Lead Optimization of Thiazolo[5,4-c]piperidines: 3-Cyclobutoxy Linker as a Key Spacer for H3R Inverse Agonists

Full text of DOI:10.1002/cmdc.201200406

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DOI: 10.1002/cmdc.201200406
Lead Optimization of Thiazolo[5,4-c]piperidines: 3-Cyclobutoxy Linker as
a Key Spacer for H3R Inverse Agonists
Laurent Provins,* Frꢀdꢀric Denonne, Sylvain Cꢀlanire, Bernard Christophe, Sabine Defays, Christel Delaunoy,
Marie-Laure Delporte, Thierry Demaude, Vꢀronique Durieu, Michel Gillard, Delphine Hubert, Yves Lamberty,
Geneviꢁve Lorent, Anne Valade, Alain Vanbellinghen, and Nathalie Van houtvin[a]
In memory of Dr. Frꢀdꢀric Denonne
The H3 histamine receptor (H3R) is a G protein-coupled recep-
tor (GPCR) mainly expressed in the central nervous system
(CNS) and a key modulatory site for several neurotransmitters.
It acts as an autoreceptor on histaminergic neurons, inhibiting
the release and synthesis of histamine, but it is also present as
a heteroreceptor on other non-histaminergic neurons, where it
modulates the release of neurotransmitters such as acetylcho-
line, dopamine or norepinephrine. It is known that histamine
and acetylcholine release is increased following the blockade
of the H3R by inverse agonists, and this is thought to be key
for cognition, wakefulness and vigilance as demonstrated by
results obtained in several preclinical animal models.[1]
lar, rigidified thiazolo[5,4-c]piperidines, as exemplified by com-
pound 3, displayed very attractive overall profiles with good
pharmacokinetic properties as well as high efficacy in the
novel object recognition paradigm, although still suffering
from some interaction with the hERG channel (hERG IC50 =
6.3 mm). The introduction of more polar substituents to replace
the N-acetamide proved to be successful as far as hERG activity
was concerned, however, the membrane permeability proper-
ties were also dramatically decreased.[6]
In order to maintain the desirable aspects of the properties
profile of that series and to take advantage of the remarkable
homogeneity of its structure–activity relationships, we felt that
optimization of the substitution on the piperidine ring nitro-
gen combined with rigidification of the 3-propoxy linker could
be beneficial for decreasing interaction with hERG while main-
taining acceptable permeability. To that end, we thought that
use of a trans-3-cyclobutoxy motif as a linker to introduce ri-
gidity could be of particular interest thanks to its compact
nature and stereochemistry allowing directional fine-tuning of
the substituents. Indeed, as previously reported,[7] this particu-
lar constraint, and contrary to its cis stereoisomer, led to signifi-
cant increases in H3R affinities in several examples in the oxa-
zoline and oxazole series and emerged as a versatile and at-
tractive linker for H3R ligands.
Over the last few years, H3R has attracted the interest of sev-
eral pharmaceutical companies as a therapeutic target in a vari-
ety of therapeutic indications. However, cognitive disorders
such as Alzheimer’s disease, and somnolence disorders, for ex-
ample narcolepsy or excessive daytime sleepiness, have been
the two most studied in clinical development.[2,3]
During our medicinal chemistry investigations, we identified
several families of ligands with nanomolar affinities for the H3R.
These ligands were based on oxazoline (e.g., 1),[4] oxazole/thia-
zole (e.g., 2)[5] or bicyclic thiazole (e.g., 3)[6] scaffolds. In particu-
Therefore, we prepared a series of phenyl thiazolo[5,4-c]pi-
peridines derivatives bearing the 3-cyclobutoxy linker with a pi-
peridine as the basic moiety.[8] The cis-3-piperidin-4-ylcyclobu-
tyl 4-methylbenzenesulfonate (7) was obtained according to
a previously reported methodology[7,8] starting from 1,3-cyclo-
butanedione 4, as its dicyclohexylammonium salt (Scheme 1).
Liberation of the parent dione with trifluoroacetic acid and
subsequent stirring with piperidine afforded enaminone 5,
which is reduced with sodium borohydride then treated with
p-toluenesulfonyl chloride to give the tosylate 7. Phenol 10
was obtained by a condensation reaction between commer-
cially available 4-hydroxythiobenzamide and tert-butyloxycar-
bonyl (Boc)-protected 3-bromopiperidine-4-one (9), prepared
by bromination of 8 (Scheme 2). Treatment of 10 with sodium
hydride and then with cis-3-piperidin-4-ylcyclobutyl-4-methyl-
benzenesulfonate (7) afforded compound 11 in good yield. De-
protection with trifluoroacetic acid (TFA) gave rise to amine 12,
which could be further derivatized into various phenyl
thiazolo[5,4-c]piperidines 13–19 bearing polar substitution on
the nitrogen atom (Scheme 2).
[a] Dr. L. Provins, Dr. F. Denonne, Dr. S. Cꢀlanire,+ Dr. B. Christophe, S. Defays,
C. Delaunoy, Dr. M.-L. Delporte,++ T. Demaude, V. Durieu, Dr. M. Gillard,
D. Hubert, Dr. Y. Lamberty, Dr. G. Lorent, Dr. A. Valade, A. Vanbellinghen,
N. Van houtvin
UCB NewMedicines, UCB Pharma
Chemin du Foriest, 1420 Braine-L’Alleud (Belgium)
E-mail: laurent.provins@ucb.com
[+] Current address: Addex Therapeutics, Geneva (Switzerland)
++] Current address: Novartis Pharma AG, Basel (Switzerland)
In order to allow comparisons with the results obtained in
the thiazolo[5,4-c]piperidine series bearing a propoxy linker,[6]
[
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poxy series of derivatives.[6] Interestingly, compound 13
showed a threefold lower hERG activity than its propoxy coun-
terpart 3 (20 versus 6.3 mm, respectively), confirming that cy-
clobutyl rigidification has an effect on its own.
A combination of polar substituents, in particular those
bearing hydrogen-bond donors, on the bicycle moiety and ri-
gidification of the linker proved to be quite a successful strat-
egy to decrease hERG interaction, however, the issue of brain
receptor occupancies remained questionable. Therefore, we
decided to evaluate the potential for brain penetration by per-
forming ex vivo binding experiments in rats. In vitro binding of
[3H]-N-a-methylhistamine was measured in rat cortex homoge-
nates prepared one hour after intraperitoneal (i.p.) administra-
tion of the compounds.
We then compared the brain receptor occupancy data ob-
tained for compounds in both the propoxy[6] and cyclobutoxy
linker series (Table 2). Despite the presence of polar groups
and numerous hydrogen-bond donors and acceptors, most
compounds bearing a cyclobutoxy linker, with the exception
of the malonamide derivative (15), successfully occupy rat
brain H3R at low dose one hour after administration. The same
trend is observed three hours after administration. Further-
more, brain receptor occupancies are significantly improved
compared with the analogues in the propoxy linker series[6] de-
spite similar affinities for H3R. The behavior of cyclobutoxy de-
rivatives might be rationalized by combining a significant in-
crease in LogD (close to 1log unit in all cases) due to the addi-
tional methylene bridge, together with a decrease in the
number of rotatable bonds.
Scheme 1. Reagents and conditions: a) TFA, dioxane, 208C, 4 h, then piperi-
dine, 208C, 20 min (66%); b) NaBH4, EtOH, 508C, 12 h (78%); c) TsCl, N-meth-
ylimidazole, AcOEt, 208C, 48 h (55%).
we selected a few polar substituents bearing either hydrogen-
bond donors or acceptors. As anticipated from previous re-
sults, all compounds from this series were characterized by
high H3R affinity, which is compatible with polar substitution
on the fused thiazole ring, and high selectivity for H3R over
more than 70 other targets, determined using a Cerep panel
(Table 1). All compounds showed favorable solubility and lipo-
philicity profiles (Table 1), although LogD values were in-
creased compared with analogous compounds containing an
acyclic linker.[6] In vitro intestinal permeability (Papps), deter-
mined in a Caco-2 cell-based assay, was nevertheless signifi-
cantly increased in all cases and no P-glycoprotein (P-gp)-
mediated efflux was detected.
Several very interesting compounds, in particular acetamide
13 and urea 19 displaying the best overall properties, were
therefore identified for further profiling.
As far as the interaction with the hERG channel is concerned,
all compounds tested, with the exception of 18, displayed
much lower activity against hERG (IC50 >30 mm for most com-
pounds) therefore confirming the data obtained with the pro-
However, we first wondered whether the advantages offered
by the cyclobutoxy linker in terms of improved brain penetra-
tion and decreased hERG activity could be translated to other
series, in particular to lower molecular weight scaffolds.
Scheme 2. Reagents and conditions: a) Br2, CHCl3, RT, 12 h (82%); b) 4-hydroxythiobenzamide, iPrOH, 608C, 2 h (40%); c) NaH, DMF, RT, 30 min, then 7, 808C,
7 d (64%); d) TFA, CH2Cl2, RT, 2 h (83%); e) AcCl, NEt3, CH2Cl2, RT, 3 h (54%, 13); f) HOCH2CO2H, N-hydroxybenzotriazole (HOBt), 1-ethyl-3-(3-dimethylaminopro-
pyl)carbodiimide (EDCI), 4-dimethylaminopyridine (DMAP), CH2Cl2, 208C, 30 min (30%, 14); g) 1. ClC(O)CH2CO2Me, Et3N, CH2Cl2, RT, 12 h; 2. NH3, MeOH, 908C,
20 h (17%, two steps, 15); h) 1. BocNHCH2CO2H, HOBt, EDCI, DMAP, CH2Cl2, 208C, 12 h; 2. TFA, CH2Cl2, RT, 12 h (10%, two steps, 16); i) (2R)-3-chloropropane-
1,3-diol, K2CO3, NaI, MeCN, 808C, 54 h (21%, 17); j) triphosgene, morpholine, NEt3, CH2Cl2, RT, 1 h (46%, 18); k) TMS-NCO, CH2Cl2, RT, 12 h (36%, 19).
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Table 1. In vitro properties of thiazolo[5,4-c]piperidines 13–19.
Compd
Structure
H3R pKi[a]
hERG IC50
[mm][b]
LogD[c]
S[d]
[mgmLÀ1
Clint[e] (h/r)
[mLminÀ1 mgÀ1 protein]
Papps[f]
]
[nmsÀ1
]
13
14
8.7Æ0.1
8.9Æ0.1
20
2.55
1.92
0.1
7/3
1/1
114
>30
0.06
183
49
15
8.6Æ0.0
>30
1.48
0.2
1/1
16
17
9.0Æ0.1
8.9Æ0.1
>30
>30
2.06
1.63
NT
0.3
1/9
86
88
1/50
18
8.5Æ0.3
3.7
2.54
0.2
16/10
121
19
8.6Æ0.1
>30
2.33
0.1
1/1
87
[a] H3R binding affinities (pKi) were assessed by competition with [3H]-N-a-methylhistamine in CHO cell membranes expressing human H3R; [3H]-N-a-meth-
ylhistamine: Kd =0.4 nm; assay concentration: 0.2 nm; thioperamide: pKi =6.82Æ0.13 (n>75); results are the mean of 2–6 experiments, when only two ex-
periments were performed, measurements were within 0.2 log units of each other. [b] hERG assay was performed on HEK293 cells transfected with the
hERG potassium channel. Cells were incubated for 5 min with test compound at 0.1, 1, 10 and 30 mm in water with up to 0.3% DMSO (n=3 per cell per
concentration). The potassium current was recorded while stimulating the cells every 15 s. [c] LogD was determined at pH 7.4. [d] Solubility (S) at pH 7.4
[e] Human (h) and rat (r) intrinsic metabolic clearance (Clint) measured from parent drug disappearance following incubation with liver microsomes.
[f] Apical-to-basolateral permeability (Papps) determined in Caco-2 cell-based assay.
Indeed, although the thiazolo[5,4-c]piperidines look very prom-
ising considering their overall profile, both their molecular
weight (>400) as well as their lipophilicity (LogD ~2–2.5) are
still on the high side. As a consequence, their lipophilic ligand
efficiency (LLE)[9] values have decreased compared with their
propoxy counterparts. Several options were offered to us but
we decided to first explore the simplest one: keeping the basic
moiety, the cyclobutoxy linker, and the phenyl ring, considered
as the minimal recognition elements, but dramatically simplify-
ing the right-hand part of the molecule and removing the het-
erocyclic system, only maintaining a small amide group con-
nected to the aromatic part (Scheme 3).
Scheme 3. Retrosynthetic rationale for the synthesis of cyclobutoxy benza-
mides.
Benzamides bearing propoxy linkers have been previously
reported,[10] and these analogues are known to suffer from lim-
ited penetration of the blood–brain barrier. In order to assess
the properties of these compounds and to evaluate their po-
tential before starting more extensive profiling, we performed
a quick amine scan. Benzamides were prepared by amino-car-
bonylation of 1-[trans-3-(4-iodophenoxy)cyclobutyl]piperidine
(27), obtained by condensation between 4-iodophenol 26 and
tosylate 7 under microwave irradiation (Scheme 4).[11] Molyb-
dene hexacarbonyl was used in combination with 1,8-diazabi-
cycloundec-7-ene (DBU) to easily obtain the required carbon
monoxide pressure (~5 bars) in the reaction tube.[12]
We first focused on a set of small cyclic amines in order to
keep lipophilicity in check. All compounds prepared displayed
high H3R affinities (Table 3). Surprisingly, and contrary to other
series, the selectivity for H3 over s1 was somewhat decreased
for some compounds, especially for the most lipophilic deriva-
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We also explored the possibility of replacing the piperidine
ring on the cyclobutyl linker by a 2-methylpyrrolidine—a basic
moiety often seen in the literature[4]—to significantly increase
H3R affinities. For that purpose, we prepared analogues of
compound 29 bearing either a (R)- or (S)-2-methylpyrrolidine
moiety, according to the synthetic routes described in
Schemes 1 and 4. In this case, formation of the enaminone and
the subsequent reduction were much slower, and poor overall
yields were obtained. However, to our surprise, it appeared
that the compound prepared from (S)-2-methylpyrrolidine was
the most potent enantiomer (pKi =9.1Æ0.1). This is in contrast
to what was observed in all other propoxy linker series, where
the (R)-enantiomer was always the more potent. Given the rel-
atively tedious nature of the linker synthesis, these compounds
were not investigated further.
Table 2. Receptor occupancy (%) in rat cortex 1 h and 3 h after i.p. ad-
ministration (1 mgkgÀ1).[a]
R
Compd
1 h
77
3 h
Compd
1 h
93
3 h
89
3
NM
13
21
22
70
20
50
14
14
15
94
27
89
4
From that initial set of amides, we decided to select mor-
pholinamide 29 as a promising compound deserving some fur-
ther in vitro and in vivo profiling due to its well-balanced pre-
liminary properties: In particular, its selectivity, low lipophilicity
but rather good in vitro permeability, and high solubility (in
water or phosphate-buffered saline (PBS) buffer at pH 7.4). The
properties of compound 29 were compared with those of
compounds 13 and 19, the two selected thiazolo[5,4-c]piperi-
dines offering the best overall profile.
23
24
55
15
80
38
16
17
91
94
92
94
25
54
42
18
88
94
The inverse agonistic profiles of compounds 13, 19 and 29
were confirmed in a GTPgS assay (inhibition of basal constitu-
tive activity: pIC50 =9.2, 9.2 and 9.4, respectively; thioperamide
pIC50 =7.0; see Figure 1 for compound 29) and in assays with
[a] All experiments were approved by the local ethics committee for
animal experimentation according to Belgian law.
Scheme 4. Reagents and conditions: a) NaH, N,N-dimethylacetamide, RT,
30 min, then 7, 808C, 12 h (69%); b) R1R2NH, Mo(CO)6, DBU, THF, Pd(OAc)2,
mw (400 W), 1008C, 20 min (16–74%).For R groups, see Table 3.
~
)
*
Figure 1. Inverse agonist profile of compound 29 ( ), with thioperamide (
!
and histamine ( ) shown for comparison. Assay was performed in CHO cells
expressing the hH3 histamine receptors.
tives, such as compounds 28, 31 or 37. Polar groups were
therefore preferred to ensure both s1 and hERG affinities were
kept to a minimum while maintaining the basic center needed
for H3 affinity. In vitro drug metabolism and pharmacokinetic
(DMPK) properties indicated that some of the most polar com-
pounds, as could have been anticipated, displayed very low
microsomal clearance but exhibited decreased Caco-2 permea-
tion, with values of around 30 nmsÀ1 (see compounds 32, 38
and 39). The solubilities of these compounds were also much
higher than in the case of thiazolo[5,4-c]piperidines.
electrically stimulated guinea pig myenteric plexus (pA2 =9.8,
9.7 and 8.9, respectively). All three compounds displayed at
least a 100-fold selectivity for H3R over more than 70 targets
screened during profiling by Cerep. No detectable interaction
with major CYP450 isoforms was observed. In vivo H3R recep-
tor occupancies were estimated, as mentioned earlier, by
ex vivo binding experiments in rat brain homogenates after
oral (p.o.) administration. Observed IC50 values of 0.68, 2.55
and 0.86 mmolkgÀ were obtained for 13, 19 and 29, respective-
ly. These results confirmed that compounds 13 and 29 could
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Table 3. In vitro properties of benzamides 28–39.
Compd
NR1R2
H3R pKi[a]
s1 pKi[b]
hERG IC50
[mm][c]
LogD[d]
S[e]
[mgmLÀ1
Clint[f] (h/r)
[mLminÀ1 mgÀ1 protein]
Papps[g]
]
[nmsÀ1
]
28
29
30
8.9Æ0.1
8.4Æ0.1
8.9Æ0.2
7.6Æ0.2
6.4Æ0.1
7.1Æ0.1
>30
>30
NT
1.83
0.66
1.50
1.3
>1.5
0.7
0/23
1/7
NT
166
114
NT
31
32
8.6Æ0.1
8.5Æ0.1
7.7Æ0.1
17
1.68
0.58
0.5
1.2
0/1
2/0
126
27
47%
>30
33
34
35
8.8Æ0.2
8.1Æ0.1
8.8Æ0.1
54%
>30
NT
0.93
0.54
1.32
>1.5
>1.5
NT
NT
5/15
4/4
NT
60
5.3Æ0.1
6.8Æ0.1
>30
267
36
8.6Æ0.1
7.3Æ0.0
NT
1.47
1.4
4/3
353
37
38
39
7.5Æ0.1
8.1Æ0.1
8.5Æ0.1
7.2Æ0.1
5.4Æ0.1
18%
NT
NT
NT
1.94
0.10
0.23
1.1
1.3
1.3
2/5
3/0
0/0
241
35
26
[a, c–g] For details, see the appropriate footnote in Table 1. [b] s1 receptor binding affinities are expressed as the pKi values, except for compounds 32, 33
and 39, where the % inhibition at 10 mm is given. Binding affinities were assessed by competition with [3H]-(+)-pentazocine in CHO cell membranes ex-
pressing human s1 receptors. [3H]-(+)-pentazocine: Kd =37Æ21 nm (n=7); assay concentration: 1–2 nm; haloperidol: pKi =8.3Æ0.2 (n>126); results are
the mean of 2–3 experiments, when only two experiments were performed, measurements were within 0.2 log units of each other.
Table 4. In vivo pharmacokinetic data for compounds 13, 19 and 29.[a]
successfully occupy brain H3R at sub-micromolar concentra-
tions, whereas urea 19 requires higher doses to reach similar
exposures.
Compd
Cl[b] [mLminÀ1 kgÀ1
]
Vss[c] [LkgÀ1
]
t1/2[d] [h]
F[e] [%]
13
19
29
20
12
47
7.1
4.1
5.5
4.8
4.5
2.0
90
94
51
The in vivo pharmacokinetic profiles of the three com-
pounds (13, 19 and 29) were determined in male Wistar rat
after single oral and intravenous (i.v.) dosing (Table 4), and the
results were in agreement with their in vitro properties. For
compounds from the thiazolo[5,4-c]piperidine family (13 and
19), medium terminal half-life values (t1/2) and low total plasma
clearances (Cl) were observed, in accordance with the high
metabolic stability determined in vitro in both rat liver micro-
somes and hepatocytes, as well as very good oral bioavailabil-
ity values (F>90%). Amide 29 behaved differently and dis-
played a moderate total plasma clearance as well as lower but
acceptable oral bioavailability and a shorter half-life (Table 4).
Importantly, given the reported modulation of H3R on sleep–
wake cycles, it was considered key to avoid any negative effect
on the fragile sleep pattern of Alzheimer’s disease patients
that long-acting compounds could likely have. The shorter
half-life of compound 29 was confirmed in the Beagle dog (i.v.
[a] Parameters obtained after single p.o. (at 3, 6 and 1.5 mgkgÀ1 for 13,
19 and 29, respectively) and i.v. (at 1 mgkgÀ1) dosing to male Wistar rats
(n=2). All experiments were approved by the local ethics committee for
animal experimentation according to Belgian law. [b] Total plasma clear-
ance (Cl). [c] Volume of distribution (Vss). [d] Half-life (t1/2). [e] Oral bioavail-
ability (F).
dosing at 1 mgkgÀ1, t1/2 =1.7 h, compared with 9 h and 14 h
for 13 and 19, respectively).
Following this initial profiling, we considered that com-
pound 29 displayed the best overall profile compared with
thiazolo[5,4-c]piperidines 13 and 19. In particular, the lower lip-
ophilicity and higher solubility of 29, and its adequate biologi-
cal and DMPK properties, including its shorter half-life and
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therefore potentially shorter duration of action, led us to nomi-
nate 29 for advanced preclinical profiling including evaluation
in animal models of cognitive disorders, as well as toxicological
evaluations in rodents and nonrodents. Those results will be
published in due course.
Keywords: benzamides · cognitive disorders · histamine H3
receptors · structure–activity relationships · thiazoles
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In conclusion, the optimization of the thiazolo[5,4-c]piperi-
dine lead compounds allowed us to rapidly solve the issues re-
lated to hERG activity and brain receptor occupancy by rigidifi-
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feature, thanks to a slightly higher lipophilicity and a decreased
number of rotatable bonds, rendered the substitution of the
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properties of the cyclobutoxy linker by revisiting and simplify-
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Three lead compounds from both series were profiled and
compared head-to-head. Compound 29 was ultimately identi-
fied as the most promising preclinical candidate, exhibiting the
overall best profile for progression towards clinical studies.
Acknowledgements
The authors would like to thank Dr. L. Quꢀrꢀ, Dr. B. Mathieu, Mrs.
G. Longfils, Mrs. A. Descamps and Mrs. L. Ellens for lipophilicity
and solubility measurements, Dr. V. Pinilla and her team for chro-
matographic purifications, Dr. R. Dieden, Mr. A. Fauconnier, Mr. J.
Claessens, and Mrs. C. Derwa for analytical assistance, Mr. P. Col-
lart for in vitro pharmacokinetic measurements, and Dr. D. Har-
ding for cardiac safety assessment. The authors are most grateful
to Dr. C. Audouin and Dr. C. Gꢀnicot for their valuable comments
in the preparation of this manuscript. This work was financed in
part by the Walloon Region (Belgium) under convention no.
5650.
˝
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Received: September 5, 2012
Published online on October 5, 2012
2092
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