of the desired cyclohexylamines began with the
commercially available 4-(4-hydroxyphenyl)cyclohexanone 1,
which was alkylated with 1-bromo-3-chloropropane (Scheme 1).
The resulting chloride 2 was then treated with piperidine to afford
cyclohexanone 3. Finally, various primary or secondary amines
were introduced by reductive amination with sodium triacetoxy-
borohydride to yield the corresponding cis and trans cyclohexyl-
amines 4c–16c and 4t–16t. Despite of a poor cis/trans selectivity,
careful flash chromatographies over silica allowed to isolate pure
isomers in most cases.
⇑
Corresponding author. Tel.: +33 299280440; fax: +33 299380444.
E-mail address: o.labeeuw@bioprojet.com (O. Labeeuw).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.06.102

O. Labeeuw et al. / Bioorg. Med. Chem. Lett. 21 (2011) 5384–5388
5385
O
F
N
O
N
N
N
O
Cl
Pitolisant INN (BF2.649, tiprolisant)
Phase III
JNJ-39220675
Phase II
O
N
H
O
N
H
N
N
F
N
O
F
GSK-189254
Phase II
PF-03654746
Phase II
Figure 1. Selection of most advanced histamine H3 ligands in clinical trials.
tion. Finally, alkylation with the mesylate of the 3-piperidinyl-
propan-1-ol yielded cyclohexylamines 6t, 7t and 10t.
N
N
O
Histamine H3 binding affinities of compounds 3–16 were
evaluated by displacement of [125I]-iodoproxyfan (IPX) binding to
membranes of HEK-293 cells19 stably transfected with the human
H3 receptor or to native mouse brain cortex H3R.20 Results are
reported in Table 1.
JNJ-5207852
Figure 2.
Most ligands displayed subnanomolar affinities. Molecular
modeling suggests that the binding mode is similar to that
described for BF2.649.21 The second amine moiety forms a salt
bridge with Glu191 in the extracellular loops e3 (Fig. 3). This would
explain the stronger affinities of amines in comparison with the
non basic compounds 3 and 16t. Nature of the aliphatic amine
appended to the cyclohexyl did not modify the human H3R binding
A second approach was also devised to synthesize trans isomers
6t, 7t and 10t with a better selectivity (Scheme 2). The common
precursor 3 was treated with p-toluenesulfonic acid and the vari-
ous amines to yield the corresponding enamines 19. Subsequent
reduction with sodium borohydride at low temperature (À20 °C)
furnished the desired pure trans intermediates 20 after crystalliza-
b
a
O
O
HO
O
Cl
2
1
R1
R2
O
N
N
N
N
4t-16t
c
+
O
O
R1
R2
O
N
3
4c-16c
Scheme 1. Synthesis of cis and trans 1,4-cyclohexylamine compounds 4–16. Reagents and conditions: (a) 1-bromo-3-chloropropane, K2CO3, DMF, rt, 15 h; (b) piperidine,
K2CO3, KI, DMF, 100 °C, 15 h, (c) HNR1R2, NaBH(OAc)3, AcOH, THF, rt, 15 h and flash chromatography over silica.
R1
a
b
HO
HO
HO
O
N
N
R2
19
R1
R2
R1
, HCl
R2
c
( )3O
N
N
20
6t, 7t, 10t
Scheme 2. Synthesis of enriched trans stereoisomers. Reagents and conditions: (a) HNR1R2, toluene, APTS, reflux, Dean-Stark, 10 h; (b) NaBH4,NaOH, MeOH, 1,2-
dichloroethane, À20 °C then 3 N aq HCl and crystallization; c) 3-piperidin-1-ylpropyl methanesulfonate hydrochloride, K2CO3, DMF, 70 °C;15 h.

5386
O. Labeeuw et al. / Bioorg. Med. Chem. Lett. 21 (2011) 5384–5388
Table 1
Binding data for human and mouse H3 receptors for compounds 3–16
( )O3
R
N
Compound
R
Stereo-chemistry
Human recombinant H3R
[
Native mouse H3R (brain cortex)
[
125I]-IPX binding Ki (nM)b
125I]-IPX binding Ki (nM)a
3
(@O)
1.7 0.18
—
4c
4t
cis
trans
0.30 0.10
0.21 0.07
0.28 0.05
0.52 0.18
N
5c
5t
cis
trans
0.34 0.02
0.25 0.02
—
N
N
1.6 0.5
6c
6t
cis
trans
0.33 0.10
0.25 0.08
1.0 0.3
0.33 0.06
7t
trans
cis
0.64 0.08
0.56 0.09
1.0 0.2
—
N
N
N
N
N
8c
9c
9t
cis
trans
0.92 0.18
0.32 0.03
—
2.3 0.2
N
O
10c
10t
cis
trans
0.67 0.08
0.41 0.07
—
1.6 0.3
11c
11t
cis
trans
0.92 0.08
0.57 0.09
—
—
OH
12c
12t
cis
trans
0.41 0.15
0.17 0.02
—
1.4 0.3
N
13c
13t
cis
trans
0.29 0.04
0.26 0.05
—
N
H
2.1 0.5
14c
14t
cis
trans
0.53 0.07
0.64 0.05
—
—
N
H
15t
16t
trans
trans
3.2 1.1
5.5 1.3
—
—
H
N
N
SO2
a
Ki values are the mean of at least two experiments (in duplicate). Mean SEM is reported
Ki values are the mean of at least two experiments (in triplicate). Mean SEM is reported
b
Table 2
In vitro cytochrome P450 inhibition assays
a
Compound
Inhibition
2D6
3A4
2C9
% at 1
4.1
lM
IC50
(
lM)
% at 1
3.8
l
M
IC50
(lM)
% at 1
21.4
lM
IC50 (lM)
3
4c
4t
50
42.6
>100
>100
11.3
40.7
5t
6c
6t
4.2
0.8
À12.1
41.7
48
>100
>100
22.3
15.3
7t
8c
9t
5.2
26.1
20.9
1.4
33.5
52.9
46.5
À7.8
3.4
10t
11t
12t
13t
14c
14t
66.2
>100
44
3.3
8.9
39.9
25.4
26.6
15.7
21.9
20.0
2.9
3.4
25.1
47.8
53.9
54.7
À8.9
a
% inhibition or IC50 values are the mean of at least two experiments performed in triplicate. Incubation of selected compounds was carried out at 37 °C 0.5 °C under
agitation in the presence of human recombinant cytochrome P-450 isoforms, CYP isoform-selective fluorescent substrates and a NADPH generating system.
affinity (compounds 4–7). Introduction of a supplementary hetero-
atom (i.e., morpholine 10, N-methylpiperazine 9, 4-hydroxypiper-
idine 11) resulted in a maximum 2-fold loss of affinity. Aromatic
amines like isoindoline 12 and benzylamine 13 displayed equiva-
lent potencies to the best cycloalkylamines. The reduced activity
of compound 15t versus 4t may result from an important cost of

O. Labeeuw et al. / Bioorg. Med. Chem. Lett. 21 (2011) 5384–5388
5387
Table 3
400
In vitro inhibition (%) of hERG tail current by compounds
4c, 4t, 5t, 6c, 6t, 7t and 10t
Compound
hERG tail current inhibitiona (%)
350
300
250
200
at 1
lM
at 10 lM
4c
4t
5t
6c
6t
7t
19
41
19
80
41
15
22
ciproxifan
compound 10t
11
14
42
ED50 = 1.3 0.4 mg/kg, p.o.
10t
34
a
% inhibition values are the mean of at least six
0.1
1
10 100
patch clamp experiments using recombinant HEK-293
cells stably expressing the hERG channel.
Log [dose] (mg/kg, p.o.)
Figure 4. Dose-effect curve of compound 10t on N-tele-methylhistamine levels in
mouse brain. (mean SEM from 12 to 18 mice per dose).
Table 4
In vivo mouse H3R central potency evaluation for
compounds 4c, 4t, 5t, 6t, 7t and 10t.
110
100
90
Compound
ED50 mg/kg, p.o.
4c
4t
5t
6t
7t
3.7 0.6
3.7 0.7
2.8 0.2
ꢀ3
80
70
60
Human liver microsomes
Mouse liver microsomes
4.2 2.0
1.3 0.4
50
40
30
20
10
0
10t
Histamine main metabolite N-tele-methylhistamine
levels in brain were determined by enzymoimmuno-
assay, 90 min after per os administration of compounds
to at least 6 male Swiss mice per dose tested. ED50 are
provided as mean SEM.
0
50
100
150
200
250
Time (minutes)
Figure 5. Metabolic stability of compound 10t. Compound 10t (100 nM concen-
tration) was incubated with pooled human or mouse liver microsomes (0.5 mg/mL
protein concentration) in the presence of NADP. Concentration of compound 10t
over time were monitored by LC-MS/MS.
3000
2500
2000
1500
Plasma AUC0-8h = 2107.6 ng/ml*h
1000
500
0
Brain
AUC0-8h = 15618.7 ng/ml*h
0
2
4
6
8
Time (hours)
Figure 6. Pharmacokinetic profile of compound 10t following a 10 mg/kg oral dose
to male Swiss mice. Quantification in plasma and brain tissue by LC-MS/MS
(mean SEM of 3 mice).
desolvation. In agreement, a difference of 1 kcal/mol in free energy
of
solvation
is
reported
for
dimethylamine
versus
trimethylamine.22
Figure 3. Detail of the binding mode of compound 4t. The binding site is
represented by its electrostatic potential on the Connoly surface. Glu191 is visible
on the top as thin sticks.
The most promising compounds were, then, evaluated in safety
assays. In vitro inhibition of cytochromes P450 3A4, 2D6 and 2C9

5388
O. Labeeuw et al. / Bioorg. Med. Chem. Lett. 21 (2011) 5384–5388
S.; Wijtmans, M.; Talaga, P.; Leurs, R.; de Esch, I. J. P. Drug Discovery Today 2005,
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at 1 or 10
l
M is reported in Table 2. Ligands 8c, 9t, 13t, 14c and 14t
M for 2C9 (i.e., an esti-
M) which implied a reduced safety margin and
showed an inhibition of about 50% at 1
mated IC50 = 1
l
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9. (a) Efficacy and Safety Study of BF2.649 in the Treatment of Excessive Daytime
Sleepiness in Narcolepsy (NCT01067222) (www.clinicaltrials.gov.; (b) Efficacy
and Safety of BF2.649 in Excessive Daytime Sleepiness (EDS) in Parkinson’s
Disease (NCT01036139) (www.clinicaltrials.gov.; (c) BF2.649 in Patients With
Obstructive Sleep Apnea Syndrome (OSA) and Treated by Continuous Positive
Airway Pressure (CPAP) But Still Complaining of Excessive Daytime Sleepiness
(EDS) (NCT01071876) (www.clinicaltrials.gov.; (d) Lin, J. S.; Dauvilliers, Y.;
Arnulf, I.; Bastuji, H.; Anaclet, C.; Parmentier, R.; Kocher, L.; Yanagisawa, M.;
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l
the inherent risk of potential drug–drug interactions. As a result
they were not selected for further preclinical evaluation. Other li-
gands displayed no significant activity on CYP 3A4, 2D6 and 2C9.
Cardiovascular safety was assessed at the hERG channel using a
patch clamp assay (Table 3). The selection of compounds exhibited
no significant interaction with the hERG channel, with the excep-
tion of 4t and 7t which showed an IC50 at the micromolar level.
In vivo H3R activity was evaluated in mice for compounds 4c,
4t, 5t, 6t, 7t and 10t, by following the release of brain histamine
via the formation of its main metabolite (N-tele-methylhistamine)
(Table 4). All compounds demonstrated full inverse agonism
(i.a. = 1.0, defined by the maximal effect elicited by ciproxifan as
reference full inverse agonist) and high efficiencies with ED50 be-
tween 1.3 and 4.2 mg/kg, po. Ligand 10t (BP1.3432) exhibited the
highest potency (1.3 mg/kg po, dose-effect curve in Figure 4). This
promising clinical candidate demonstrated an excellent metabolic
stability (Fig. 5) on human and mouse liver microsomes as well as a
rapid and high CNS penetration with a brain/blood ratio of 7.4
(Fig. 6).
In summary, we have synthesized a novel and potent series of
cyclohexylamine-based histamine H3 receptor inverse agonists.
Various amines were introduced while keeping subnanomolar
binding affinities and no significant hERG channel interaction. A
compounds selection was more extensively evaluated regarding
their in vivo efficiency and safety issues. Compound 10t
(BP1.3432) ended to be the most promising clinical candidate. Be-
cause of the cationic amphiphilic nature of the molecule the issue
of potential phospholipidosis has to be investigated. Additional
regulatory toxicology and safety pharmacology studies are needed
to support further development.
11. 11. Study to Evaluate the Efficacy and Safety of GSK239512 in Alzheimer’s
Disease (NCT01009255) (www.clinicaltrials.gov.
12. 12. Safety and Efficacy of JNJ-39220675 in Participants With Allergic Rhinitis
(NCT00804687) (www.clinicaltrials.gov.
13. (a)
A Study to Evaluate the Safety, Tolerability, and Blood Levels of PF-
03654746 in Subjects With Mild to Moderate Alzheimer’s Disease
(NCT01028911) (www.clinicaltrials.gov.; (b) A Study to Evaluate the Efficacy
and Safety of Two Doses of PF-03654746 in Adults With Attention Deficit
Hyperactivity Disorder (ADHD) (NCT00531752) (www.clinicaltrials.gov.; (c) A
Study Of A Novel Compound For Excessive Daytime Sleepiness Associated With
Narcolepsy (NCT01006122) (www.clinicaltrials.gov.; (d) A Study to Test a New
Decongestant in Patients With Allergic Rhinitis Following a Nasal Allergen
Challenge (NCT00562120) (www.clinicaltrials.gov.; (e) Add On Treatment for
Cognitive Deficits in Schizophrenia (NCT01346163) (www.clinicaltrials.gov.
14. Non-imidazole alkylamines as Histamine H3_receptor ligands and their
therapeutic applications, WO2000006254, Bioprojet.
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C.; Schunack, W.; Stark, H. J. Med. Chem. 2002, 45, 1128; (b) Apodaca, R.;
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Acknowledgements
[16]. Levoin, N.; Labeeuw, O.; Calmels, T.; Poupardin-Olivier, O.; Berrebi-Bertrand,
I.; Lecomte, J.-M.; Schwartz, J.-C.; Capet, M. Bioorg. Med. Chem. Lett. 2011.
doi:10.1016/j.bmcl.2011.07.006.
17. Barbier, A. J.; Berridge, C.; Dugovic, C.; Laposky, A. D.; Wilson, S. J.; Boggs, J.;
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mice (10 mg/kg/per os). Brain: AUC(0–3h) = 1103.2 ng/mL h and Tmax = 3 h;
Plasma: AUC(0–3h) = 1037.7 ng/mL h and Tmax = 30 min.
The authors gratefully acknowledge Stéphanie Le Meur, Benoît
Messager, Isabelle Delimoge, Isabelle Léger, Philippe Guibet,
Jean-Claude Camelin, Marie-Paule Laville, Mikael Croyal and
Brigitte Cheval for technical assistance in the synthesis and the
evaluation of compounds.
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