Acetamide scanning around bicyclic thiazoles: SAR at the H3 receptor

Full text of DOI:10.1002/cmdc.201100248

DOI: 10.1002/cmdc.201100248
Acetamide Scanning around Bicyclic Thiazoles: SAR at the H3 Receptor
Frꢀdꢀric Denonne†,[a] Sylvain Cꢀlanire,[a, b] Bernard Christophe,[a] Sabine Defays,[a] Christel Delaunoy,[a] Marie-
Laure Delporte,[a, c] Eric Detrait,[a] Vꢀronique Durieu,[a] Michel Gillard,[a] Yves Lamberty,[a] Geneviꢁve Lorent,[a]
Jean-Marie Nicolas,[a] Alain Vanbellinghen,[a] Nathalie Van Houtvin,[a] and Laurent Provins*[a]
The third histamine receptor (H3R) is expressed mainly in the
central nervous system (CNS) and regulates the release of nu-
merous other neurotransmitters. It is highly interesting as a
target for the control of CNS disorders such as excessive day-
time sleepiness and cognitive disorders such as Alzheimer’s
disease.[1] In our medicinal chemistry investigations around this
receptor, we have identified nanomolar-affinity ligands based
on a phenyloxazole scaffold (Figure 1).[2] We noticed that affini-
ty increased between isomers I and II. Starting from thiazole
III, we embarked on a systematic comparison of rigid bicyclic
thiazoles bearing the N-acetyl side chain in all orientations in
an attempt to identify the isomer with the best properties.
This isomer was then used to further explore the structure–
activity relationships (SAR).
for the synthesis of most thiazoles, there are only two reports
of its application to a-bromoimides, and this only with the
more reactive thioureas.[4] We also developed a novel access to
N-unsubstituted thiazolo[4,5-c]piperidine F by reduction of the
corresponding pyridine in the presence of acetyl chloride and
sodium borohydride [Scheme 1, Eq. (2)]. This procedure greatly
simplifies the conventional procedure,[5] which relies on reduc-
tion of an N-methylpyridinium group, leaving a piperidine ni-
trogen, which is difficult to functionalize. For thiazolo[5,4-
b]azepine G, it was more expeditious to perform the cyclocon-
densation in two steps by first forming an amide with a-ami-
nocaprolactam followed by a cyclization mediated by Lawes-
son’s reagent [Scheme 1, Eq. (3)].[6]
Thiobenzamide 3, required for the Hantzsch con-
densation, was obtained by alkylation of commercially
available 4-hydroxybenzamide with 3-chloro-1-bromo-
propane, followed by thionation with Lawesson’s re-
agent (Scheme 2). Displacement of the terminal chlo-
ride finally gave 4.[7]
5-Acetamidocyclopentathiazole 16 was obtained
from bromoketo ester 10 obtained from cyclopen-
tene 7, itself resulting from the condensation of 1,4-
dichlorobutene and dimethyl malonate (Scheme 3).
Hydrobromination of 8 and oxidation of 9 occurred
smoothly, as well as the subsequent Curtius rear-
rangement of 12. The use of this rearrangement to
introduce the amino group was particularly useful to
introduce the required amine, as 2-bromocyclopen-
tane-1,4-dione would not lend itself to the Hantzsch
Figure 1. Nanomolar-affinity H3R ligands I, II, and III based on a phenyloxazole scaffold.
condensation.
Our primary strategy to prepare these heterocycles relies on
the Hantzsch condensation of an a-bromocarbonyl compound
with a thiobenzamide [Scheme 1, Eq. (1)].[3] This strategy has
been applied for the synthesis of thiazolotetrahydropyridines A
and C, thiazolopyrroline B, thiazoloazepine D, and thiazolocy-
clopentanes E. Although this methodology is well established
[a] Dr. F. Denonne, Dr. S. Cꢀlanire, Dr. B. Christophe, S. Defays, C. Delaunoy,
Dr. M.-L. Delporte, Dr. E. Detrait, V. Durieu, Dr. M. Gillard, Dr. Y. Lamberty,
Dr. G. Lorent, J.-M. Nicolas, A. Vanbellinghen, N. Van Houtvin, Dr. L. Provins
UCB New Medicines
Chemin du Foriest, 1420 Braine-L’Alleud (Belgium)
E-mail: Laurent.Provins@ucb.com
[b] Dr. S. Cꢀlanire
Addex Pharmaceuticals
12 Chemin des Aulx, 1228 Plan-les-Ouates, Geneva (Switzerland)
[c] Dr. M.-L. Delporte
Novartis AG, Lichtstrasse 35, 4056 Basel (Switzerland)
Scheme 1. Heterocyclic systems studied herein and their retrosynthetic anal-
[†] Deceased July 7th, 2011.
ysis.
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peridine afforded the desired product in good yield
(Scheme 5).
The isomeric thiazolo[4,5-c]piperidine 36 could not be made
in the same fashion, as bromination of protected 3-piperidones
remained unsuccessful. For this substitution pattern, we relied
on the reduction of the corresponding thiazolopyridine 31
(Scheme 6). It could be obtained from the cyclization of 3-
amino-4-chlorobenzamide 30 in the presence of Lawesson’s re-
agent.[9] Reduction of the pyridine ring was not straightfor-
ward. It had been first envisaged to reduce methylpyridinium
32 into piperidine 33 and demethylate the piperidine after-
ward. Although the reduction
Scheme 2. Reagents and conditions: a) Br(CH2)3Cl, K2CO3, MeCOEt, reflux, 24 h
(95%); b) Lawesson’s reagent, CHCl3, 228C, 12 h, (88%); c) 2-methylpyrroli-
dine, K2CO3, NaI (cat.), CH3CN, 908C, 20 h (50%).
works, we have remained unsuc-
cessful in our demethylation at-
tempts. We finally found that in-
termediate activation of the pyri-
dine through a putative acyl–
pyridinium species allowed hy-
dride-mediated reduction of the
ring system. It was later found
on a similar system that the pyri-
dine ring could be efficiently re-
duced with Adam’s catalyst[10]
under hydrogen (50 bar).
We used a similar approach to
obtain the isomeric [5,4-b] ring
system, but all attempts were
unsuccessful. In view of the low
stability of this system, we
switched to the larger homo-
Scheme 3. Reagents and conditions: a) LiH, DMF, 208C, 64 h, (86%); b) KOH, EtOH/H2O, reflux, 1 h, (67%); c) 1808C,
neat, 1 h, (93%); d) SOCl2, MeOH, ꢀ70!08C, 1 h, (65%); e) NBS, CaCO3, CH3CN/H2O, 208C, 4 h, (90%); f) Dess–
Martin, CH2Cl2, 208C, 48 h, (83%); g) 3, EtOH, reflux, 12 h, (90%); h) LiOH, THF/H2O, 208C, 12 h, (93%); i) DPPA,
Et3N, PhMe, 208C, 12 h, then BnOH, reflux, 24 h, (90%); j) 2-methylpyrrolidine, K2CO3, NaI, CH3CN, 908C, 1 h,
(37%); k) 5n aq. HCl, reflux, 1.5 h, (100%); l) AcCl, Et3N, CH2Cl2, 208C, 2.5 h, (51%).
logue to obtain the required
isomer. It was obtained through
the cyclization of bis-amide 38
with
Lawesson’s
reagent
(Scheme 7). The resulting bicycle
Thiazolopyrroline 24 proved more difficult to obtain. Using
the same approach as above, we tried to condense the re-
quired N-acetylated cyclic bromoketone, but this one seemed
to be particularly elusive. Only para-toluenesulfonyl-protected
pyrroline 17 was amenable to the synthesis of the required a-
bromoketone (Scheme 4). In this particular case,
water elimination did not occur spontaneously
during the cyclization reaction. Fortunately, it was
possible to eliminate the hydroxy group of 20 in the
form of the methanesulfonate ester. Toluenesulfonyl
deprotection from 21 had to occur under ambient
conditions, as higher temperatures destroyed this
fragile bicycle. Finally acetylation of the secondary
amine delivered the required compound 24. This is
the first reported synthesis of this particular bicycle
using a Hantzsch condensation strategy.[8]
39 slowly degraded upon storage. It could only be kept as its
hydrochloride salt. Fortunately, the corresponding amide 40
also showed reasonable stability. Debenzylation, followed by
installation of the usual aminopropoxy chain, took place un-
eventfully to yield 43.
Thiazolo[5,4-c]piperidine 28 was the most straight-
forward to obtain. It was easily formed by condensa-
tion of thioamide 3 with tert-butoxycarbonyl (Boc)-
protected 3-bromo-4-piperidone 25 with in situ de-
protection of the secondary amine. Installation of 2-
Scheme 4. Reagents and conditions: a) NBS, DMSO/H2O/CH3CN, 208C, 2 h, (100%);
b) Dess–Martin, CH2Cl2, 208C, 2 h; c) 3, DMF, 608C, 2 h (83%); d) MsCl, Et3N, CH2Cl2, 208C,
12 h, (92%); e) p-HOPhCO2H, HBr/AcOH, 208C, 5 days (9%); f) AcCl, Et3N, CH2Cl2, 208C,
methylpyrrolidine followed by acetylation of the pi- 2 h, (55%); g) 2-methylpyrrolidine, CH3CN, 1008C, 6 h, (33%).
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Scheme 5. Reagents and conditions: a) iPrOH, 908C, 1 h, (81%); b) 2-methyl-
pyrrolidine, CH3CN, NaI, 908C, 24 h, (45%); c) AcCl, DMAP, CH2Cl2, 208C, 2 h,
(59%).
Scheme 8. Reagents and conditions: a) TCE, Br2, 1108C, 2 h, (43%); b) 4, DMF,
908C, 12 h (56%); c) BH3·DMS, THF, 208C, 12 h, (52%); d) AcCl, Et3N, CH2Cl2,
208C, 3 h, (71%).
The symmetrical thiazoloazepane 53 is prepared
by a route reminiscent of our work on thiazolocyclo-
pentane 16 (Scheme 9). The required bromoketone
50 is obtained by hydrobromination of 48 followed
by oxidation. In contrast to its equivalent 21 in the
[5.5] series, the acid-mediated detosylation of 51
worked smoothly at higher temperatures, highlight-
ing the increased stability of thiazoloazepanes.
The compounds thus obtained were tested against
H3R and profiled against their drug-like in vitro prop-
erties (Table 1). The comparison of 16 and 24 high-
lights the very small difference in binding affinity of
exo- versus endocyclic amides. This result oriented
Scheme 6. Reagents and conditions: a) NaH, 3-amino-4-chloropyridine, THF, 808C, 8 h
(38%); b) Lawesson’s reagent, PhMe, 1108C, 4 h (51%); c) MeI, DMF, 808C, 4 h (100%);
d) NaBH4, MeOH, 208C, 1 h (26%); e) 2-methylpyrrolidine, K2CO3, CH3CN, 908C, 20 h
(71%); f) AcCl, NaBH4, THF, ꢀ408C, 1 h (31%); g) AcCl, Et3N, CH2Cl2, 208C, 3 h (75%);
h) (R)-2-methylpyrrolidine, K2CO3, NaI, CH3CN, 808C, 20 h (32%).
our synthesis toward endocyclic amides, as they have
a lower hydrogen bond count and are thus likely to
show facilitated brain penetration. This also removes
one stereogenic atom and sim-
plifies the chemistry.
To our surprise, variation of
the amide position did not sig-
nificantly influence the binding
affinity of those compounds
toward H3R. The only visible
trend is that acetamides 36 and
47, placed closer to the nitrogen
atom of the thiazole, tend to
have lower affinities.
Among the endocyclic amines,
interaction with the hERG chan-
nel occurred at micromolar
levels, with the exception of 36,
which required >10 mm concen-
trations to interact. However,
this comes at the expense of
Scheme 7. Reagents and conditions: a) (COCl)2, CH2Cl2 then a-aminocaprolactam, Et3N, CH2Cl2, 208C, 1 h, (80%);
b) Lawesson’s reagent, pyridine, 1008C, 20 h, (23%); c) AcCl, Et3N, CH2Cl2, 208C, 2 h, (64%); d) BBr3 (5 equiv),
CH2Cl2, 208C, 12 h (79%); e) K2CO3, Br(CH2)3Cl, MeCOEt, reflux, 20 h, (100%); f) (R)-2-methylpyrrolidine, NaI, CH3CN,
808C, 1 h, (56%).
The [4,5-b] ring system 47 was prepared analogously to the
Hantzsch conditions, with a-bromoglutarimide in the role of
the starting a-bromocarbonyl compound (Scheme 8).[11] Bromi-
nation of glutarimide was difficult to perform reproducibly,
and the bromoimide was used immediately in the cyclization
reaction. Reduction of lactam 45 followed by acetylation finally
yielded the target compound.
membrane permeation, and the overall selectivity of H3R
versus hERG was not increased relative to 28. All compounds
showed favorable logD values, with low in vitro metabolic
clearance and good in vitro intestinal permeability.
Overall, compound 28 offered the best potential for further
investigations. It is more potent (even slightly so) than 36, 47,
and 53, has better properties than equipotent 16 and 43, and
offers an easier synthetic access than 24. Independent synthe-
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sis of the two enantiomers confirmed that the R isomer offers
superior affinity toward H3R, as was already the case in the
monocyclic thiazoles and oxazoles.[2] This isomer was used to
further explore the SAR, with a focus on polar substituents to
decrease hERG affinity. A series of thiazolopiperidines with
polar side chains was thus prepared by starting from inter-
mediate (R)-27 (Scheme 10).
As is apparent from Table 2, introduction of polar substitu-
ents on the fused thiazole ring is compatible with H3R affinity.
For compounds 55 and 57, the slight increase in polarity
allowed a decrease in hERG affinity. However, this was not the
case with the other examples. This can be attributed to the ex-
tensive aromatic surface of those compounds, which, in combi-
Scheme 9. Reagents and conditions: a) NBS, DMSO/H2O, 208C, 60 h, (100%);
b) Dess–Martin, CH2Cl2, 208C, 20 h, (75%); c) 4, EtOH, 658C, 65 h, (74%);
d) HBr, PhOMe, 1008C, 48 h, (81%); e) AcCl, Et3N, CH2Cl2, 208C, 1 h, (55%).
Table 1. In vitro properties of tested compounds.[a]
[e]
[g]
Compd
H3 Ki [nm][b]
hERG IC50 [mm][c]
logD[d]
S [mgmLꢀ1
]
CLint (H/R)[f]
Papps [nmsꢀ1
]
16
2.0ꢁ0.9
1.6ꢁ0.6
1.5
0.4
24
28
1.1
1.3
>1.5
1/4
1/1
118
216
2.0ꢁ0.6
(R) 1.00ꢁ0.4
(S) 10.0ꢁ0.8
6.3
1.3
36
43
47
(R) 5.0ꢁ0.2
(R) 1.6
15.8
1.5
2.0
2.2
>1.4
1.4
1/5
60
5.0
8/27
153
5.0
1.4
53
4.0ꢁ0.5
5.0
1.4
1.3
1/4
112
[a] Unless otherwise indicated, the data reported refer to racemates. [b] H3R binding affinities were assessed by displacement of [3H]N-a-methylhistamine
in CHO cell membranes expressing human H3 receptors; Kd [3H]N-a-methylhistamine: 0.4 nm; assay concentration: 0.2 nm; pKi thioperamide: 6.82ꢁ0.13
(n>75); results are the mean of two to six experiments, and when only two experiments were done, the two measurements were within 0.2 log units.
[c] 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. [d] Log D at pH 7.4 was measured by sonicating a solution of compound in PBS-saturated octanol with the same volume of water. The concentration
of product in both phases was determined by HPLC. [e] Water solubility at pH 7.4, 208C. [f] Human (H) and rat (R) intrinsic metabolic clearance measured
from parent drug disappearance following incubation with liver microsomes [mLminꢀ1 (mg protein)ꢀ1]. [g] Apical-to-basolateral permeability in Caco-2 cell
assay.
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the best overall characteristics, it was thus further profiled in
vitro and in vivo.
The inverse agonistic profile of (R)-28 was confirmed in a
GTPgS assay (pEC50 =9.2; thioperamide pEC50 =7.0) and in
assays with electrically stimulated guinea pig myenteric plexus
(pA2 =9.4). For comparison, thioperamide had a pA2 value of
7.6 in the same assay. Compound (R)-28 had greater than 100-
fold selectivity toward 50 targets of the CEREP receptogram,
and there were no detectable interactions with major cyto-
chrome P450 isoforms (inhibitory concentrations >10 mm).
The in vivo pharmacokinetic (PK) profile of (R)-28 in rat was
consistent with its physicochemical and in vitro DMPK proper-
ties (Table 3). The compound shows excellent oral bioavailabil-
ity coupled with a reasonable elimination rate (t1/2 =3.4 h; total
plasma clearance: CL=24 mLminꢀ1 kg). Notably, its volume of
distribution (Vss) is 5.85 Lkgꢀ1, which is acceptable for a basic
compound. In addition, in vitro plasma protein binding was
found to be low (~70%), irrespective of the species.
Scheme 10. Reagents and conditions: a) HOCH2CO2H, HOBt, EDCI, DMAP,
CH2Cl2, 208C, 2 h, (52%, 54); b) 1. ClC(O)CH2CO2Me, Et3N, CH2Cl2, 2 h, 2. NH3,
MeOH, 908C, 20 h (14% over two steps, 55); c) BrCH2C(O)NH2, K2CO3, NaI,
CH3CN, 808C, 20 h (32%, 56); e) ClCH2CH(OH)CH2OH, (58%, 57); f) triphos-
gene, CH2Cl2, 08C, 1 h, then morpholine, Et3N, 0–208C, 12 h, (48%, 58);
f) EtNCO, CH2Cl2, 208C, 12 h, (62%, 59).
nation with the basic site, matches quite well with the hERG
pharmacophore.[12]
While some of these derivatives have significantly decreased
hERG affinities, all the compounds with polar side chains have
lower membrane permeability than 28. Because none of the
new derivatives could improve over (R)-28, which still displays
Ex vivo binding experiments were performed in rats. Binding
of radiolabeled thioperamide was measured on rat cortex ho-
mogenates 1 h after oral (p.o.) administration of (R)-28. The ob-
served EC50 value of 26 nm confirmed that the compound
Table 2. In vitro properties of thiazolo[5,4-c]piperidines.
[e]
[g]
Compd[a]
H3 Ki [nm][b]
hERG IC50 [mm][c]
logD[d]
S [mgmLꢀ1
]
CLint (H/R)[f]
Papps [nmsꢀ1
]
(R)-28
1.0ꢁ0.4
1.2ꢁ0.7
6.3
1.3
0.9
1.3
1.4
1/1
1/4
216
75
54
10.0
55
1.2ꢁ0.7
>100
0.5
1.4
NT
56
57
2.0
6.3
0.91
0.61
0.7
1.4
1/5
2/8
17
17
0.8ꢁ0.6
>100
58
59
2.0
6.3
6.3
1.6
2.0
0.6
0.8
5/8
1/7
32
59
5.0ꢁ0.5
[a] All compounds are enantiomerically pure (R) at the pyrrolidine; compound 57 is a diastereomeric mixture of epimers at the hydroxy group. [b] H3R
binding affinities were assessed by displacement of [3H]N-a-methylhistamine in CHO cell membranes expressing human H3 receptors; Kd [3H]N-a-methyl-
histamine: 0.4 nm; assay concentration: 0.2 nm; pKi thioperamide: 6.82ꢁ0.13 (n>75); results are the mean of two to six experiments, and when only two
experiments were done, the two measurements were within 0.2 log units. [c] hERG assay was performed on HEK293 cells transfected with the hERG potas-
sium 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 concentra-
tion). The potassium current was recorded while stimulating the cells every 15 s. [d] Log D at pH 7.4 was measured by sonicating a solution of compound
in PBS-saturated octanol with the same volume of water. The concentration of product in both phases was determined by HPLC. [e] Water solubility at
pH 7.4, 208C. [f] Human (H) and rat (R) intrinsic metabolic clearance measured from parent drug disappearance following incubation with liver microsomes
[mLminꢀ1 (mg protein)ꢀ1]. [g] Apical-to-basolateral permeability in Caco-2 cell assay; NT: not tested.
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Table 3. In vivo PK data for (R)-28.[a]
Parameter
Value
Parameter
Value
[b]
[d]
DNC [ngmLꢀ1
]
80
24
Vss [Lkgꢀ1
t1/2 [h][e]
F [%][f]
]
5.85
3.4
100
CL [mLminꢀ1 kgꢀ1
]
[c]
[a] Parameters obtained after single p.o. and i.v. dosing at
6
and
1 mgkgꢀ1 to male and female Wistar rats (n=2 per gender); data are re-
ported as males and females combined, as no gender effect could be ob-
served. All experiments were approved by the local ethics committee for
animal experimentation according to Belgian law. [b] Dose-normalized
maximum concentration Cmax after p.o. administration. [c] Total plasma
clearance. [d] Volume of distribution. [e] Half-life. [f] Oral bioavailability.
Figure 3. Promnesiant effect of (R)-28 in the two-trial object recognition test
in mice using scopolamine to induce recognition memory deficit. Results are
expressed as the exploration difference (mean ꢁSEM) between novel and
familiar objects during the retention trial. All groups received scopolamine
(0.3 mgkgꢀ1 i.p.) 30 min before the acquisition trial; drugs were adminis-
tered i.p. 40 min before acquisition trial. Vehicle was 1% methylcellulose/5%
DMSO in water; Thiop=thioperamide (1.2 mmolkgꢀ1). Statistical analysis was
carried out by one-way ANOVA followed by Dunnett’s post hoc comparison
versus vehicle; statistical significance was set at *p<0.05, n=8–9 subjects
per group.
could successfully occupy brain H3R at sub-micromolar concen-
trations (Figure 2).
Finally, the promnesiant effect of (R)-28 was evaluated after
intraperitoneal (i.p.) administration in a two-trial object recog-
the novel object during the retention trial, such that the explo-
ration difference is close to zero, indicating that mice spend
nearly the same amount of time exploring the familiar and
novel objects during the retention trial (NꢀF=ꢀ1). Compound
(R)-28 at doses of 2.3–10 mmolkgꢀ1, is able to significantly pre-
vent scopolamine-induced amnesia. This is indicated by the
fact that mice spend more time exploring the novel object
than the familiar one. The prototypical H3R antagonist thioper-
amide, used as a positive control, is also shown to prevent sco-
polamine-induced deficit (0.5 mgkgꢀ1). Compound (R)-28 does
not alter locomotor activity (data not shown).
3
^
Figure 2. Ex vivo binding of (R)-28 ( ). The binding of [ H]thioperamide was
measured on rat cortex homogenate 1 h after p.o. administration of (R)-28.
In conclusion, we have identified several novel rigidified
phenylthiazoles bearing an N-acetamide that interact with H3R
at nanomolar-level affinities. More polar derivatives retained
good affinities toward H3R and showed lower hERG affinities,
but this came at the expense of decreased permeation. Com-
pound (R)-28 showed good in vivo PK properties and activity
in the novel object recognition paradigm, supporting the ther-
apeutic potential for this compound in cognitive disorders.
nition test[13] in adult C57 black male mice. Scopolamine
(0.3 mgkgꢀ1, i.p.) was used to induce recognition memory defi-
cits.[14] Mice were submitted to a habituation session the day
before the object recognition test, during which they were al-
lowed to freely explore the arena in the presence of two ob-
jects. On the experimental day, mice were submitted to two
trials. During the first trial (T1), mice were placed in an arena
containing two identical objects, and the time required to
complete 20 s of object exploration was determined with a
12 min cutoff time. In the retention trial or trial two (T2), per-
formed 1 h later, one of the two objects had been replaced by
a novel object, and the amount of time spent to explore each
object was determined for 5 min. The results are expressed as
the exploration difference (NꢀF), which is time spent exploring
the novel object minus time spent exploring the familiar
object. Compound (R)-28, thioperamide (positive control) or
vehicle (1% methylcellulose/5% DMSO in pure water) were ad-
ministered 40 min before T1, and scopolamine was adminis-
tered 30 min before T1.
Acknowledgements
The authors thank Mr. A. Safronov and Mr. M. Yakovlev (Chem-
Bridge Corp.) for their skillful syntheses; Dr. L. Quꢀrꢀ, Ms. G. Long-
fils, and Ms. L. Ellens for lipophilicity and solubility measure-
ments; Ms. V. Pinilla for chromatographic purifications; Dr. R.
Dieden, Dr. B. Mathieu, Mr. A. Fauconnier, Mr. J. Claessens, Ms. A.
Descamps, and Ms. C. Derwa for analytical assistance; Mr. P. Col-
lart for in vitro PK measurements; and Dr. D. Harding for cardiac
safety assessment. Dr. V. Bertaina-Anglade, E. Enjuanes, and Dr.
C. Drieu la Rochelle (Biotrial) are greatly acknowledged for the
testing of compounds in the two-trial object recognition model.
The authors are most grateful to Dr. C. Audouin and Dr. C. Gꢀni-
The results (Figure 3) indicate that treatment with scopola-
mine alone (vehicle group) prevents preferential exploration of
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cot for their valuable comments in the preparation of this manu-
script.
Keywords: bicyclic thiazoles · cognitive disorders · drug-like
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·
histamine H3 receptor
·
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relationships
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Received: May 18, 2011
Revised: June 16, 2011
Published online on July 14, 2011
ChemMedChem 2011, 6, 1559 – 1565
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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