Novel benzothiophene H1-antihistamines for the treatment of insomnia

Article abstract of DOI:10.1016/j.bmcl.2010.01.134

SAR of lead benzothiophene H₁-antihistamine 2 was explored to identify backup candidates with suitable pharmacokinetic profiles for an insomnia program. Several potent and selective H₁-antihistamines with a range of projected half-li

Full text of DOI:10.1016/j.bmcl.2010.01.134

Bioorganic & Medicinal Chemistry Letters 20 (2010) 2316–2320
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Novel benzothiophene H1-antihistamines for the treatment of insomnia
*
Wilna J. Moree , Florence Jovic, Timothy Coon, Jinghua Yu, Bin-Feng Li, Fabio C. Tucci, Dragan Marinkovic,
Raymond S. Gross, Siobhan Malany, Margaret J. Bradbury, Lisa M. Hernandez, Zhihong O’Brien,
Jianyun Wen, Hua Wang, Samuel R. J. Hoare, Robert E. Petroski, Aida Sacaan, Ajay Madan, 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:
SAR of lead benzothiophene H1-antihistamine 2 was explored to identify backup candidates with suitable
pharmacokinetic profiles for an insomnia program. Several potent and selective H1-antihistamines with a
range of projected half-lives in humans were identified. Compound 16d had a suitable human half-life as
demonstrated in a human microdose study, but variability in pharmacokinetic profile, attributed to met-
abolic clearance, prevented further development of this compound. Compound 28b demonstrated lower
predicted clearance in preclinical studies, and may represent a more suitable backup compound.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 30 December 2009
Revised 27 January 2010
Accepted 28 January 2010
Available online 2 February 2010
Keywords:
H1 receptor
H1-antihistamines
Insomnia
Benzothiophenes
Histamine
Histamine elicits effects on arousal through central action at the
H1 and H3 receptor subtypes.1 While first generation H1-antihista-
mines are sedating and are used in over-the-counter sleep aids,
these agents are functional antagonists of muscarinic (M) recep-
tors,2 a property thought to cause undesirable side effects such
as dry mouth, blurred vision, constipation, tachycardia, urinary
retention, and memory deficits.3,4 Next-day impairment, presumed
to result from protracted CNS exposure and a consequence of long
plasma half-life, has also been seen with these compounds.5,6 Thus,
selective H1-antihistamines with appropriate duration of CNS
exposure may provide an alternative to current medications for
the treatment of insomnia.
Previously, we described the use of the selective (À)-R-dimeth-
indene (1)7 as a starting point to generate novel series of selective
and brain penetrating H1-antihistamines with pharmacokinetic
profiles suitable for use as night time sleep aids.8 The benzothio-
phene analog (2) was selected as a lead compound with a suitable
receptor selectivity profile and, based on modeling of its clearance
profile, a projected half-life in a desirable range of 5–18 h (Fig. 1).
In this Letter, we describe the SAR of benzothiophene series 3.
The objective of this study was to identify backup compounds with
similar or improved selectivity to 2, but with differences in clear-
ance profiles and hence projected half-life.8 Backup compounds
with a range of projected half-lives that model optimal plasma
exposure over time as a function of dose were desirable to mitigate
any risk of next day residual effects should they be observed in our
lead.
From our previous observations, a pyridyl or other heteroaryl
was required for R3 in 3 to confer selectivity versus cytochrome
CYP2D6 inhibition.8 We also demonstrated that variation of the
heteroaryl provided subtle changes to clearance in preclinical
models. The importance of the chiral center for binding affinity
and selectivity in 3 had also been established.8,9
Initial efforts described in this Letter focused on subtle modifi-
cations of the pyridyl moiety (R3) and amine substituents (R1R2) in
3. To achieve a selectivity profile comparable to 2,8 candidate com-
pounds were required to demonstrate potent H1 affinity
(Ki <10 nM) and acceptable selectivity versus other receptor targets
(M1, M3, H3, serotonin 5HT2A, >100-fold) and CYP2D6 and CYP3A4
* Corresponding authors. Tel.: +1 858 336 4479 (W.J.M.); +1 858 337 1801 (G.B).
E-mail addresses: wilna.moree@gmail.com (W.J. Moree), beaton.graham@gmail.
com (G. Beaton).
Figure 1. (À)-R-Dimethindene (1), its direct benzothiophene analog (2) and series
(3) described in this communication.
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.01.134

W. J. Moree et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2316–2320
2317
Scheme 1. Reagents and conditions: (a) CH3(CH2)3OCH@CH2, Pd(OAc)2, P(o-Tol)3, Et3N, CH3CN, 100 °C; (b) 10% HCl in THF; (c) n-BuLi, TMEDA, toluene or DCM, À78 °C; (d)
R3CN; (e) 6 N HCl, MeOH; (f) R3CHO; (g) MnO2, DCM; (h) R3Br or R3H/ n-BuLi, À78 °C, DCM; (i) MeMgCl or MeLi, toluene, À78 °C; (j) PPh3MeBr, t-BuOK, THF; (k) Pd/C or
Pd(OH)2 in MeOH, H2; (l) H2SO4 in TFA or MsOH in DCM; (m) NaI, TMSCl, CH3CN, reflux; (n) fractional crystallization, chiral HPLC or chiral SFC; (o) Cl(CO)OCH(CH3)Cl, DIPEA,
DCE, 40 °C; (p) MeOH.
enzymes (>1000-fold). Since 2 lacked an in vivo cardiovascular
risk,8 despite weak hERG channel inhibition, we reasoned that
compounds with hERG IC50/H1 Ki selectivity of 400 or greater
would be acceptable for lead candidates. To minimize the risk asso-
ciated with next day impairment, only H1-antihistamines with a
projected half-life of 18 h or less were considered acceptable.10
Various synthetic schemes were employed to generate benzo-
thiophenes 3 (Schemes 1–3) dependent on the availability of rele-
vant starting materials. A Heck reaction of bromide 48 with n-butyl
vinyl ether, followed by hydrolysis, gave the acetyl intermediate
5.11 Addition of a lithium heteroaryl, generated in situ from the
heteroarene or heteroaryl bromide, yielded alcohol 7. Alterna-
tively, lithium–halogen exchange of bromide 4, followed by the
Scheme 2. Reagents and conditions: (a) Br2, CHCl3; (b) NaH, BnBr, DMF, 0 °C (c) s-
addition of a heteroaryl nitrile and subsequent acidic hydrolysis,
afforded the heteroaryl ketone 6, which was converted to the alco-
hol 7 by addition of MeLi or MeMgBr. An alternative route to ke-
tone 6 was developed involving lithium–halogen exchange of
bromide 4, followed by treatment with a heteroaryl aldehyde
and a subsequent oxidation. Compound 7 was either dehydrated
with a strong acid followed by hydrogenation, or directly deoxy-
genated with in situ TMSI to yield 8–13.12 Alternatively, ketone 6
was subjected to a Wittig reaction, followed by hydrogenation to
yield 8, 9, 12 and 13. Fractional crystallization or chiral chromatog-
raphy (HPLC or SFC) of racemic 8–13 afforded the enantiomers 14–
21.13 Demethylation of 14 to generate the secondary amine 22 was
accomplished with 1-chloroethyl chloroformate followed by treat-
ment with methanol. (See Supplementary data for specific syn-
thetic steps to each final compound.)
BuLi, TMEDA, PyrCN, toluene, À78 °C; (d) 6 N HCl, MeOH; (e) MeLi or MeMgBr,
toluene, À78 °C; (f) TMSCl, NaI, CH3CN, reflux; (g) MsCl, Et3N, DCM, 0 °C; (h)
R1R2NH, IPA, 85 °C; (i) chiral HPLC.
Scheme 3. Reagents and conditions: (a) (i) Cl(CO)OCH(CH3)Cl, DIPEA, DCE, 40 °C;
(ii) MeOH; (b) Boc2O, DCM; (c) n-BuLi, TMEDA, CH3C(O)H, toluene, À78 °C; (d) MsCl,
DIPEA, DCM, 0 °C; (e) HetAryl/NaH, DMF, rt to 80 °C; (f) 50% TFA in DCM, 0 °C; (g) aq
HC(@O)H, NaBH(OEt)3, THF; (h) Chiral HPLC or SFC.
Benzothiophenes, containing a cyclic amine, were generated
through an alternative sequence (Scheme 2). Alcohol 23 was trea-
ted with bromine, protected with a benzyl group and subjected to a
lithium–halogen exchange. Reaction with 2-pyridinecarbonitrile
followed by hydrolysis afforded the ketone intermediate 24. After

2318
W. J. Moree et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2316–2320
Table 2
addition of MeLi, treatment with TMSCl/NaI resulted in both deox-
ygenation and removal of the protecting group to yield alcohol 25.
Conversion of the alcohol to the mesylate, displacement with cyclic
amines followed by chiral HPLC, gave the desired (À)-R enantio-
mers 26.
SAR profiles of substituted 2- and 3-pyridyl-benzothiophenes
N-Linked heterocycle substituted benzothiophenes 28
(Scheme 3) were prepared from 4 by a sequence that involved a
temporary conversion of –NMe2 to –NMeBoc via demethylation
and Boc protection. Subsequent lithium–halogen exchange and
addition of acetaldehyde yielded 27. This alcohol was converted
to the mesylate and reacted with the sodium salts of different het-
erocycles. Removal of the Boc group and reinstallment of the Me
moiety by reductive amination, followed by chiral HPLC gave the
(À)-R enantiomers 28. The NMeBoc group was required to prevent
intramolecular cyclization of the mesylate intermediate. More effi-
cient syntheses were developed for compounds 28 with promising
in vitro profiles.14
Compounds were tested in an histamine H1 receptor binding as-
say.8 To confirm initial selectivity, compounds were assessed for
M1 receptor binding affinity8 and inhibition of CYP2D6 and
CYP3A4.8 Selectivity over the hERG channel was evaluated using
the high-throughput dofetilide binding assay.15 Compounds of
interest were subsequently tested in an hERG patch clamp func-
tional assay.8 (Tables 1–4).
a,b
Compd
Isomer
R4
H1 Ki
CYP2D6c
hERGe
IC50 (lM)
(nM)
IC50
(
lM)
8b
8c
8d
14b
14c
14d
14e
14f
9b
rac
rac
rac
(À)-R
(À)-R
(À)-R
(À)-R
(À)-R
rac
4-Me
6-OMe
6-F
3-Me
3-OMe
3-F
390 15
59 10
38
9.3 0.8
5.0 2.0
2.7 0.3
8.0 1.3
13
69
120 15
17
2.9 0.2
1.7 0.2
2.9 0.5
NTd
NT
NT
5.5
9.5
4.0
1.5
>10
NT
NT
NT
NT
0.91
3.0
0.33
NT
0.24
NT
NT
NT
1.8
2.3
1.5
4
3-Cl
5-F
2
8
6-Me
6-OMe
2-Me
2-OMe
2-F
9c
rac
NT
16b
16c
16d
16e
(À)-S
(À)-S
(À)-S
(À)-S
1
>10
9.6
7.5
9.5
2-Cl
a
SEM for Ki values derived from dose–response curves generated from triplicate
or more data points.
Benzothiophene 2,8 was a high affinity H1-antihistamine with a
good selectivity profile and moderate hERG activity. Similar to
dimethindene,7 the (+)-S enantiomer (15a) showed significantly
lower affinity and selectivity for H1 than its (À)-R enantiomer. This
observation was consistent in all the enantiomeric pairs we stud-
ied. A tertiary amine was more potent and selective than a second-
ary amine as exemplified by comparison of 2 to 22. Incorporation
of cyclic amines at NR1R2 position (26a, 26b) yielded compounds
with similar affinity to 2 and promising in vitro profiles albeit with
a slight increase in hERG inhibition. Examination of the role of the
nitrogen position in the pyridine indicated that the 3-pyridine
(16a) had a very similar profile to 2 with marginally lower selectiv-
ity for the hERG channel. The racemic 4-pyridine (10) did not ap-
pear to offer an advantage with respect to H1 affinity and
selectivity, and therefore the enantiomers were not profiled.
b
M1 Ki > 10 lM for all compounds except for 14d (Ki = 2.2 lM).
c
d
e
CYP3A4 IC50 > 10
NT = not tested.
lM.
In dofetilide binding assay: hERG Ki > 5 M for all compounds except for 14f
M).
(Ki = 2.5
l
Subsequent SAR focused on the substituent effect of Me, OMe, F,
and Cl in both the 2-pyridyl and 3-pyridyl moieties. Initially, the
racemates were assessed for H1 binding and when affinity was suffi-
cient (Ki <25 nM), the (À) enantiomers were isolated and profiled
against H1, M1, CYP2D6, CYP3A4 and hERG (Table 2). These data indi-
cated that substitution in the 4- (8b) or 6-position (8c, 8d) of the
2-pyridyl moiety reduced H1 binding. In contrast, substitution at
the 3-position of the 2-pyridine was tolerated (Ki of racemates
<20 nM). Of the enantiomers, the 3-F analog (14d) had highest H1
Table 1
Primary profile of unsubstituted pyridyl-benzothiophenes
R1
R2
H1 Ki (nM)
M1 Ki (
lM)
CYP2D6d IC50
(l
M)
hERGe Ki (
l
M)
hERGf IC50
(lM)
b
c
Compd
Isomer
8a
2
rac
Me
Me
Me
H
Me
Me
Me
Me
12 1.5
4.0 0.5
256 16
1.4
5.3
0.99
3.7
5.8
>10
4.7
28
6.9
28
>5
>5
>5
>5
1.1
4.2
>5
>5
>5
1.8
NTg
1.4
NT
6.5
NT
0.73
NT
0.49
NT
(À)-R
(+)-S
(À)-R
(À)-R
(À)-R
rac
15a
22
26a
26b
9a
16a
17a
10
3.3
9.8
2.7
>10
7.3
5.2
2.0
0.85
32
6
–(CH2)4–
–(CH2)3–
6.1 1.2
3.9 0.9
Me
Me
Me
Me
Me
Me
Me
Me
10
2
(À)-Sa
(+)-Ra
rac
3.5 0.6
79
23
4
2
>10
5.6
NT
a
b
c
d
e
f
R/S nomenclature inverted.
SEM for Ki values derived from dose–response curves generated from triplicate or more data points.
Ki values derived from dose–response curves generated from duplicate data points.
CYP3A4 IC50 >10 lM except for 16a (IC50 = 4.0 lM) and 10 (IC50 = 2.8 lM).
Dofetilide binding assay.
Patch clamp analysis.
NT = not tested.
g

W. J. Moree et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2316–2320
2319
Table 3
SAR profiles of pyridine isosteres
a
b
Compd
Isomer
R3
H1 Ki (nM)
M1 Ki (nM)
CYP2D6c IC50 (nM)
856
hERGd IC50
NTe
(lM)
11
rac
35
2072
4759
N
S
18
20
(À)-R
(À)-R
4.6
5.2
4
2
4926
1.7
NT
N
S
S
>10,000
>10,000
N
N
N
28a
28b
rac
122
4.4
NT
8012
NT
2.0
N
(À)-R
3
>10,000
>10,000
N
a
b
c
SEM for Ki values derived from dose–response curves generated from triplicate or more data points.
Ki values derived from dose response curves generated from duplicate data points.
CYP3A4 IC50 values >10 lM for all compounds, except for 28a CYP3A4 IC50 = 5.2 lM.
In dofetilide binding assay: hERG Ki >5 lM for all compounds.
d
e
NT not tested.
Table 4
hERG Selectivity and pharmacokinetic parameters for key compoundsa
Compd
hERG IC50/H1 Ki
Pred hClsys (ml/min/kg)
[P]b 4 h (ng/mL)
[B]b 4 h (ng/g)
B/Pb 4 h
hClsysc,e (ml/min/kg)
Humanc AUC0-t (h ng/mL)
2
339
629
1370
443
9.7
14.8
13.5
6.0
2.8
37.5
3.0
23
347
83
8
9
26
20
6.2 (5.8–7.2)
NTd
12.1 (4.6–18.5)
NT
2.78 (1.90–4.23)
NT
0.64 (0.21–1.86)
NT
16c
16d
28b
0.6
11
a
b
c
All compounds highly permeable (Caco-2: Papp > 21.7 Â 10À6 cm/s; A > B/B > A > 0.7), no evidence for pGP substrate.
Rat 30 mpk oral.
Microdose of 0.1 mg/kg; data are median values of four individual subjects; data in parentheses are the range of four subjects (for full details see Ref. 17).
NT not tested.
Calculated for an average weight of 60 kg.
d
e
affinity. However, hERG inhibition for this and the 5-F analog 14f
was increased compared to 2. The 3-OMe analog (14c) had compara-
ble H1 affinity to 2 with a marginally improved selectivity versus
hERG. These data along with the profile of methyl analog (14b) sug-
gested an electronic effect at the 3-position on hERG affinity. In the
case of the 3-pyridyl moiety, substitutions at the 6-position were
not tolerated (9b, 9c) whereas substitutions at the 2-position met
the definedcriteria for affinity. Interestingly, in the3-pyridyl subser-
ies the 2-OMe, 2-F and 2-Cl compounds (16c, 16d, 16e) all demon-
strated improved in vitro profiles. H1 affinities were comparable to
16a, while selectivities versus hERG were significantly improved.
In contrast, the 2-Me substituent (16b) resulted in an H1-antihista-
mine with reduced binding. Electronic effects were not apparent
for this subseries, resulting in improved selectivity profiles for these
compounds compared to the 2-pyridyl subseries.
were comparable to 2, with the pyrazole 28b demonstrating
acceptable selectivity versus hERG (hERG/ H1 Ki = 443).
Compounds with the best primary profiles (16c, 16d and 28b)
were subsequently screened against other receptor off-targets
(M3, H3 and 5HT2A) and assessed for pharmacokinetic parameters
(Table 4) to determine how they compared to 2.8 Compounds
exhibited >1000-fold selectivity over these three off-target recep-
tors, except 16c (400-fold selective over 5HT2A) and 28b (200-fold
selective over H3). Predicted microsomal stability in humans (HLM
assay8) indicated that both 16c and 16d showed higher clearance,
whereas 28b appeared more stable relative to 2. Like benzothio-
phene 28, compounds 16c, 16d and 28b were unstable in rat liver
microsomes with projected clearances approaching hepatic blood
flow rate (Pred. systemic clearance >67 ml/min/kg). Discrete oral
PK studies of these compounds in rat at a relatively high dose
(30 mpk) indicated that each of these compounds was brain-pene-
trating as judged by B/P ratios (4 h post dose) with brain levels suf-
ficient to produce efficacy in a rat EEG/EMG model.16 Subsequently,
efficacy was demonstrated for 16c and 16d and found to be com-
parable to 2 (See Supplementary data).8
Compounds 3 with pyridine isosteres (R3) were also investi-
gated (Table 3). The racemates of either a 4- or 5-thiazolyl moiety
were tolerated in the H1 pharmacophore (Ki <20 nM), whereas the
2-thiazolyl analog (11) had reduced binding. While introduction of
a N-1 pyrazole moiety was acceptable, the corresponding imidazo-
lyl modification (28a) negatively impacted H1 binding. The primary
profiles of the enantiomers for the active racemates (18, 20, 28b)
As a higher clearance alternative with lower projected half-life,
16d was selected for comparison of pharmacokinetic profile to 2 in

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W. J. Moree et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2316–2320
a human microdose study.17 While clearance projections from allo-
metric scaling were reasonably predictive (predicted clearance:
13.5 mL/min/kg, measured mean clearance: 12.1 mL/min/kg), the
measured human half-life for 16d was longer than anticipated
(13 h vs the estimate of 1.6 h predicted from allometry) and longer
than for 2 (6.8 h). This discrepancy in half-life prediction was
attributed to both an underestimate of the volume of distribution
of 16d (Vss measured as 5.6 L/kg in humans16 versus 1.7 L/kg from
allometric scaling) and an overestimate of clearance. Even though a
small sample size was used in the microdose study, 16d showed an
increasing trend to high variability in exposure compared to 2 fol-
lowing both iv (hClsys, Table 4) and oral dosing (AUC0-t, Table 4).
PK variability in our leads was considered a significant issue be-
cause of the potential for varying exposures to adversely impact
duration of action. Although a specific mechanism for the higher
variability remains unclear, the higher clearance of 16d compared
to 2, coupled with lower bioavailability (23% vs 47% for 2) is con-
sistent with mechanistic expectations that reduced metabolic sta-
bility generally contributes to increased variation in PK profile.17
Based on these human PK data, neither compound 16d nor 2 was
pursued further. The more stable 28b may therefore represent a
more suitable backup to 2 and warrants further assessment.
In summary, discrete modifications around a lead benzothio-
phene 2 provided several compounds with a comparable in vitro
profile and a small improvement in hERG selectivity. From rat PK
studies, compounds with a range of projected human half-lives
were identified. Compound 16d was chosen as a representative
high clearance compound and assessed in a human microdose
study. In contrast to allometric projections, this compound had a
longer half-life in humans compared to 2. Unfortunately, both
compounds 2 and 16d showed a trend to high PK variability indi-
cating neither analog was suitable for further development. Com-
pound 28b, with improved metabolic stability, may represent the
more promising backup candidate.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2010.01.134.
References and notes
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9. The corresponding achiral analog of 2 with a methylene moiety instead of the –
CH(CH3) group had H1 Ki = 30 nM and CYP2D6 IC50 = 2157 nM.
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Seiden, D.; Lankford, A. Sleep 2007, 30, 1555; (b) Virtanen, R.; Scheinin, M.;
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13. Key chiral products were characterized by chiral SFC and/or optical rotation.
Crystallographic data were obtained for compounds 28, and 26b to confirm
absolute stereochemistry.
14. Larger quantities of pyrazole 28b were synthesized from 5 by treatment with
NH2NH2/EtOH at 100 °C, followed by a reduction with NaCNBH3 in 50% aq
HOAc to yield the hydrazine, and
bis(dimethyl acetal) in conc. HCl/EtOH at 95 °C and subsequent chiral SFC
separation.
a cyclization using malonaldehyde
15. Coon, T.; Moree, W. J.; Li, B.; Yu, J.; Zamani-Kord, S.; Malany, S.; Santos, M. A.;
Hernandez, L. M.; Petroski, R. E.; Sun, A.; Wen, J.; Sullivan, S.; Haelewyn, J.;
Hedrick, M.; Hoare, S.; Bradbury, M. J.; Crowe, P. D.; Beaton, G. Bioorg. Med.
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Acknowledgments
16. Unpublished data has indicated that compounds that achieve brain
concentrations >10 ng/g during this time period produce significant increases
in nonrapid eye movement (NREM) sleep.
17. Madan, A.; O’Brien, Z.; Wen, J.; O’Brien, C.; Farber, R. H.; Beaton, G.; Crowe, P.
D.; Oosterhuis, B.; Garner, R. C.; Lappin, G.; Bozigian, H. P. Br. J. Clin. Pharmacol.
2009, 67, 288.
The authors wish to thank Michael Johns for permeability
determinations, John Harman, Shawn Ayube and Chris DeVore for
analytical support. Dr. Tao Hu and Mila Lagman for chiral separa-
tions and Dr. John Saunders, Dr. Paul Conlon, Dr. H. Bozigian, and
Dr. Wendell Wierenga for program support.