Novel and highly potent histamine H3 receptor ligands. Part 3: An alcohol function to improve the pharmacokinetic profile

Article abstract of DOI:10.1016/j.bmcl.2013.02.118

Synthesis and biological evaluation of potent histamine H₃ receptor antagonists incorporating a hydroxyl function are described. Compounds in this series exhibited nanomolar binding affinities for human receptor, illustrating a new possible component for the H₃ pharmacophore. As demonstrated with compound BP1.4160 (cyclohexanol 19), the introduction of an alcohol function counter-intuitively allowed to reach high in vivo efficiency and favorable pharmacokinetic profile with reduced half-life.

Full text of DOI:10.1016/j.bmcl.2013.02.118

Bioorganic & Medicinal Chemistry Letters 23 (2013) 2548–2554
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Novel and highly potent histamine H3 receptor ligands. Part 3: An
alcohol function to improve the pharmacokinetic profile
⇑
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 potent histamine H3 receptor antagonists incorporating a hydroxyl
function are described. Compounds in this series exhibited nanomolar binding affinities for human recep-
tor, illustrating a new possible component for the H3 pharmacophore. As demonstrated with compound
BP1.4160 (cyclohexanol 19), the introduction of an alcohol function counter-intuitively allowed to reach
high in vivo efficiency and favorable pharmacokinetic profile with reduced half-life.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 28 January 2013
Revised 22 February 2013
Accepted 28 February 2013
Available online 14 March 2013
Keywords:
Histamine
Histamine H3 receptor
Pharmacophore
Half-life
Pharmacokinetics
The histamine H3 receptor (H3R) has been widely studied and
reviewed1 since its discovery in 1983 by Arrang et al.2 This G-pro-
tein-coupled receptor mainly controls histamine biosynthesis and
release via a negative-feedback process. It also regulates the re-
lease of several other neurotransmitters: acetylcholine,3 noradren-
aline,4 dopamine5 and serotonin.6 Specifically the release of
histamine in brain, which is associated waking and pro-cognitive
action, is triggered by inverse agonists rather than neutral antago-
nists of H3R.7 These observations led to an intensive search for po-
tent H3R inverse agonists. Such compounds could be useful in
several CNS-related disorders such as narcolepsy, attention deficit
hyperactivity disorder (ADHD), schizophrenia, Alzheimer’s disease,
and excessive daytime sleepiness in obstructive sleep apnea or Par-
kinson’s disease. More than a dozen of chemical entities have al-
ready entered into clinical trials (Fig. 1). Among them several
molecules had been discontinued, partly due to too long effect
duration responsible for insomnia reported as a main adverse
event. For instance APD916 exhibited excessive half-life (T1/2) of
50 h.8
distribution. However its long half-life precluded its clinical
development.
Here we report our efforts to design potent histamine H3 li-
gands with better pharmacokinetic profile. We first tried a small
modification of BP1.3432 and hypothesized that the introduction
of an alcohol function would favor metabolic conjugation reactions
such as O-glucuronidation and clearance of the molecule. Thus we
prepared an analog of morpholine BP1.3432 where an exocyclic
hydroxyl group replaces the ether function (synthesized analo-
gously to BP1.3432.9). Compound 21 retained comparable binding
affinity for the human H3 receptor but displayed disappointing T1/2
values and a less favorable plasma/CNS ratio (Fig. 2).
Since undesirable long half-life may be due to the dibasic nature
of the molecules10 we decided to set aside the cyclohexylamine
series and to focus on the hydroxyl group. To our knowledge, no
systematic study of an alcohol moiety has been reported in the lit-
erature for H3R antagonists/inverse agonists. This is certainly be-
cause ‘rules of thumb’ for CNS drugs tell us that lowering the
number of hydrogen-bond donor favors better blood–brain barrier
(BBB) penetration (case of passive diffusion).11 However an hydro-
xyl may be compatible with the traditional pharmacophore mod-
el1c,g (Fig. 3), consisting of a basic amine connected through a
linear (usually a propyloxy chain12) or structurally constrained lin-
ker to an aromatic central core, which can be further substituted by
a lipophilic residue, a second amine moiety (like JNJ-5207852 and
analogs13), an acidic14 or more surprisingly metallic15 element or
other polar groups.
In a previous paper9 we reported the synthesis of novel and po-
tent cyclohexylamine-based histamine H3 receptor antagonists.
The best compound BP1.3432 demonstrated subnanomolar bind-
ing affinity for the human receptor, no significant interaction with
the hERG channel, high in vivo efficiency and preferential brain
⇑
Corresponding author. Tel.: +33 299280440; fax: +33 299380444.
E-mail address: o.labeeuw@bioprojet.com (O. Labeeuw).
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.02.118

O. Labeeuw et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2548–2554
2549
O
N
O
N
O
N
N
Cl
Pitolisant INN (BF2.649, tiprolisant)
Phase III
Bavisant INN (JNJ-31001074)
Phase II
O
O
N
H
F
N
F
N
N
N
O
F
JNJ-39220675
Phase II
PF-03654746
Phase II (discontinuated)
O
N
O
N
O
H
N
N
N
N
O
GSK-239512
Phase II
GSK-189254
Phase II (discontinuated)
N
N
N
O
N
N
CF3
O
CF3
O
N
O
MK-0249
Phase II (discontinuated)
MK-3134
Phase I
O
O
S
O
O
N
N
H
N
O
N
APD916
Phase I (discontinuated)
Irdabisant INN (CEP-26401)
Phase I
Figure 1. A selection of most advanced histamine H3 ligands in clinical trials.
OH
O
N
N
cis/trans mixture
O
N
O
N
Cpd 21
BP1.3432
BP1.4432
Cpd 21
Binding
hH3R Ki (nM)
mH3R Ki (nM)
0.41 0.07
1.6 0.3
0.57 0.09
nd
Swiss mouse pharmacokinetics
AUC (ng.h/mL)
Tmax (min)
Plasma
2107
90
Brain
15618
90
Plasma
Brain
1519
180
2074
90
Cmax (ng/mL)
357
5
2385
>10
399
6
215
>10
T1/2 (h)
Figure 2. Properties of compounds BP1.3432 and 21.

2550
O. Labeeuw et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2548–2554
intermediate (Scheme 3). Treatment of various ketones with Grig-
Lipophilicrreessididuuee
or
nard reagent of 24 yielded the corresponding tertiary alcohols.
The procedures used to prepare phenethyl alcohol 14 or 4-phe-
nylbutan-2-ols 15 and 16 are similar to those described previously
starting from 4-hydroxybenzyl cyanide or 4-(4-hydroxyphenyl) bu-
tan-2-one (Scheme 4). Propargyl or homopropargyl alcohols 17 and
18 were synthesized via Sonogashira coupling reaction of aryl iodide
25 (Scheme 5). Lastly cyclohexanols 19 and 20 were obtained from
phenol 26 and commercially available 4-(4-hydroxyphenyl)cyclo-
hexanone (Schemes 5 and 6).
Histamine H3 receptor binding affinities of compounds 1–20
were evaluated by displacement of [125I]-iodoproxyfan (IPX) bind-
ing to membranes of HEK-293 cells stably expressing the human
H3 receptor16 or to native H3R in mouse brain cortex.17 Results
are reported in Tables 1 and 2.
In the benzyl alcohol series, the affinity of non-cyclic com-
pounds (1–7, Table 1) increases with the number of carbon atoms.
Remarkably, we observed a correlation between the hydrophobic-
ity of the whole set of molecules and human H3R binding affinity
(correlation coefficient r2 = 0.72, n = 20).18 This property is logically
explained by the lipophilic nature of the binding site, which fa-
vours van der Waals interactions. In the case of cyclic compounds
2nd Basic moiety
1st Basic
moiety
or
Aromatic
central core
Linker
Linker
Acidic element
or
Polar group
(alcohol function?)
Figure 3. Traditional pharmacophore for H3R antagonists/inverse agonists.
To explore various possible interactions between the hydroxyl
function and the H3 receptor, chemical series with the alcohol res-
idue located at various lengths from the phenyl ring were designed.
The synthesis of a benzyl alcohol series is shown in Schemes 1–3.
Compounds 3, 4, 12 and 13 were easily prepared by addition of
Grignard reagents on benzaldehyde 22 (Scheme 1). This common
intermediate was synthesized from 4-hydroxybenzaldehyde by
alkylation with 1-bromo-3-chloropropane and subsequent treat-
ment with piperidine. Scheme 2 details the synthesis of benzyl
alcohols 1 and 7. Methyl benzoate 23 was prepared analogously
to 22. Reduction with LiAlH4 furnished compound 1 whereas con-
densation with excess allylmagnesium chloride yielded alcohol 7.
Preparation of compounds 2, 5, 6, 8–11 is based again on a key
c
a,b
O
( )3
CHO
O
( )3
R
HO
CHO
OH
3
N
N
22
OH
OH
OH
R=
O
4
12
13
Scheme 1. Synthesis of compounds 3, 4, 12 and 13. Reagents and conditions: (a) 1-bromo-3-chloropropane, K2CO3, DMF, rt, 15 h; (b) piperidine, K2CO3, KI, DMF, 110 °C, 3 h;
(c) vinylmagnesium bromide (for 3) or allylmagnesium chloride (for 4) or cyclohexylmagnesium bromide (for 12) or tetrahydropyran-4-ylmagnesium chloride (for 13), THF,
40 °C, 20 min.
O
OMe
O
OMe
a,b
c or d
O
( )3
O
( )3
R
HO
N
N
23
OH
R=
OH
1
7
Scheme 2. Synthesis of compounds 1 and 7. Reagents and conditions: (a) 1-bromo-3-chloropropane, K2CO3, DMF, rt, 15 h; (b) piperidine, K2CO3, KI, DMF, 100 °C, 15 h; (c)
LiAlH4, THF, rt, 5 h (for 1); (d) allylmagnesium chloride, THF, reflux, 2 h (for 7).
c,d
a,b
O
( )3
Br
O
( )3
R
HO
Br
N
N
24
OH
OH
OH
OH
OH
OH
OH
R=
O
2
5
6
8
9
10
11
Scheme 3. Synthesis of compounds 2, 5, 6, 8–11. Reagents and conditions: (a) 1-bromo-3-chloropropane, K2CO3, DMF, rt, 15 h; (b) piperidine, K2CO3, KI, DMF, 100 °C, 15 h; (c)
Mg, THF; (d) acetone (for 2) or pentan-3-one (for 5) or heptan-4-one (for 6) or cyclobutanone (for 8) or cyclopentanone (for 9) or cyclohexanone (for 10) or tetrahydro-4H-
pyran-4-one (for 11), THF, reflux, 1 h 30 min.

O. Labeeuw et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2548–2554
2551
c, d
a,b
O
( )3
O
( )3
HO
N
CN
N
CO2Me
CN
e
O
N
OH
( )3
14
OH
R1
O
O
a,b
f or g
N ( )3O
N ( )3O
HO
15 (R1=H)
16 (R1=CH3)
Scheme 4. Synthesis of compounds 14–16. Reagents and conditions: (a) 1-bromo-3-chloropropane, K2CO3, DMF, rt, 15 h; (b) piperidine, K2CO3, KI, DMF, 100 °C, 15 h; (c) 1 N
NaOH, EtOH, reflux, 15 h; (d) oxalyl chloride, DMF, DCM, rt, 3 h then MeOH, 0 °C, 1 h; (e) LiAlH4, THF, rt, 15 h; (f) NaBH4, MeOH, 0 °C to rt, 2 h (for 15); (g) MeMgCl, THF, rt,
15 h (for 16).
c
a,b
( )n
OH
O
( )3
I
O
( )3
HO
I
N
N
25
17 (n=1)
18 (n=2)
O
( )3
OH
d
O
a,b
O
( )3
HO
O
N
N
19
Scheme 5. Synthesis of compounds 17–19. Reagents and conditions: (a) 1-bromo-3-chloropropane, K2CO3, DMF, rt, 15 h; (b) piperidine, K2CO3, KI, DMF, 100 °C, 15 h; (c) 2-
propyn-1-ol (for 17) or 3-butyn-1-ol (for 18), Pd(OAc)2, PPh3, CuI, diisopropylamine, AcOEt, 50 °C, 5 h; (d) NaBH4, MeOH, rt, 1 h and flash chromatography over silica gel.
a,b
c, d
O
BnO
+
Cl ( )3O
PPh3 Cl
HO
O
O
26
e,f
N ( )3O
OH
cis/trans mixture
20
Scheme 6. Synthesis of compound 20. Reagents and conditions: (a) 1,4-dioxaspiro[4.5]decan-8-one, NaH, DMF, rt, 1 h; (b) 10% Pd/C, H2, EtOH, rt, 24 h; (c) 1-bromo-3-
chloropropane, K2CO3, DMF, rt, 20 h; (d) 2 N HCl, THF, rt, 20 h; (e) piperidine, K2CO3, KI, DMF, 100 °C, 15 h; (f) NaBH4, MeOH, rt, 15 h.
Table 1
Binding data for human and mouse H3 receptors for the benzyl alcohol series (compounds 1–13)
R
O
N
Compounds
R
Human recombinant H3R [125I]-IPX bindinga Ki (nM)
Native mouse H3R (brain cortex) [125I]-IPX bindingb Ki (nM)
1
22.7 2.5
nd
OH
OH
2
3
4
6.8 1.9
8.6 3.1
6.9 2.1
nd
OH
OH
18 2.0
nd
(continued on next page)

2552
O. Labeeuw et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2548–2554
Table 1 (continued)
Compounds
R
Human recombinant H3R [125I]-IPX bindinga Ki (nM)
Native mouse H3R (brain cortex) [125I]-IPX bindingb Ki (nM)
OH
OH
5
6
1.4 0.19
14 4.0
0.74 0.16
0.54 0.05
2.5 0.60
OH
7
4.3 1.0
OH
OH
8
9
18 10
nd
0.82 0.12
7.6 1.2
OH
OH
OH
10
11
3.9 0.39
4.1 0.60
nd
nd
O
12
13
2.9 0.41
13 3.9
nd
nd
OH
O
nd: Non-determinated.
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
Binding data for human and mouse H3 receptors for compounds 14–20
R
O
N
Compounds
R
Human recombinant H3R [125I]-IPX bindinga Ki (nM)
Native mouse H3R (brain cortex) [125I]-IPX bindingb Ki (nM)
OH
OH
14
32 0.84
nd
15
16
3.3 0.11
4.0 1.7
nd
nd
OH
17
18
15 3.0
19 3.6
nd
nd
OH
OH
OH
19
2.6 0.22
6.9 1.4
20
1.9 0.25
6.3 2.4
OH
cis/trans mixture
nd: Non-determinated.
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

O. Labeeuw et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2548–2554
2553
Figure 4. Detail of the binding mode of compound 10 (a), BP1.3432 (b) and 19 (c). The binding site is represented by its electrostatic potential on the Connoly surface. The
binding mode is similar to that described for BF2.649.19
8–13, conformational effects also modulate H3R binding. In such a
hydrophobic environment the hydroxyl function would deeply
7000
penalize the affinity. However molecular modeling suggests that
6000
an H-bond interaction with Tyr_374 (see compound 10, Fig. 4a)
compensates the desolvation penalty.19 Again the reduced activity
5000
of compound 13 versus 12 may result from an important cost of
Plasma AUC = 4975 ng/mL*h
4000
AUC00--88hh = 18028 ng/mL*h
desolvation, a phenomenon possibly counterbalanced in tetrahy-
dropyran 11 by a supplementary H-bond interaction with Asn_195.
In the second series of compounds, position of the hydroxyl func-
tion clearly affects human H3R binding affinities (Table 2). Whereas
alcohols 15 and 16 maintain the H-bonding with Tyr_374, shorter
phenethyl alcohol 14 or more rigid acetylenic 17 and 18 loose the
interaction and displayed a 5 to 10-fold loss of affinity. In the case
of cyclohexanols 19 and 20 which exhibited nanomolar range affin-
ities, molecular modeling suggests a H-bond interaction with
Asn_195 and/or with Glu_191 (Fig. 4c). The morpholine BP1.3432
interacts with the same amino acid Glu_191 through a salt bridge
and a supplementary H-bond with Tyr_189 (Fig. 4b).
Brain
3000
2000
1000
0
T1/2 = 2.6 h
0
2
4
6
8
Time (hours)
Figure 5. Pharmacokinetic profile of compound 19 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).
The most promising compounds (6, 9, 19 and 20) were then fur-
ther evaluated in regard to their pharmacokinetic profiles. Only
cyclohexanol 19 proved to achieve a satisfactory oral absorption
and brain penetration (Fig. 5): like reference compound
BP1.3432 it retained a favorable brain/plasma ratio (3.6) adequate
for a CNS indication. Interestingly our pharmacokinetic hypothesis
is confirmed, and the molecule exhibited the expected shortened
half-life (T1/2 = 2.6 h).
In vivo H3R activity of compound 19 was evaluated in mice
(Fig. 6) by following the release of brain histamine via the
Table 3
In vitro cytochrome P450 inhibition and hERG binding assays of compound 19
Cytochrome P450 inhibitiona IC50
(l
M)
hERG bindingb Ki (
lM)
3A4
30.3
2D6
2C9
>100
40.3
5.8 0.94
a
IC50 values are the mean of at least two experiments performed in triplicate.
Incubation of selected compounds was carried out at 37 0.5 °C under agitation in
the presence of human recombinant cytochrome P450 isoforms, CYP isoform-
selective fluorescent substrates and a NADPH generating system.
Figure 6. Dose-effect curve of compound 19 (BP1.4160) on N-tele-methylhista-
mine brain levels. Determination by enzymoimmunoassay, 90 min after per os
administration of compound to at least 6 male Swiss mice per dose tested. ED50 is
provided as mean SEM.
b
Ki value is the mean of four experiments (in duplicate). Mean SEM is reported.

2554
O. Labeeuw et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2548–2554
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This molecule demonstrated full inverse agonism (i.a. = 1.0, de-
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(only 1.3 mg/kg for dibasic BP1.3432).
These results being particularly promising, the compound was
evaluated against usual antitargets to further assess its potential
as future new chemical entity. Cyclohexanol 19 exhibited no signif-
icant interaction with the hERG channel and cytochrome P450 3A4,
2D6 and 2C9 (Table 3).
In summary, we successfully introduced a hydroxyl moiety into
potent histamine H3 receptor ligands as a pharmacokinetics mod-
ulator. As demonstrated with compound BP1.4160 (compound 19),
the introduction of an alcohol function allowed to reach nanomolar
binding affinity, in addition to a favorable pharmacokinetic profile
with reduced half-live. Surprisingly this cyclohexanol group also
improved bioavailability and in vivo efficiency in comparison to
reference compound BP1.3432. Additional regulatory toxicology
and safety pharmacology studies are needed to support further
development of this promising clinical candidate.
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Acknowledgments
The authors gratefully acknowledge Stéphanie Le Meur, Isabelle
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Supplementary data
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Anglade, V.; La Rochelle, C. D.; d’Aniello, F.; Rouleau, A.; Gbahou, F.; Arrang, J.
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19. Levoin, N.; Calmels, T.; Poupardin-Olivier, O.; Labeeuw, O.; Danvy, D.; Robert,
P.; Berrebi-Bertrand, I.; Ganellin, C. R.; Schunack, W.; Stark, H.; Capet, M. Arch.
Pharm. 2008, 341, 610. The use of more recent GPCR templates, particularly
crystal structure of H1R, did not improve the accuracy of our H3R model (Levoin
et al., submitted manuscript).
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2013.02.
118. These data include MOL files and InChiKeys of the most
important compounds described in this article.
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