Investigation of 4-piperidinols as novel H3 antagonists

Article abstract of DOI:10.1016/j.bmcl.2010.08.099

Compounds containing a substituted 4-piperidinol core have been found to be potent antagonists of the human H₃ receptor. The compounds exhibited up to a 60-fold preference for inhibiting the human H₃ receptor over the mouse and showed a low binding affinity for the hERG channel.

Full text of DOI:10.1016/j.bmcl.2010.08.099

Bioorganic & Medicinal Chemistry Letters 20 (2010) 6246–6249
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Investigation of 4-piperidinols as novel H antagonists
3
⇑
James T. Anderson , Michael Campbell, Jianmin Wang, Kurt R. Brunden, John J. Harrington,
Alain Stricker-Krongrad, Jianping Song, Chris Doucette, Steven Murphy, Youssef L. Bennani
Athersys Inc., 3201 Carnegie Ave., Cleveland, OH 44115-2634, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Compounds containing a substituted 4-piperidinol core have been found to be potent antagonists of the
Received 21 June 2010
Revised 18 August 2010
Accepted 19 August 2010
Available online 24 August 2010
human H
3 3
receptor. The compounds exhibited up to a 60-fold preference for inhibiting the human H
receptor over the mouse and showed a low binding affinity for the hERG channel.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Histamine
H
3
Antagonist
Piperidinol
CNS
G-protein coupled receptor
The histamine H
3
receptor is a G-protein coupled receptor that
having a high degree of rotational freedom as in JNJ-52078527
is primarily located in the CNS and regulates the synthesis and re-
lease of the neurotransmitter histamine via a negative-feedback
3
(Fig. 1). However, there are examples of potent H modulators in
8
the literature that have reduced conformational flexibility includ-
9
mechanism. H
3
receptor activation also plays a role in the release
ing a rigidified analog of JNJ-5207852. Generally, this is a desir-
of several other neurotransmitters in the CNS, including dopamine,
serotonin, GABA, and acetylcholine, and is therefore suspected to
able physico-chemical property as it has been described that
reducing the number of rotatable bonds tends to improve oral
bioavailability. After a high-throughput screening campaign, we
1
0
possess promising therapeutic potential. Sought after indications
1
for H
3
modulators include treatments for Alzheimer’s disease,
were pleased to find that the relatively rigid and racemic com-
2
11
attention-deficit hyperactivity disorder (ADHD), cognition, and
3 3
pound 1 was a potent antagonist of the human H (hH ) receptor
3
obesity. Drug discovery efforts to modulate the histamine H
3
(Table 1). Interestingly, compound 1 showed a significant differ-
ence in IC50 potencies between mouse and human H in the FLIPR
receptor have been ongoing in both academia and the pharmaceu-
3
4
12
tical industry since its discovery in 1983. Although significant pro-
assays. However, the control H
3
antagonist clobenpropit did not
gress has been made in finding compounds that effectively target
the H receptor, no candidates have yet received clinical approval.
3
However, there are presently several compounds being evaluated
5
in early to late-stage clinical trials.
3
Early small molecule research efforts targeting the H receptor
OH
N
revealed that imidazole-containing compounds such as clobenpro-
pit showed very potent antagonistic activity. However, these com-
pounds showed metabolic liabilities and poor CNS penetration
3
likely attributable to the imidazole moiety. Potent H antagonists
1
were eventually discovered that lacked the imidazole core and
NH
6
N
exhibited an improved CNS and metabolic profile. A common fea-
N
S
N
ture present in these ‘non-imidazole’ H
3
modulators is a basic
H
N
O
HN
Cl
amine group that is tethered to an aryl system via an alkyl chain
Clobenpropit
JNJ-5207852
⇑
Corresponding author.
E-mail addresses: andersj12@wyeth.com, jtanders45@yahoo.com (J.T. Ander-
Figure 1. Structure of lead compound 1, imidazole and non-imidazole based H
3
son).
antagonists.
0
960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.08.099

J. T. Anderson et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6246–6249
6247
Table 1
Potency of piperidinols against mouse and human H
3
Ar OH
R5
R2
N
1
R
N
N
Ar =
A
B
C
D
E
F
G
Compounda
Ar
R1
R2
R5
FLIPR IC50 (nM)
b
hERG
mH
1
280 (±92)
119 (±19)
1318d
3
hH
1
3
Clobenpropit
1
5
nd
nd
15% @ 50
nd
nd
20% @ 10
15% @ 10
16% @ 10
nd
0% @ 10
23% @ 10
nd
c
c
c
A
A
A
A
B
C
C
D
E
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
11 (±2)
c
9 (±3)
l
M
e
ent-5
41
e
e
1
6
7
8
9
1
1
1
1
1
(O-acetate)
>10,000
5508
570d
20
d
lM
lM
lM
c
d
480 (±300)
17
d
d
85
2
e
e
810
122
280
345
690
9730
84
e
e
0
2
5
lM
e
e
3
4
5
6
A
C
F
(–CH
(–CH
2
)
)
3
lM
e
e
2
3
14
12
e
e
Me
Me
Me
Me
3% @ 10
nd
l
M
e
e
G
709
a
b
c
Compounds 5, ent-5, and 8 are single enantiomers. All other compounds are racemic.
Measured reduction of intracellular calcium flux induced by agonist (R)-
Mean of at least three experiments, standard error of the mean.
Average of two determinations.
a-methylhistamine.
d
e
Single determination.
show a bias in potency toward either species. In addition to its high
potency as a lead compound against hH , the unique structure of 1
generated interest in further exploration of this scaffold for im-
proved H receptor antagonism.
formed in the addition reaction was easily isolated by silica gel
chromatography.
A classical resolution was used to isolate each enantiomer of
pure diastereomer 1. Re-crystallization of the salt formed from
3
3
The general synthesis of compounds 1 and 5–10 is described in
Scheme 1. The piperidone intermediate 4 was synthesized using a
modification of a previously reported procedure.13 Compound 2,
prepared from ethyl 3-aminobutyrate and ethyl methacrylate,
was subjected to Eschweiler–Clarke conditions to give the N-meth-
ylated product 3. Dieckmann cyclization of 3 and subsequent
decarboxylation gave the piperidone 4 as an unresolved mixture
of diastereomers. Final compounds were accessed via deprotona-
tion of aryl acetylenes using BuLi followed by addition to piperi-
done 4. There was concern that the creation of a third chiral
center would yield a mixture of piperidinol diastereomers that
may be difficult to purify. However, the major diastereomer
optically pure di-p-toluoyl-(L)-tartaric acid gave an enantiomer
1
4
having >95% de X-ray crystal structure determination of the salt
15
(Fig. 2) provided the absolute stereochemistry of 5. The crystal
structure also confirmed the mode of aryl acetylene addition as
being axial. The free base of 5 showed a 2- to 3-fold improvement
in potency against mH
in hH potency. The antipode ent-5 was isolated from recrystalliza-
tion of the di-p-toluoyl-( )-tartrate salt of 1 and was found to be
much less potent than 5 against both mH and hH . Another obser-
3
over the racemate 1, but no improvement
3
D
3
3
vation was that the free 4-hydroxyl group was important for
potency as the corresponding acetate of 1 was not active against
3 3
mH and very weakly active against hH at the highest concentra-
tions tested (Table 1).
The trans-alkene 6 was obtained after lithium aluminum hy-
dride reduction of alkyne 1 and showed a loss in activity against
both mH and hH . This result was not surprising given the altered
3 3
spatial arrangement of the naphthyl ring. The alkene was further
reduced to alkane 7 using standard Pd-catalyzed hydrogenation
EtO
2
C
CO
2
Et
EtO
2
C
2
CO Et
a
b
N
H
N
2
3
3
conditions. We anticipated a recovery in H potency for 7 due to
Ar
the increased conformational flexibility of the ethyl chain, but no
improvements were seen over the alkene. However, upon chiral
resolution of 7, as previously described, enantiomer 8 was found
O
OH
c
N
3
to possess excellent potency against hH .
N
0
Altering the position of the alkyne moiety to the 2 -position of
4
the naphthyl ring gave compound 9 that was less potent than
0
the corresponding 1 -substituted analog 1 in both mH
3
(ꢀ3-fold)
Scheme 1. Reagents and conditions: (a) (i) (CH
HCO H, reflux; (b) (i) Na, EtOH, xylenes, reflux; (ii) 20% aq HCl, reflux; (c) Ar-CCH,
nBuLi, THF, 0 °C.
2 n
O) , Toluene-nBuOH; then (ii)
and hH
3
(ꢀ8-fold). However, the opposite trend was observed
2
upon reduction of alkyne 9 to the alkane 10. Comparison of

6
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J. T. Anderson et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6246–6249
In summary, we have identified a unique piperidinol-based
pharmacophore that shows potent human H inhibition and a very
good overall hERG profile. However, this series showed a signifi-
cant disparity in potency between the human and mouse H recep-
tors as only moderate potency was achieved against the mouse,
The lack of mH potency was disappointing because in vivo assays
were to be performed in mouse. This result is somewhat surprising
given the reported high H receptor homology (94%) between
mouse and human. A few antagonists have been reported that
are biased toward hH over mH albeit to a much lesser extent
3
3
3
3
2
0
3
3
2
1
than our observations with the piperidinol series. In our case,
the observed differences in potency between the two species
3
appear to result from the human H receptor being much more
accommodating for the piperidinol pharmacophore.
Acknowledgements
The authors thank Ms. Judith Galucci at The Ohio State Univer-
sity for the X-ray structure determination of 5.
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3
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3
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% aq AcOH, reflux.
5

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6249
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