Brain-penetrating 2-aminobenzimidazole H1-antihistamines for the treatment of insomnia

Article abstract of DOI:10.1016/j.bmcl.2009.05.086

The benzimidazole core of the selective non-brain-penetrating H₁-antihistamine mizolastine was used to identify a series of brain-penetrating H₁-antihistamines for the potential treatment of insomnia. Using cassette PK studies, brain

Full text of DOI:10.1016/j.bmcl.2009.05.086

Bioorganic & Medicinal Chemistry Letters 19 (2009) 4380–4384
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Brain-penetrating 2-aminobenzimidazole H1-antihistamines
for the treatment of insomnia
*
Timothy Coon, Wilna J. Moree , Binfeng Li, Jinghua Yu, Said Zamani-Kord, Siobhan Malany, Mark A. Santos,
Lisa M. Hernandez, Robert E. Petroski, Aixia Sun, Jenny Wen, Sue Sullivan, Jason Haelewyn, Michael Hedrick,
*
Samuel J. Hoare, Margaret J. Bradbury, Paul D. Crowe, Graham Beaton
Neurocrine Biosciences, 12780 El Camino Real, San Diego, CA 92130, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The benzimidazole core of the selective non-brain-penetrating H1-antihistamine mizolastine was used to
identify a series of brain-penetrating H1-antihistamines for the potential treatment of insomnia. Using
cassette PK studies, brain-penetrating H1-antihistamines were identified and in vivo efficacy was demon-
strated in a rat EEG/EMG model. Further optimization focused on strategies to attenuate an identified
hERG liability, leading to the discovery of 4i with a promising in vitro profile.
Received 16 March 2009
Accepted 19 May 2009
Available online 27 May 2009
Keywords:
Histamine
Ó 2009 Elsevier Ltd. All rights reserved.
H1
Antihistamine
2-Aminobenzimidazole
Brain-penetrating
Insomnia
H1 receptors mediate allergic responses to histamine in the
periphery, while centrally they mediate the effects of histamine
on arousal.1 First generation antihistamines including diphenhy-
dramine (1) cross the blood–brain barrier (BBB) and cause sedation
in humans.2 Although first generation over-the-counter (OTC) anti-
histamines are used extensively for the treatment of insomnia,
they exhibit several undesirable side effects such as drying of
mucosal membranes attributed to muscarinic receptor blockade
and next day impairment as a result of protracted CNS exposure.3
Second and third generation antihistamines have been developed
with diminished side effects due to improved selectivity profile
although BBB penetration is limited. Despite improved receptor
selectivity, some second generation antihistamines (i.e., terfena-
dine and astemizole) are potent inhibitors of the human ether-a-
go-go (hERG) channel4 implicated in prolongation of cardiac QTc
and leading to serious and sometimes fatal cardiac arrhythmias.5
We have been interested in the discovery of selective H1-anti-
histamines for development of an effective insomnia therapeutic
free of the issues exhibited by OTC antihistamines. The benzimid-
azole core of mizolastine6 (2), a highly selective second generation
antihistamine with no detectable brain levels (at 10 mg dose po in
humans), was used as a starting point and optimized for BBB
penetration. Many factors have been described to contribute to
the BBB penetration of antihistamines including lipophilicity, pKa,
hydrogen bonding capacity, mw, protein binding and affinity for
Pgp.7 The pyrimidinone side chain was thought to be a key contrib-
utor to limited BBB penetration at physiological pH, due to its rel-
atively acidic nature (pKa 4.7) and the fact that it can form 2
hydrogen bonds resulting in a relatively high polar surface area.8
The benzimidazole core does not appear to be a contributing factor
since this motif occurs in other related compounds with CNS ef-
fects.9 We planned to generate novel and brain-penetrating H1-
antihistamines (4) from modification of the N-methyl pyrimidi-
none side chain with several N-alkyl, aryl, alkoxy and (hetero)aryl
side chains (NR1R2), while simultaneously exploring substitution
(R3) on the benzyl moiety (Fig. 1).
The synthesis is outlined in Schemes 1 and 2. Benzimidazole
chloride (5) was N-alkylated with a variety of alkylating agents
in the presence of NaOH and subsequently coupled to N-Boc amin-
opiperidine in the presence of DIPEA to yield 7. Sodium hydride-
mediated alkylation installed the methyl group and removal of
the Boc group afforded 8. Amine functionalized analogs (9) were
obtained by reductive amination with aldehydes, alkylation with
alkyl halides or acylation with acylchlorides.
Alternatively, N-alkylated benzimidazole chloride (6) was cou-
pled to 4-hydroxypiperidine in the presence of DIPEA to yield 10,
which was converted to the mesylate (11). Displacement of the
mesyl group with a variety of amines or heterocycles afforded ana-
* Corresponding authors.
E-mail addresses: wjmoree@sbcglobal.net (W.J. Moree), graham.beaton@cox.net
(G. Beaton).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.05.086

T. Coon et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4380–4384
4381
N
N
N
N
HN
OH
N
N
OH
N
O
H
N
6
N
N
O
a
10
1
2
R3
OMs
F
N
N
N
b
c
R1
R2
N
4
N
N
N
N
11
N
R3
3
4
R3
Scheme 2. Reagents and conditions: (a) DIPEA, neat, 139 °C; (b) MsCl, DIPEA, 0 °C
to rt; (c) HNR1R2, DIPEA, 80 °C or NaH/HNR1R2, rt.
Figure 1. Diphenhydramine (1), mizolastine (2), triprolidine (3) and SAR explora-
tions (4).
Table 1
Exploration of the R1 substituent
logs (4). All final compounds were purified by mass-triggered pre-
parative HPLC.
N
N
R1
N
N
Compounds were tested in a histamine H1 receptor binding as-
say (Supplementary data). To confirm initial selectivity, com-
pounds were subsequently tested for muscarinic M1 receptor
binding affinity (Supplementary data) and inhibition of cyto-
chrome P450 enzymes CYP2D6 and CYP3A4.10 Data are shown in
F
Tables 1, 4 and 5. No significant CYP3A4 inhibition (IC50 > 10
was observed unless specifically indicated.
lM)
Compound
R1
H1 Kia (nM)
M1 Kib (nM)
CYP2D6 IC50 (nM)
>20,000
The pyrimidinone moiety was modified, while the p-F substitu-
ent (R3) on the benzyl and the Me substituent (R2) in 4 were kept
constant. Removal of the keto group (9a) or substitution by phenyl
(9b) significantly abolished activity. Extension to benzyl (9c) and
phenethyl (9d) greatly improved H1 binding affinity but decreased
selectivity for M1 and CYP2D6, presumably due to the additional
hydrophobicity. Incorporation of heteroatoms (9h, 9i) to reduce
hydrophobicity (c Log P ꢀ 2 log units less compared to 9f and 9e,
respectively) and increase polar surface area (34 vs 24 for 9e and
9f) improved the selectivity profile. The smaller aliphatic substitu-
ent (9g) resulted in a potent H1 inhibitor with acceptable selectiv-
ity over M1 and CYP2D6. With several selective compounds
identified we then examined whether increased brain levels over
mizolastine could be achieved. Compounds were assessed for their
ability to penetrate the BBB in rodents using cassette PK studies
(Supplementary data). Groups of 5 compounds including the short
acting brain-penetrating antihistamine triprolidine11 (3) were
administered (iv) to rats and brain levels and B/P ratios were deter-
mined. Results for 9g, 9h and 9i are shown in Table 2 and com-
pared to 2 and 3. All compounds had B/P ratios and brain levels
that were significantly improved over 2 and comparable to or
H
N
2
2.7 0.7
>10,000
N
O
N
9a
75.2 11.9
>10,000
1036
N
9b
9c
9d
9e
9f
–Ph
–Bn
–(CH2)2 Ph
–CH2–cHex
–cHex
80.5 10.2
3.6 0.3
2.4 0.4
4.4 0.2
2.8 0.5
1.8 0.1
2.4 0.6
>10,000
3581
89
3860
2745
1486
988
>20,000
805
502
360
2053
12,798
6664
9g
8a
–Me
H
9h
3.3 0.2
14,747
6360
O
9i
3.9 0.8
6486
11,017
O
a
SEM for Ki values derived from dose response curves generated from triplicate
or more data points.
b
Ki values average of 2 data points.
HN
NHBoc
N
a
N
N
N
N
Cl
Cl
N
NHBoc
N
b
H
6
7
5
R3
N
R3
N
N
N
N
c,d
e or f
N
N
N
O
R1
H
9
8
R3
R3
Scheme 1. Reagents and conditions: (a) R3BnX, NaOH; (b) DIPEA neat, 120 °C; (c) NaH, MeI; (d) TFA; (e) R1(@O)H, NaBH(OEt)3, HOAc; (f) R1X, DIPEA, 95 °C or R1COCl, DIPEA.

4382
T. Coon et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4380–4384
Table 2
Cassette PK studies (dose 1 mg/kg for each compound, iv, 2 h post dose)
Compound
[B] (ng/g)
[P] (ng/g)
B/P
[B] triprolidine (ng/g)
Pred. hCLinta (ml/min/kg)
Pred. rCLintb (ml/min/kg)
2
3
9g
9h
9i
0
55.6
50
55
104
6.3
7.1
10.9
18.1
19.2
0
55.6
55.6
55.3
39.4
39.4
92
9.4
34.8
126
106
NTc
4.5
4.6
3.5
6.3
4993
716
436
312
a
Predicted based on HLM stability studies.
Predicted based on RLM stability studies.
NT = not tested.
b
c
better than 3. Predicted clearance for 9h–i was similar to 2 in hu-
man liver microsome studies.12 Notably, the predicted intrinsic
clearance in rats of all compounds was significantly higher than
for human implying that brain exposure upon oral dosing might
be an issue for these compounds.
ment of the tertiary amine for the secondary amine in 4c. Once
combined with the p-OMe benzyl substituent, (4d) hERG binding
was decreased to 1461 nM, although H1 binding also decreased
slightly. Addition of a second positive charge in diamine 9o offered
an approximate 50-fold improvement in selectivity over hERG
while maintaining H1 potency. Removal of the basic center in some
compound classes21 including antihistamines22 has been used to
modulate hERG activity although with concomitant loss of H1 po-
tency.22 In this series, removal of the basic center by incorporation
of a lactam (4e) resulted in a potent H1 binder with no detectable
hERG inhibition. Additional heterocycles were explored at this
position. Comparison of the pyrrole (4f), to the imidazole (4g)
and pyrazoles (4h–j) indicated improved H1 affinity for analogs
4g–j. The pyrazoles exhibited a more promising selectivity profile.
Methyl substitution in 4i and 4j improved both H1 binding and
selectivity over 4h. With 4i and 4j, hERG selectivity was improved
ꢀ100-fold over the original lead 9i. Patch clamp analysis showed
that 4i (IC50 = 809 nM) and 4j (IC50 = 580 nM) had significant, yet
comparable hERG inhibition to mizolastine (IC50 = 441 nM at
37 °C).4b
As expected, at an oral dose of 10 mg/kg in Sprague Dawley rats,
9i exhibited high clearance (134 ml/min-kg) and poor bioavailabil-
ity (2% measured against an iv dose of 5 mg/kg) with measured
plasma exposure of 9 ng/ml (4 h). Nevertheless, brain levels
(94 ng/g at 4 h) were sufficient to assess its hypnotic potential in
rats using EEG/EMG recordings. Rats, equipped with EEG and
EMG biopotential leads,13 were orally dosed with either vehicle,
zolpidem14 (GABA-A modulator) as positive control or test com-
pound 6 h into the dark phase. EEG and EMG signals were collected
24 h prior to, and 18 h after, compound administration. As shown
in Table 3, 9i significantly increased time spent in NREM and the
duration of NREM sleep bouts as compared to vehicle. Results were
similar to that for the positive control zolpidem. NREM sleep la-
tency was decreased and REM sleep latency was increased by 9i,
but these did not reach statistical significance. Analysis of effects
on REM sleep indicated that 9i did not significantly affect time in
REM sleep or the length of REM sleep bouts in contrast to zolpidem
at doses used. Overall, these studies were consistent with reported
effects of antihistamines on sleep/wake parameters in rats.15
Compound 9i was further profiled against other GPCRs and the
hERG channel to examine any possible off-target liabilities. 9i did
not show appreciable binding to either H3 or 5HT2a (Supplemen-
tary data) excluding off-target effects on the EEG results,16 but
was a very potent hERG inhibitor (patch clamp IC50 of 29 nM).12
Both lactam 4e and pyrazole 4i were considered for further pro-
filing. From in vitro studies,12 4e had acceptable stability (Pred.
hClint 45 ml/min/kg) and good permeability (Caco-212
: Papp
12.4 Â 10À6 cm/s; A > B/B > A = 0.6) with no evidence for Pgp sub-
strate. However, from cassette PK studies, no detectable brain lev-
els and very low plasma concentrations (estimated 2 ng/ml) were
observed implying a plasma stability issue, making this compound
unsuitable for further evaluation. In contrast 4i had a promising
profile in comparison to 9i (Table 5). Compound 4i was selective
for M3, 5HT2a and H3 with significantly less hERG inhibition than
9i. While intrinsic clearance was higher and brain penetrability
lower than observed for 9i, discrete rat PK studies revealed suffi-
cient brain exposure to anticipate a hypnotic effect in EEG studies.
In conclusion, we were able to use the benzimidazole core of a
highly selective yet non-sedating antihistamine to identify a series
of brain-penetrating H1-antihistamines. With the use of cassette
PK studies, compounds suitable for in vivo efficacy studies were
rapidly identified and efficacy in a rat EEG/EMG model was demon-
strated with compound 9i. Unfortunately, the series showed poor
selectivity for the hERG channel. Exchange of the amine NR1R2
for certain heterocycles proved most beneficial in attenuation of
this liability and resulted in compound 4i, which exhibited brain
exposure in rat models and had a similar hERG selectivity as
A
3H-dofetolide binding assay (Supplementary data) was used as
a high-throughput screening alternative to whole cell patch clamp
electrophysiology to evaluate all compounds for hERG. In this as-
say 9i had a Ki of 18 nM (Table 4).
A number of strategies were explored to improve hERG selectiv-
ity (Table 4).17 Changes in electron density in the benzyl substitu-
ent only had a modest effect on hERG based on comparison of 9g
(p-F) to 9j (p-Me) and 9k (p-OMe) or 9i (p-F) to 9l (p-OMe). Given
our requirement for CNS activity, zwitterionic moieties were not
explored to attenuate hERG function as previously described for
19
antihistamines.18 Reduction of pKa and/or log P had modest im-
pact on hERG selectivity as exemplified by comparison of 9i to
compounds 9g, 9m and 9n.20 The more significant improvement
in hERG selectivity (ꢀ20-fold increase) was noted through replace-
Table 3
EEG profile of 9i
Compound
NREM in 4 h (%)
NREM latency (min)
Longest 3 NREM bouts in 6 h (min)
REM in 4 h (%)
Longest 3 REM bouts in 6 h (min)
REM Latency (min)
Vehicle
9ia
24.7 2.8
47.2 3.2*
48.3 2.1*
47
21
7
6
4.7 0.9
11.0 1.6*
10.9 1.6*
2.9 0.7
2.6 0.8
0.4 0.1*
1.4 0.2
0.5 0.2
1.4 0.3
94 14
110 18
186 32*
2
Zolpidemb
1*
a,bDose 30 mg/kg, po.
*
P < 0.05 versus vehicle (10% cremophor EL/H2O).

T. Coon et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4380–4384
4383
Table 4
Table 5
Profile of 4i compared to 9i
Exploration of R1–R3 substituents for H1 affinity and attenuation of hERG
R1
N
Compounds
Selectivity over
hERG
IC50 (nM)
Predicted
hCLint
(ml/min/kg)
B/P ratio
4 h
[B] 4 h
(ng/g)
N
N
M1, M3, 5HT2a
,
R2
N
H3
9ia
4ib
>1000
>1000
29
809
106
242
10
2.3
94
262
R3
a
Dose 10 mg/kg, po.
Dose 30 mg/kg, po.
b
Compound
NR1R2
R3
H1 Ki
CYP2D6c IC50
(nM)
hERGd Ki
(nM)
a,b
(nM)
N
N
H
N
Acknowledgments
2
F
F
2.7 0.7
>20,000
7258
O
The authors wish to thank Michael Johns for permeability
determinations, John Harman, Shawn Ayube and Chris DeVore for
analytical support and Dr. John Saunders, Dr. Paul Conlon, Dr. A.
Madan and Dr. H. Bozigian for program support.
9g
9j
1.8 0.1
1.5 0.1
2.4 0.1
12,798
7210
57
73
N
N
Me
9k
OMe
6072
158
Supplementary data
N
N
9i
9l
F
3.9 0.3
14.1 1.6
2.2 0.3
3.2 0.5
4.5 0.3
14.1 1.6
2.9 0.3
6.6 0.7
11,017
8185
18
102
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2009.05.086.
O
N
OMe
References and notes
O
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9m
9n
4c
F
4444
40
N
N
O
F
35,150
12,134
16,309
6134
116
OH
H
N
F
426
O
O
H
N
4d
9o
4e
OMe
1461
776
F
F
N
O
N
NMe2
4353
>7500
4f
F
F
59.3 10.6
1.30 0.1
1534
157
137
N
N
N
4g
1117e
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N
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4h
4i
F
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18.3 1.9
6.9 0.9
1480
5219
3536
3849
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N
N
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N
N
4j
OMe
7.1 0.8
7319
>5000
a
SEM for Ki values derived from dose response curves generated from triplicate
or more data points.
b
all compounds >1000Â selective for M1 (data not shown).
c
CYP3A4 IC50 > 5 lM (data not shown).
d
e
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CYP3A4 IC50 72 nM.
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20. Calculated properties (ACD/Log P and pKa DB, version 9.02, Advanced
Chemistry Development, Inc., Toronto, ON, Canada): 9g (c log P 4.4, fragment
trimethylamine pKa 9.9), 9i (c log P 4.8, fragment dimethyl-(tetrahydro-pyran-
4-ylmethyl)-amine pKa 9.5), 9m (c log P 3.5, fragment (2-methoxy-ethyl)-
dimethyl-amine pKa 8.9), 9n (c log P 4.0, fragment 2-dimethylamino-ethanol
pKa 8.9).