Parallel solid-phase synthesis of zatebradine analogues as potential If channel blockers

Article abstract of DOI:10.1016/S0960-894X(01)00424-3

The first solid-phase synthesis of zatebradine 1 and its analogues is reported. This has resulted in the preparation of compounds with increased ability to reduce the spontaneous beating of isolated guinea-pig atria in a concentration-dependent manner. One example, 8g, showed a maximum reduction of beating of 80% at 3 μM compared to a reduction of 40% at 3 μM with zatebradine 1.

Full text of DOI:10.1016/S0960-894X(01)00424-3

Bioorganic & Medicinal Chemistry Letters 11 (2001) 2351–2354
Parallel Solid-Phase Synthesis of Zatebradine Analogues as
Potential If Channel Blockers
Anton Bom,b Susan Booth,a,* John Bruin,b John Clark,a Susan Millerb
and Bernard Watheya
aLead Discovery Unit, Organon Laboratories Ltd, Newhouse, Lanarkshire, ML1 5SH, Scotland, UK
bPharmacology Department, Organon Laboratories Ltd, Newhouse, Lanarkshire, ML1 5SH, Scotland, UK
Received 26 March 2001; revised 13 June 2001; accepted 20 June 2001
Abstract—The first solid-phase synthesis of zatebradine 1 and its analogues is reported. This has resulted in the preparation of
compounds with increased ability to reduce the spontaneous beating of isolated guinea-pig atria in a concentration-dependent
manner. One example, 8g, showed a maximum reduction of beating of 80% at 3 mM compared to a reduction of 40% at 3 mM with
zatebradine 1. # 2001Elsevier Science Ltd. All rights reserved.
Channel-mediated currents, consisting of small back-
ground currents such as IK1, IB and If and large voltage-
gated currents such as Ica and IK, play an important role
in the generation of spontaneous diastolic depolarisa-
tion and action potential of cardiac pacemaking cells.1,2
They can contribute to changes in spontaneous pace-
maker activity, affecting slow diastolic depolarisation
and hence threshold potential for action potential gen-
eration and resting potential of pacemaker cells. Selec-
tive reduction in heart rate with no important changes
in contractility and wall tension, may have several
advantages in the treatment of ischaemic heart dis-
eases.3 A slower heart rate would increase the diastolic
perfusion time, thus increasing coronary perfusion and
contractile function, and reduce the oxygen require-
ments of the myocardium.3
The synthesis of zatebradine analogues 8 and 9 is out-
lined below (Scheme 1).
Amines 3a–g were attached to REM resin7 by Michael
addition to give the resin-bound secondary amines 4a–g.
Attempted alkylation of 4a–g with N-chloro- or N-bro-
mopropylbenzazepinone under a variety of conditions
did not afford the desired products after cleavage from
the resin. Optimum conditions for alkylation were
found to be using N-iodopropylbenzazepinone 5 in
dimethylformamide DMF at 50 ꢀC in the presence of
diisopropylethylamine (DIPEA).8 The resultant tertiary
amine 6 was quaternised with activated alkyl halides
and the resin-bound quaternary salt 7 subsequently
treated with DIPEA to liberate the dehydrozatebradine
analogues 8. Products were purified by solid-phase
extraction (silica cartridges with dichloromethane–2%
ammonia saturated methanol as eluent). Subsequent
cleavage from the resin followed by hydrogenation
afforded the zatebradine analogues 9.4
Zatebradine 1 is a representative compound of the
therapeutic class of sino-atrial node modulators which
has been shown to inhibit the hyperpolarisation-acti-
vated current If.3À5 Selective blockade of the If current
causes a slowing down of the spontaneous rate of firing
of the pacemaker cells without resulting in abolition of
pacemaker activity.6
*Corresponding author. Tel.: +44-1698-736000; fax: +44-1698-
736187; e-mail: s.booth@organon.nhe.akzonobel.nl
0960-894X/01/$ - see front matter # 2001Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(01)00424-3

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A. Bom et al. / Bioorg. Med. Chem. Lett. 11 (2001) 2351–2354
Scheme 1.
Preliminary biological data suggested that the dehy-
drozatebradine analogues 8 also inhibited the If current
to a similar degree as zatebradine itself. It was, there-
fore, decided to prepare a library of 21compounds
comprising of seven different amines at R1 and three
different alkyl halides at R2 (Table 1).
experimental method does not differentiate between the
blockade of the If channel and blockade of the L-type
calcium channel. Compounds that block both channels
will show a stronger inhibition than compounds that
act at one single channel. To differentiate between the
two mechanisms, vascular preparations that lack the If
channel but retain the L-type calcium channel will be
needed
The effects of dehydrozatebradine analogues 8a–o on
the rate of beating were studied in isolated guinea-pig
atria. The potency and efficacy data are summarised and
compared to zatebradine in Table 2. Eight compounds
(8b, e, g, h, j, k, l and n) showed a stronger inhibition,
four compounds (8a, c, f and m) were similar, whilst
three (8d, i and o) were less effective than zatebradine at
3 mM. There is no conclusive structure–activity rela-
tionship which can be drawn from the data, as the
A solid-phase synthesis of zatebradine and its analogues
has been developed allowing the rapid synthesis of a 21-
compound library. This has resulted in the discovery of
a series of compounds with increased ability to reduce
the spontaneous beating of isolated guinea-pig atria.
Further studies are needed to study the putative actions
on calcium channels.
Table 1. Library building blocks
R1-NH2 (3)
R2-X

A. Bom et al. / Bioorg. Med. Chem. Lett. 11 (2001) 2351–2354
2353
Table 2. Effects of amines on beating rate
R1
R2
Beating rate9
% inhibition at 3 mM
Max. inhibition
8a
42Æ11
53Æ0
100Æ0
8b
8c
8d
8e
8f
80Æ6
100Æ0
Æ2
44Æ27
31Æ160
54Æ3
91Æ9
84Æ16
81Æ2
Æ4
43Æ11
80Æ2
8g
8h
8i
60Æ169
31Æ160
60Æ2
Æ2
8j
68Æ7
71Æ1
8k
8l
53Æ6
60Æ1
2
Æ2
Æ13
Æ8
8
69
7
8m
8n
8o
1
34Æ1
2
59Æ1
7
0
25Æ159
40Æ1
Æ4
Æ1
6
MeanÆSEM; n=2.

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A. Bom et al. / Bioorg. Med. Chem. Lett. 11 (2001) 2351–2354
the procedure outlined in ref 4. It was converted to N-iodo-
Acknowledgements
propylbenzazepinone by heating with sodium iodide (5 mol
equiv) in acetone under reflux for 12 h.
The authors thank R. Roy and W. Finlay for supplying
the N-iodopropylbenzazepinone.
9. Male Dunkin–Hartley guinea pigs (Harlan) of 250–300 g
were used throughout. Guinea pigs were killed by cervical
dislocation, the thorax opened and the right atria removed.
Atria were suspended on tissue holders in 30 mL organ baths
containing Krebs solution, maintained at 37 ꢀC and gassed
with 95% O2 and 5% CO2. The composition of Krebs was
References and Notes
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were left for approximately 1h to equilibriate. Resting force
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paration was tested with 0.1 mm (Æ)-isoprenaline. All pre-
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