Tetrahydronaphthalene-derived amino alcohols and amino ketones as potent and selective inhibitors of the delayed rectifier potassium current I Ks

Article abstract of DOI:10.1016/j.bmcl.2003.10.003

Class III anti-arrhythmic drugs (e.g., dofetilide) prolong cardiac action potential duration (APD) by blocking the fast component of the delayed rectifier potassium current (I_Kr). The block of I_Kr can result in life threatening ventr

Full text of DOI:10.1016/j.bmcl.2003.10.003

Bioorganic & Medicinal Chemistry Letters 14 (2004) 99–102
Tetrahydronaphthalene-derived amino alcohols and amino
ketones as potent and selective inhibitors of the delayed rectifier
potassium current IKs
Saleem Ahmad,* Lidia Doweyko, Aaila Ashfaq, Francis N. Ferrara, Sharon N. Bisaha,
Joan B. Schmidt, John DiMarco, Mary Lee Conder, Tonya Jenkins-West,
Diane E. Normandin, Anita D. Russell, Mark A. Smith, Paul C. Levesque,
Nicholas J. Lodge, John Lloyd, Philip D. Stein and Karnail S. Atwal
Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 4000, Princeton, NJ 08543, USA
Received 2 July 2003; revised 30 September 2003; accepted 5 October 2003
Abstract—Class III anti-arrhythmic drugs (e.g., dofetilide) prolong cardiac action potential duration (APD) by blocking the fast
component of the delayed rectifier potassium current (IKr). The block of IKr can result in life threatening ventricular arrhythmias
(i.e., torsades de pointes). Unlike IKr, the role of the slow component of the delayed rectifier potassium current (IKs) becomes sig-
nificant only at faster heart rate. Therefore selective blockers of IKs could prolong APD with a reduced propensity to cause pro-
arrhythmic side effects. This report describes structure–activity relationships (SARs) of a series of IKs inhibitors derived from 6-
alkoxytetralones with good in vitro activity (IC50 ꢀ30 nM) and up to 40-fold IKs/IKr selectivity.
# 2003 Elsevier Ltd. All rights reserved.
Potassium currents in cardiac myocytes play an impor-
tant role in repolarization of the membrane potential
after each contraction. Potassium channel blockers
delay repolarization and prolong action potential dura-
tion (APD) thus producing a class III anti-arrhythmic
effect.1 The delayed rectifier potassium current (IK) is
conducted through potassium channels that exhibit slow
(IKs), rapid (IKr) and ultra-rapid (IKur) activation–deac-
tivation kinetics.2À4 Current class III anti-arrhythmic
therapies are based on prolonging action potential
duration by blocking IKr (dofetilide 1, azimilide 2) and
thus have the potential to cause life-threatening ven-
tricular arrhythmias (i.e., torsades de pointes).5 Because
of the slow activation kinetics of IKs, the contribution of
this current is minimal at normal heart rates. However,
at faster heart rates this current accumulates and plays a
significant role in the repolarization of membrane
potential. Therefore, selective blockade of this current
can be an effective way of lengthening APD only at fast
heart rate with no negative rate dependence and poten-
tially reduced pro-arrhythmic risk relative to agents that
block IKr.6 Furthermore, several IKs blockers have been
evaluated in dogs and have shown efficacy in models of
atrial and ventricular arrhythmias suggesting their
potential utility for the treatment of these conditions.7a,b
Several groups have reported discovery of selective IKs
blockers and reviews describing their potential as anti-
arrhythmic agents have been published.8aÀd We had
previously disclosed a novel benzamide series of highly
9
potent and selective blockers of IKs
.
This report
describes synthesis and structure–activity relationship of
a series of tetrahydronaphthalene derivatives based on
the initial screening lead 3 (IC50=5 mM) (Fig. 1).10,11
Compounds 4b and 4c were prepared by reacting 6-
methoxytetralone (4a) with refluxing 48% HBr to afford
6-hydroxytetralone (84% yield)12 followed by treatment
with respective alkyl bromides in the presence of potas-
sium carbonate in dimethylformamide (55–65% yield).
Compound 4d was prepared in 41% yield by heating a
mixture of 6-hydroxytetralone with bromobenzene in
the presence of CuCl and KHCO3 in a sealed tube at
200 ꢁC. Treatment of 6-hydroxytetralone with tri-
fluoromethanesulfonic anhydride in methylene chloride
in the presence of pyridine afforded the corresponding
* Corresponding author. Tel.:+1-609-252-6955; fax:+1-609-252-6804;
e-mail: saleem.ahmad@bms.com
0960-894X/$ - see front matter # 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2003.10.003

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S. Ahmad et al. / Bioorg. Med. Chem. Lett. 14 (2004) 99–102
sodium borohydride in THF-diglyme at À78 ꢁC to rt
followed by a careful workup under weakly acidic (pH
4–4.5) conditions to afford 11 as 8:1 trans/cis mixture.14
The crude hydroxy acid 11 was converted to the trans
lactone 12a by treatment with 1-(3-dimethylaminopro-
pyl)-3-ethylcarbodiimide hydrochloride (EDCI) and N-
methylmorpholine followed by silica gel chromato-
graphy (54% yield, two steps). DIBAL reduction of the
lactone 12a in toluene at À78 ꢁC afforded the trans
hydroxy aldehyde 13a in 92% yield. The predominantly
trans hydroxy acid 11 was also converted to the cis lac-
tone 12b by treatment with catalytic (1%, by wt) p-
TsOH in refluxing toluene-diglyme (68% yield, 2 steps).
DIBAL reduction of this compound afforded the cis
lactol 13b in 90% yield. The trans hydroxy aldehyde 13a
and the cis lactol 13b were readily converted to the cor-
responding amino alcohols 14a and 14b, respectively, by
reductive amination with 4-phenylpiperidine and
Na(OAc)3BH in THF in 80–90% yield (Scheme 2).
Figure 1.
triflate (99% yield). This was converted (98% yield) to
the biaryl compound 4e via Suzuki coupling with phe-
nylboronic acid in the presence of a catalytic amount of
tetrakis(triphenylphosphine)palladium(0) and potas-
sium carbonate in toluene at 80 ꢁC.
While most compounds were tested for biological activ-
ity10 as racemates, several key compounds were resolved
by chiral chromatography and evaluated in enantio-
merically pure form for activity.16 The lead amino-
ketone 3 displayed only modest inhibition of IKs
(IC50=5 mM, see Table 1). However, this compound
had a limited solution stability as it underwent a slow
retro Mannich degradation. Efforts made to stabilize 3
without substantially sacrificing the IKs inhibitory
activity included homologation of the group linking the
4-phenylpiperidine moiety to the tetrahydronaphthalene
group and reduction of the ketone group to an alcohol.
Thus the homologous ethylene analogue 8a was pre-
pared and evaluated for biological activity. When com-
pared to the parent lead 3 (racemic), compound 8a
(homochiral, IC50=0.4 mM) showed a ca. 12-fold
increase in the IKs inhibitory activity. The amide 6b was
inactive at 30 mM perhaps indicating a need for the
presence of a charged interaction at the binding site.
Efforts to optimize substituents at the 6-position of the
tetralone group resulted in the discovery of the 6-ben-
zyloxy compound 8b (IC50=69 nM) with ca. 70-fold
improvement in potency. Although more potent than
the parent lead 3, the phenoxy and phenyl analogues 8d
and 8e were significantly less potent than the corre-
sponding benzyloxy compound. Replacement of the
Treatment of tetralones 4a–e with equimolar lithium
bis(trimethylsilyl)amide and hexamethylphosphoramide
(HMPA) at 0 ꢁC in THF, followed by treatment with
ethyl bromoacetate (3 equivalents) at rt afforded the
corresponding keto esters which were hydrolyzed to give
the keto acids 5a–e in 60–70% yield (two steps). Cou-
pling of 5a–e with 4-phenylpiperidine was carried out in
N,N-dimethylformamide (DMF) in the presence of BOP
reagent and N-methylmorpholine (90–95% yield) to
give the keto amides 6a–e. Lithium aluminum hydride
reduction of the keto amides gave amino alcohol 7a–e
(ca. 3:1 trans/cis, 80–90% yield). The amino ketones 8a,
b, 8d and 8e were prepared via oxidation of the corre-
sponding alcohols with Dess–Martin’s periodinane13 or
Jones reagent (75–85% yield). Compounds 10a–f were
conveniently prepared from 8b via hydrogenolysis fol-
lowed by alkylation of the resulting phenol 9 with var-
ious benzyl halides (Scheme 1).
The trans and cis amino-alcohols 14a and 14b were
initially prepared by resolving a mixture of the two
compounds (7c). Subsequently,
a
more efficient
approach was developed. The key step in this route
involves a stereoselective reduction of the keto acid 5c
to the hydroxy acid 11 which could be achieved with
Scheme 1. (a) (Me3Si)2NLi/HMPA/THF at 0 ꢁC then ethyl bromoacetate at rt; (b) aqueous KOH/dioxane/60–70% yield (two steps); (c) BOP reagent/
4-phenylpiperidine/N-methylmorpholine/DMF/90–95% yield; (d) LAH/THF/80–90% yield; (e) Dess–Martin periodinane/t-BuOH/methylene chlo-
ride or Jones reagent, 75–85%; (f) H2/10% Pd/C/EtOH–EtOAc/88% yield; (g) ArCH2Cl or ArCH2Br/K2CO3/n-Bu4NI/DMF 90–95% yield.

S. Ahmad et al. / Bioorg. Med. Chem. Lett. 14 (2004) 99–102
101
Scheme 2. (c) EDCI hydrochloride/N-methylmorpholine/methylene chloride-diglyme/0 ꢁC/54% yield for two steps; (d) DIBAL/toluene/À78 ꢁC/90–
92% yield; (e) 4-phenylpiperidine/Na(AcO)3BH/HOAc/THF/80–90% yield; (f) 1% (by wt) p-TsOH/toluene-diglyme/reflux/68% yield.
Table 1. IKs and IKr activity of the various tetrahydronaphthalene
derived analoguesa
optimized to afford compounds with good potency and
selectivity. Furthermore, a stereoselective synthetic
approach based on utilizing a common intermediate
(trans hydroxy acid 11) to give either the trans or the cis
amino alcohols (14a or 14b) has been developed.
Compd #
IKs IC50 (mM)
IKr IC50 (mM)
3
6b
5
>30
4
ND
7b
8a
8b
8d
0.15 (1.3)b
0.4 (1.7)b
0.069 (2.2)b
1.5
0.17 (0.11)b
1.7 (ND)b
0.16 (0.22)b
ND
Acknowledgements
8e
2.4
1.3
0.38
0.2
ND
ND
ND
ND
We greatly appreciate the support of Bristol-Myers
Squibb Department of Analytical Sciences.
10a
10b
10c
10d
10e
10f
14a
14b
0.03 (0.34)b
0.47
0.26 (1.6)b
ND
ND
1.5 (ND)b
ND
References and notes
1
0.037 (1.0)b
0.39
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benzyloxy group (compound 8b) with pyridyl (10a–c)
resulted in significant loss of activity perhaps indicating
somewhat reduced hydrophobic interactions at the
binding site. A study of the effect of substituents on the
benzyloxy group resulted in the discovery of the 2-
(phenyl)phenylmethoxy analogue 10d (IC50=30 nM) as
the most potent compound prepared in this series.
The ketone functionality of several IKs inhibitors
described herein was replaced with a secondary alcohol.
Thus, while the benzyloxy amino alcohol 7b was ca. 2-
fold less potent than the corresponding amino ketone
8b, the 2(phenyl)phenylmethyl analogue 14a exhibited
potency comparable to the corresponding amino ketone
10d. Furthermore, evaluation of the trans amino alcohol
14a and the corresponding cis analogue 14b revealed
that the trans isomer was significantly more potent
(IC50=37 nM) than the cis compound (IC50=390 nM).
Several key compounds were evaluated for selectivity
for the IKs current over IKr. While most amino ketones
prepared in this series showed little to modest selectiv-
ity, the amino alcohol 14a was ca. 40-fold selective. In
conclusion, a novel series of potent IKs inhibitors has
been identified. The initial lead (compound 3) with
modest IKs activity and no selectivity over IKr was

102
S. Ahmad et al. / Bioorg. Med. Chem. Lett. 14 (2004) 99–102
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16. Compounds 7b, 8a, 8b and 10d were obtained in enantio-
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ALCEL1 OD column (hexane–isopropanol–triethyl-
amine 90:10:0.2–80:20:0.2). The more potent enantiomers
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