Class III antiarrhythmic activity in vivo by selective blockade of the slowly activating cardiac delayed rectifier potassium current I(Ks) by (R)- 2-(2,4-trifluoromethyl)-N-[2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)-2,3- dihydro-1h-benzo[e][1,4]diazepin-3-yl]acetamide

Full text of DOI:10.1021/jm970517u

J . Med. Chem. 1997, 40, 3865-3868
3865
Most selective class III antiarrhythmic agents, nota-
bly D-sotalol,9 dofetilide,10 and MK-4998 from these
laboratories, selectively block Ikr.11 Recent work on IKr
blocking agents has shown the tendency of members of
this class to exhibit proarrhythmic effects in vivo. The
incidence of the polymorphic ventricular tachycardia
torsade de pointes has been significant (2-5%) in
clinical trials with IKr blocking class III agents.12 The
proarrhythmia seen with this class is related to their
reverse rate dependent effects on cardiac refractori-
ness13 whereby they prolong APD more at slow rates
than at rapid rates. Exaggeration of this effect may
occur at very slow rates leading to exaggerated QT
intervals and early afterdepolarizations14 which are
thought to be one mechanism of torsade de pointes.15
Conversely, at faster heart rates the class III effect of
these compounds (lengthening of ERP, QT interval
prolongation) is diminished leading to lowered efficacy.
Cla ss III An tia r r h yth m ic Activity in Vivo
by Selective Block a d e of th e Slow ly
Activa tin g Ca r d ia c Dela yed Rectifier
P ota ssiu m Cu r r en t IKs by (R)-2-(2,4-
Tr iflu or om eth yl)-N-[2-oxo-5-p h en yl-
1-(2,2,2-tr iflu or oeth yl)-2,3-d ih yd r o-
1H-ben zo[e][1,4]d ia zep in -3-yl]a ceta m id e
Harold G. Selnick,*,† Nigel J . Liverton,†
J ohn J . Baldwin,† J ohn W. Butcher,†
David A. Claremon,† J ason M. Elliott,†
Roger M. Freidinger,† Stella A. King,†
Brian E. Libby,† Charles J . McIntyre,†
David A. Pribush,† David C. Remy,† Garry R. Smith,†
Andrew J . Tebben,† Nancy K. J urkiewicz,‡
J oseph J . Lynch,‡ J oseph J . Salata,‡
Michael C. Sanguinetti,‡ Peter K. S. Siegl,‡
Donald E. Slaughter,§ and Kamlesh Vyas§
Because IKs deactivates slowly, it tends to become
relatively more important for repolarization at faster
rates. A selective IKs blocker would therefore not
demonstrate reverse use dependence.11,17 Such a class
III agent would then be inherently safer than a blocker
of IKr. Currently there are no selective IKs blocking class
III antiarrhythmic agents in use. Several marketed
compounds, including amiodarone,18 as well as at least
one compound in development, Azimilide,19 exhibit
blockade of IKs as part of their spectrum of pharmaco-
logical activity. Amiodarone is a nonspecific agent that
interacts with a variety of ion channels and receptors
but has shown utility as an effective antiarrhythmic
agent. Azimilide predominantly blocks IKr and also
effects L-type Ca channels. Described herein is a sum-
mary of the discovery of L-768,673 (1), an orally active,
potent, and selective IKs blocking agent that exerts
significant class III activity in vivo and does not cause
early afterdepolarizations in vitro.
Departments of Medicinal Chemistry, Pharmacology, and
Drug Metabolism, Merck Research Laboratories,
West Point, Pennsylvania 19486
Received August 4, 1997
The high incidence of sudden cardiac death (SCD) is
of continuing medical concern.1,2 The primary mecha-
nism of SCD is the degeneration of normal cardiac
rhythm into ventricular tachycardia followed by ven-
tricular fibrillation.3 The underlying cause of these
rhythm disturbances in most cases is coronary artery
disease that has resulted in prior ischemic damage to
the heart. The classification system of Vaughn Wil-
liams,4 defines several major classes of antiarrhythmic
action. Class I antiarrhythmic agents block sodium
channels, thereby inhibiting impulse conduction and
contractility in the myocardium. Class II agents are â
blockers, and class III agents act by delaying repolar-
ization of cardiac myocytes. The consequence of delayed
repolarization is a lengthening of the action potential
duration (APD) of the cell and a concomitant increase
in the effective refractory period (ERP). The cardiac
arrhythmia suppression trial (CAST)5 demonstrated
that conventional antiarrhythmic treatment with cer-
tain class I agents actually increased mortality com-
pared with placebo. Since CAST, there has been in-
creasing interest in compounds that exert their antiar-
rhythmic effects by means other than sodium channel
blockade.6
Resu lts a n d Discu ssion . The observation that
compound 2, in development as a CCK-B antagonist,20
markedly increased the electrocardiographic QT interval
in dogs at high (100 mpk) oral doses led to its evaluation
in a single cell voltage clamp protocol. These studies
revealed that 2 was a potent blocker of IKs in isolated
guinea pig ventricular myocytes. The concentrations
required for 50% block of the IKs and IKr currents (IC50)
were 214 nM and 5000 nM, respectively (Table 1). The
S enantiomer 2b was significantly less potent (IC50
)
10 µM) for blockade of the IKs current. This key finding
of a moderately selective IKs blocker became the impetus
for a medicinal chemistry program.
The outward delayed rectifier potassium current, IK,
that contributes to repolarization, consists of two kineti-
cally distinct and identifiable currents, a rapidly acti-
Replacement of the urea group with amides at the
C-3 amine resulted in compounds that exhibited com-
parable potencies for blockade of IKs and minimized
CCK-B receptor affinity (compounds 3-10, Table 1). The
addition of halogens to the aryl ring greatly improved
activity of the benzoyl, phenylacetyl, and phenylpropio-
nyl series (compare compounds 4, 6, and 9 to 3, 5, and
8). The introduction of polar substituents on the amide
side chain resulted in severe losses of potency for IKs
blockade (compounds 11-13). It was clear that non-
polar, lipophilic substitution enhanced IKs blockade and
other lipophilic groups such as the cyclohexylpropion-
amide side chain provided potent inhibition of IKs (com-
pound 14). Removal of the N-1 methyl and replacement
7
vating, Ikr, and a slowly activating component, IKs
.
Selective blockade of either IKr or IKs would lead to a
prolongation of the refractory period and be, by defini-
tion, a class III effect. Clinically, changes in the APD
and ERP of ventricular cells are reflected in the length
of the QT interval of the electrocardiogram, thus provid-
ing a convenient, clinical measurement of drug action.
The development of an effective antiarrhythmic agent
for the prevention of SCD has been a long-standing goal
for these laboratories.8
† Department of Medicinal Chemistry.
‡ Department of Pharmacology.
§ Department of Drug Metabolism.
S0022-2623(97)00517-7 CCC: $14.00 © 1997 American Chemical Society

3866 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 24
Ta ble 1. Effect of Substitution on IKs Potency
Communications to the Editor
abs
conf
IKs
IKr IC50 (nM)c or
CCK-B IC50
(nM)e
compda
R
n
R′
IC50 (nM)b % inhn at concn (nM)
mp °C
220
2b20
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
1
R
S
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
0
0
0
0
1
1
1
2
2
0
0
2
2
2
2
2
2
0
0
1
0
1
1
1
1
m-NHPhCH3
m-NHPhCH3
phenyl
3,5-dichlorophenyl
phenyl
2,4-dichlorophenyl
2,4-bis(trifluoromethyl)phenyl
phenyl
2,4-dichlorophenyl
CHdCH-2,4-dichlorophenyl
CH(NH2)CH2Ph
4-aminophenyl
4-acetamidophenyl
cyclohexyl
cyclohexyl
2,4-dichlorophenyl
cyclohexyl
3,5-dichlorophenyl
3,5-dichlorophenyl
3,5-dichlorophenyl
3,5-dichlorophenyl
3,5-dichlorophenyl
2,4-dichlorophenyl
2,4-bis(trifluoromethyl)phenyl
2,4-bis(trifluoromethyl)phenyl
214
10000
600d
45d
5000
10000
2 ( 0.3
151 ( 12
>1000
R
R
R
R
R
R
R
R
R
R
R
R
RS
RS
R
R
S
23% at 1000
17% at 1000
31% at 1000
224-225
179-180
241-242
209-210
100-103
179
92-95
137-139
84-86
175-178
138-142
144-145
192-193
199-201
154-155
140-141
140-141
90-96
300d
35
>1000
140
200d
14d
32% at 1000
31% at 100
1500
>1000
>1000
>1000
>1000
>1000
>1000
>1000
6d
2800d
4400d
>10000
10d
8800
1000
100
1000
520d
20d
Me2NCH2CH2
i-Pr
i-Pr
i-Pr
i-Pr
F3CCH2
F3CCH2
F3CCH2
F3CCH2
F3CCH2
>1000
>1000
6
110
6% at 1000
R
R
R
R
S
10d
>1000
11d
25% at 100
4000
2400
35% at 1000
6000
140-143
93-100
143-145
30
9
60d
>1000
>1000
R
6d
132-134
a
b
All compounds gave satisfactory spectral and analytical data (C, H, and N; (0.4% of theoretical values). Molar concentration of
compound required to inhibit 50% of the IKs current in isolated guinea pig myocytes during a 1 s voltage clamp step from -50 to +50 mV
(n g 3 for all concentrations tested) (see ref 19 for protocol). IC50 value determined graphically from concentration response relationships.
c Molar concentration of compound required to inhibit 50% of the IKr current in isolated guinea pig myocytes during a 0.5 s voltage clamp
step from -50 to -10 mV (see ref 19 for protocol). n g 4. e Concentration for half-maximal inhibition of binding of [125I]CCK-8 to receptors
d
in guinea pig cerebral cortex.20
with hydrogen was detrimental to IKs blocking activity
(compound 15). Incorporation of polar groups at this
position also had a detrimental effect on potency and
selectivity (compound 16). Replacement of the N-1
methyl group with lipophilic groups, such as isopropyl
or trifluoroethyl, gave compounds that were similar in
terms of in vitro potency for Iks (compounds 17-24). As
in the lead compound 2, optimal IKs activity requires
the absolute stereochemistry at C-3 to be R (compound
18 vs 19 and 1 vs 24)
Promising compounds were evaluated for oral activity
in dogs equipped with Holter monitors. At an oral dose
of 10 mpk compound 9 ellicited a QT interval prolonga-
tion of approximately 10% that dissipated over several
hours, indicating a clear, albeit short-lived, class III
effect. In vitro metabolic studies of 9 with liver micro-
somes, as well as literature precedent for related ben-
zodiazepines,21 suggested that N-1 dealkylation was a
major metabolic pathway. The N-1 trifluoroethyl series
was therefore chosen in an attempt to minimize this
particular pathway. In addition, several metabolites in
which the amide side chain had been hydroxylated were
isolated indicating that the aromatic ring, and side
chains were also major sites of metabolic degradation.
In view of these results compounds with shorter side
chains and electron withdrawing groups such as tri-
fluoromethyl (to minimize oxidation) on the aromatic
ring were studied. Of the compounds reported here, 1
displayed enhanced oral activity in Holter-monitored
dogs (Figure 1). At doses of between 0.1 and 1 mpk
there was a 5-15% increase in QT interval that
lasted for the duration of the monitoring period (15 h)
(Figure 1).
On the basis of its oral activity profile, 1 was chosen
for detailed pharmacological study. The full hemody-
namic profile of 1 in chloralose anesthetized dogs after
iv administration showed dose dependent increases in
QT intervals consistent with IKs blockade. There were
no significant changes in ventricular excitation thresh-
old, heart rate, or mean arterial pressure. There was
also no effect on A-V nodal or ventricular conduction.
After dosing as a methocell suspension, 1 had an oral
bioavailability of 27% in dogs and 40% in rats.
Further voltage clamp studies showed that 1 had no
effect on the inward rectifier K+ current (IK1) in isolated
guinea pig myocytes. In human atrial myocytes the
transient outward current (Ito) and ultrarapid activating
delayed rectifier, Ikur, were unaffected by 1. Human
Kv1.5 expressed in Xenopus oocytes was also unaffected
by the compound. At high concentrations (>300 nM) 1
blocked L-type calcium currents with an IC50 of 3 µM.
At doses sufficient to block all of the IKs current, 1
caused only a 30% increase in APD indicating a self-
limiting effect to IKs blockade with this compound. Also
there was no indication of early afterdepolarizations at
any of the concentrations tested. In contrast, at doses

Communications to the Editor
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 24 3867
F igu r e 1. Duration of Class III effect of 1 in conscious dogs after single dose administration. Compound 1 was administered
orally as a suspension in 1% methylcellulose at several doses. Class III activity was determined by examination of the
electrocardiographic QT interval as recorded on Holter monitors. Values are mean ( SEM.
Sch em e 1. Synthesis of 2a
a
Reagents: (a) bromoacetyl bromide, CH2Cl2 then NH4OH, EtOH (86%); (b) ICH2CF3, Cs2CO3, DMF (60%); (c) KOt-Bu, trisyl azide,
THF; (d) PPh3, THF, H2O (83% from 26); (e) Boc-D-Phe-OH, EDC, HOBT, DMF then HCl(g), EtOAc then separate diastereomers (46%);
(f) PhNCS, CH2Cl2 then TFA (71%); (g) 2,4-bis(trifluoromethyl)phenylacetic acid, EDC, HOBT then crystallize (78%).
sufficient to cause a 30% APD prolongation, IKr blockers
cause early afterdepolarizations.14
derivatizing with phenylalanine and removing the BOC
protecting group to give 30 after chromatographic
separation of the diastereomers.24 The absolute stereo-
chemistry was confirmed by single-crystal X-ray analy-
sis of 30. Removal of the phenylalanine via an Edman
degradation gave 3-R amine 31. Acylation of 31 with
2,4-bis(trifluoromethyl)phenylacetic acid gave 1.
In conclusion, the compounds based on the benzodi-
azepine nucleus described herein are potent and selec-
tive IKs blocking class III antiarrhythmic agents both
in vitro and in vivo. An appreciation for the in vitro
metabolism of compounds in this class has led to the
discovery of compound 1 which exhibits excellent oral
activity in dogs providing significant increases in elec-
trocardiographic QT interval for >15 h after a single
dose and displays good oral bioavailability. The com-
bination of in vitro selectivity and long lasting activity
after oral dosing suggest that 1 be considered a candi-
Ch em istr y. The preparation of 1 is shown in Scheme
1. Aminobenzophenone (25) was acylated with bro-
moacetyl bromide and then treated with ammonia in
ethanol to effect cyclization to the benzodiazepine
nucleus 26 in a modification of the published method.22
Alkylation of the amide nitrogen is accomplished with
trifluoroethyl iodide and cesium carbonate in DMF to
generate 27. The N-1 methyl compounds and the N-1
isopropyl compounds were prepared in a similar fashion.
The introduction of an amine at C-3 was carried out in
two steps using 2,4,6-trimethylbenzenesulfonyl azide as
the source of nitrogen. Treatment of 27 with potassium
tert-butoxide and then trisyl azide23 at -78 °C gave
azide 28 after workup. Reduction to the amine 29 was
conveniently done with triphenylphosphine. The reso-
lution of enantiomers was carried out at this point by

3868 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 24
Communications to the Editor
J . J .; Elliott, J . M.; Butcher, J . W.; Remy, D. C.; Ponticello, G.
S.; Selnick, H. G.; Lynch, J . J .; Sanguinetti, M. C. Selective IKr
Potassium Channel Blockers as Class III Antiarrhythmic Agents.
Perspect. Med. Chem. 1993, 389-404. (c) Elliott, J . M.; Selnick,
H. G.; Claremon, D. A.; Baldwin, J . J .; Buhrow, S. A.; Butcher,
J . W.; Habecker, C. N.; King, S. W.; Lynch, J . J ., J r.; Phillips,
B. T.; Ponticello, G. S.; Radzilowski, E. M.; Remy, D. C.; Stein,
R. B.; White, J . I.; Young, M. B. 4-Oxospirobenzopyran-2,4′-
piperidines as Class III Antiarrhythmic Agents; Pharmacological
Studies on 3,4-Dihydro-1′-[2-(benzofurazan-5-yl)ethyl]-6-meth-
anesulfonamidospiro [(2H)-1-benzo-pyran-2,4′-piperidine]-4-one
(L-691,121). J . Med. Chem. 1992, 35, 3973-3976.
date for evaluation in humans. More extensive phar-
macological evaluation of 1 and its congeners is ongoing
and will be the subject of forthcoming publications.
Ack n ow led gm en t. We thank Peter Guinoso and
Brian J ow for their technical assistance and perfor-
mance of Voltage clamp assays, Audrey Wallace and
Gary Stump for in vivo pharmacology studies, Deborah
Walsh for in vitro metabolic studies, Stephen Freedman
and Smita Patel for CCK assays, and Hossain J ohan-
sous for formulation studies. The X-ray crystal structure
of 30 was determined by Richard Ball of these labora-
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