Discovery of 5-Phenyl-N-(pyridin-2-ylmethyl)-2-(pyrimidin-5-yl)quinazolin-4-amine as a Potent IKur Inhibitor

Article abstract of DOI:10.1021/acsmedchemlett.6b00117

A new series of phenylquinazoline inhibitors of K_v 1.5 is disclosed. The series was optimized for K_v 1.5 potency, selectivity versus hERG, pharmacokinetic exposure, and pharmacodynamic potency. 5-Phenyl-N-(pyridin-2-ylmethyl)-2-(pyrimidin-5-yl)quinazolin-4-amine (13k) was identified as a potent and ion channel selective inhibitor with robust efficacy in the preclinical rat ventricular effective refractory period (VERP) model and the rabbit atrial effective refractory period (AERP) model.

Full text of DOI:10.1021/acsmedchemlett.6b00117

Subscriber access provided by UNIV OF NEBRASKA - LINCOLN
Letter
Discovery of 5-phenyl-N-(pyridin-2-ylmethyl)-2-
Kur
(pyrimidin-5-yl)quinazolin-4-amine as a potent I inhibitor
Heather J. Finlay, James A. Johnson, John L. Lloyd, Ji Jiang, James Neels, Prashantha
Gunaga, Abhisek Banerjee, Naveen Dhondi, Anjaneya Chimalakonda, Sandhya Mandlekar,
MaryLee Conder, Harinath Sale, Dezhi Xing, Paul C. Levesque, and Ruth R. Wexler
ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.6b00117 • Publication Date (Web): 09 Jun 2016
Downloaded from http://pubs.acs.org on June 10, 2016
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
ACS Medicinal Chemistry Letters is published by the American Chemical Society. 1155
Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 5
ACS Medicinal Chemistry Letters
1
2
3
4
5
6
7
8
9
Discovery of 5-phenyl-N-(pyridin-2-ylmethyl)-2-(pyrimidin-5-
yl)quinazolin-4-amine as a potent IKur inhibitor
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Heather J. Finlay,*,† James A. Johnson,† John L. Lloyd,† Ji Jiang,† James Neels,†, Prashantha Gunaga, † †
Abhisek Banerjee, † † Naveen Dhondi, † †Anjaneya Chimalakonda, # Sandhya Mandlekar, ## Mary Lee
Conder, ‡ Harinath Sale## Dezhi Xing, ‡ Paul Levesque, ‡ Ruth R. Wexler. †
†Departments of Discovery Chemistry, ‡Biology and #Preclinical Candidate Optimization, Bristol-Myers Squibb, Research
and Development, P.O. Box 5400, Princeton, New Jersey 08543-5400.
††Departments of Discovery Chemistry, ‡‡Biology and ##Preclinical Candidate Optimization, BBRC, Bangalore, India
*To whom correspondence should be addressed. Heather Finlay Phone: 609-818-3734. Fax: 609-818-3550. E-mail:
heather.finlay@bms.com.
KEYWORDS (Word Style “BG_Keywords”). If you are submitting your paper to a journal that requires keywords, provide
significant keywords to aid the reader in literature retrieval.
ABSTRACT: A new series of phenylquinazoline inhibitors of Kv 1.5 is disclosed. The series was optimized for Kv 1.5 potency,
selectivity versus hERG, pharmacokinetic exposure and pharmacodynamic potency. 5-phenyl-N-(pyridin-2-ylmethyl)-2-
(pyrimidin-5-yl)quinazolin-4-amine (13k) was identified as a potent and ion channel selective inhibitor with robust efficacy in the
pre-clinical rat ventricular effective refractory period (VERP) model and the rabbit atrial effective refractory period (AERP) model.
Atrial fibrillation (AF) is the most common form of sustained
cardiac arrhythmia and, in addition to significantly affecting
quality of life, AF is directly associated with increased risk of
stroke (5-fold) and increased mortality (2-fold).1 The preva-
lence of AF increases significantly with age and affects an
estimated 34 million patients worldwide.2 Recent approval of
novel anti-coagulants indicated for the treatment of AF have
been successful in risk reduction with respect to stroke.3 These
agents and rate control anti-arrhythmics, however, do not
restore normal sinus rhythm (NSR) in patients and there is a
potential additional benefit to maintaining NSR concomitant
with anti-coagulation therapy.4
We
have
recently
disclosed
optimized
dihydro-
pyrazolopyrimidines, 1 and phenylcyclohexane heterocycles 2
and 3 as potent and selective blockers of IKur (Figure 1).9,10,11
The most widely used anti-arrhythmic drugs, for example
amiodarone/dronedarone5 are efficacious, but are non-
selective and inhibit ion channels which are expressed in the
human atrium and ventricle. Agents which inhibit ion chan-
nels that prolong ventricular effective refractory period have
the potentially life threatening arrhythmia torsades de pointe6
and, therefore, administration of non-selective drugs is often
limited to a hospital setting with monitoring. There is current-
ly an unmet medical need for agents which effectively restore
NSR and have an increased margin for safety for the treat-
ment of AF.
Figure 1. Recently disclosed Kv 1.5 inhibitors
Concomitant with these efforts, we sought to identify and ad-
vance a structurally distinct back up series. Disclosed in the
literature were thienylpyridine and furanopyrimidine series,
however, we were concerned about the potential for reactive
intermediate formation and modified the template to replace
12,13
the thienyl/furano group.
The resulting quinazoline
chemotype is described extensively in the kinase literature.14
However, from analysis of the literature, we noted that sub-
stitutents were generally required at the C6 and C7 position
for compounds described with kinase activity.15 We synthe-
sized regioisomers 6a-d as described in Scheme 1 and were
gratified to see that only the C5 phenyl analog, 6a had Kv 1.5
potency 16 and selectivity for hERG17,18 (hERG flux IC50 > 80
µM). In addition, compound 6a was assayed against an in
house kinase panel and found to be devoid of kinase activity
for those kinases tested.
IKur is a delayed rectifier repolarization potassium current
encoded by the hKv 1.5 gene in humans7 which is functionally
expressed in the human atrium and not in the ventricle. Selec-
tive inhibition of IKur leads to a prolongation in effective re-
fractory period and should terminate AF without being pro-
arrhythmic in the ventricle leading to a potentially safer
treatment for patients with AF.8
ACS Paragon Plus Environment

ACS Medicinal Chemistry Letters
Page 2 of 5
3
1
2
3
* % inhibition at 0.3 µM, average of n=2,3
Scheme 2. Reagents and conditions: a) Dimethylaniline in
MeOH, 2M, 150 °C, microwave irradiation, 10 min, quantita-
tive yield; b) Zn(CN)2, Zn, Pd2(dba)3.dppf, DMA, 150 °C, mi-
crowave irradiation, 30 min, 21% yield; c) Al(CH3)3, THF,
Pd(PPh3)4, 50 °C, 90 min, 75 °C 14 h, 100 °C, microwave irra-
diation, 5 min, 21% yield; d) ZnBr2, Pd(dppf)Cl2.DCM, THF,
cyclopropylmagnesium bromide, -78 °C, 1h to RT 18h, 7%
yield; e) KOH, THF, H2O, 100 °C, microwave irradiation, 30
min, 120 °C, microwave irradiation, 30 min, 48% yield.
4
5
6
7
8
9
KV1.5 potency
(% inhibition at 0.3
µM, average of
n=2,3)
Example
Phenyl position
6a
6b
6c
6d
5
6
7
8
86 (IC50 0.07 µM)
14
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
9
9
Scheme 1. Reagents and conditions: a) NaOH; b) H2O2, crude
yield range, 2 steps 50-88%; c) NaOCN, H2O, yield range,
50% - 88%; d) PhB(OH)2, Pd(PPh3)4, K2CO3, dioxane, H2O,
yield range, 44% - 50%; e) POCl3, DIPEA, yield range, 36% -
59%; f) amino-methyl-2-pyridine, 65 °C, 14h, yield range,
75% - 91%.
Scheme 3. Reagents and conditions: a) Pyridine, trifluoroace-
tic anhydride, chloroform, RT addition; reflux 2 h, RT addi-
tion of NH3(g), 37% yield; b) Pd(OAc)2, KF, 2-(di-tert-
butylphosphino)biphenyl, phenylboronic acid, microwave
irradiation, 100 °C, 10 min; c) POCl3, N,N-dimethylaniline,
100 °C, 10 min then DCM, 1.5 M KH2PO4, 83% yield for 2
steps; d) Pyridin-2-ylmethanamine, TEA, RT, 46% yield.
Despite low rat liver microsomal stability, Compound 6a
demonstrated sufficient rat i.v. pharmacokinetic exposure
(Table 1) to test in the rat hemodynamic and VERP model.11
In human and rabbit, IKur is functionally expressed in atrium
and not ventricle, however, in rats, it is expressed in both.
Therefore, in the rat model, changes in VERP were measured
using a multielectrode catheter inserted into the left ventricle
for pharmacodynamic effect and in the rabbit model, changes
in AERP were measured. The VERP increase in the rat mod-
el at plasma concentration 26 ± 4 µM (10 mg/Kg i.v. infusion
over 10 minutes, n = 2) was 98 ± 3% and the compound was
subsequently also tested in the rabbit AERP model.19 A mod-
est 9.0 ± 2.4% AERP increase was observed (3 mg/Kg i.v. infu-
sion over 30 mins, plasma concentration at the end of the infu-
sion of 9.1 ± 1.1µM, n = 4). We, therefore, focused our subse-
quent efforts on analogs with the C5 phenyl group and further
optimized the substituent at the C2 position with the goal of
increasing both the in vitro potency and pharmacodynamic
potency. Additional groups at C2 were explored, (synthetic
routes are shown in Schemes 2 and 3) and SAR indicated that
electron rich substituents at C2 were not as potent for Kv 1.5
and did not maintain selectivity versus hERG.
Compound 8 had good potency and selectivity versus hERG,
thus combining the sp2 character at C2 with incorporation of
additional heteroatoms led to the synthesis of targeted hetero-
cycles. Various C2 heterocycle analogues were prepared from
6a as shown in Scheme 4. Multiple heterocycles including 13a,
13c, 13e, 13g, 13h, 13i, 13j, 13k were potent inhibitors of
Kv1.5, however, all had low selectivity versus hERG with the
exception of 13f. On further profiling, Compound 13f had low
microsomal metabolic stability (7% remaining at 10 min in
rat and 22% remaining in mouse) and was a potent inhibitor
of CYP2C9 (1 µM) and CYP2C19 (1 µM). Compound 13k
demonstrated potency, selectivity versus hERG, acceptable
metabolic stability (58% remaining at 10 min in rat and 75%
remaining in mouse) and CYP profile CYP2C9 (4 µM) and
CYP2C19 (3 µM). Structurally close analogues to 13k, com-
pounds 13l and 13m indicated a narrow SAR for potency and
hERG selectivity with substitution. The C2 pyrimidine was
therefore selected as the optimal heterocycle to further ex-
plore SAR in the series.
Scheme 4. Reagents and conditions: a) RSnBu3, Pd(PPh3)2Cl2,
DMF, THF, 100 °C, microwave irradiation, 60 min, 46 and
50% yield; b) RB(OH)2, K2CO3, Pd(PPh3)2Cl2, DME, EtOH,
H2O, 100 °C, microwave irradiation, 10 min, yield range 16 –
86%; c) BBr3, DCM, 0 °C, 18h,77% yield.
hERG
KV1.5
potency
potency
(Flux,
IC50,
Exam-
ple
Synthet-
ic steps
R
(IC50, µM )
µM)
hERG
7
8
9
N(CH3)2
CN
a
b
c
59%*
0.05
2.5
> 80
4.6
KV1.5
potency
potency
(Flux
IC50,
Exam-
ple
Synthet-
ic steps
R
CH3
72%*
(IC50, µM)
µM)
Cyclo-
propyl
10
d
0.17
ND
13a
a
0.05
6.2
11
12
CO2NH2
CF3
b, e
9%*
0.08
ND
10
Scheme
ACS Paragon Plus Environment

Page 3 of 5
ACS Medicinal Chemistry Letters
1
2
3
4
13b
13c
a
41%*
0.09
2.7
b
3.1
5
6
7
Scheme 5. Reagents and conditions: Yields a) Ph(X)B(OH)2,
8
9
Na2CO3, Pd(dppf)Cl2DCM complex, DMF, H2O, 110 °C, mi-
crowave irradiation, 14 h, yield quantitative; b) POCl3,
DIPEA, yield range, 35% - 50%; c) aminomethyl-2-pyridine,
DIPEA, THF yield range, 46% - 80%; d) pyrimidin-5-
ylboronic acid, Pd(dppf)Cl2DCM complex, DMF, H2O, 110
°C, microwave irradiation, 14 h, yield range, 29% - 99%; e)
LiOH, MeOH, H2O, yield 48%; f) EDC.HCl, HOBt, DMF,
DIPEA, NH4OAc, RT, 14 h, yield 56%.
13d
b
20%*
ND
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
88%**
13e
13f
b
b
0.16
0.06
at 1µM
KV1.5 poten-
(IC50,
cy
20
Exam-
ple
Synthetic
steps
X
µM or %
inhibition at
0.3 µM)
13g
13h
13i
b
b
b
0.12
0.04
0.13
8.4
6.7
14a
14b
14c
4-F
3-F
a, b, c, d
a, b, c, d
a, b, c, d
0.25
37%
0.15
4-CF3
4-
CONH2
a, b, c, d, e,
f
14d
8%
51%**
at 1µM
Pharmacokinetic exposure of compound 13k was meas-
ured in rats dosed p.o. at 5 mg/Kg and was comparable to
exposure observed for Compound 6a (Table 1). Compound
13k was screened in the rat VERP model11 at 3 and 10
mg/Kg and demonstrated robust effects in the absence of
seizures at plasma concentrations of 7.7 µM (10 mg/Kg).
Compound 13k was subsequently dosed at 3 mg/Kg, infu-
sion over 30 min in the anesthetized rabbit pharmacody-
namic model and a robust increase of 21 ± 2.8% in AERP
was observed without significant effect on VERP, QTc
(Delta QTc cf, 13 ± 4.2 ms) or BP (Table 2).17
91%**
13j
b,c
0.11
at 0.3µM
43%**
13k
13l
b
b
b
0.09
0.10
at 10µM
1.9
We were encouraged by the robust increase in AERP in
this model, however, in the rat VERP studies, a significant
level of brain penetration was observed (3 mg/Kg i.v. 5
minute infusion, 10 minute post end of infusion Cplasma 3.1 ±
0.3 µM, brain exposure 8.8 ± 1.6 µM. 10 mg/Kg i.v. 5 mi-
nute infusion, 10 minute post end of infusion Cplasma 7.7
µM, brain exposure 25 µM, n = 3). Due to the multiple
potassium ion channels expressed in the brain, differential
distribution in species20 and the difficulty in screening
compounds broadly for ion channel activity, we focused
our efforts on significantly reducing brain penetration
while maintaining good efficacy in the rabbit PD model.
Our efforts to identify and further optimize this series to
our current clinical candidate will be disclosed in a subse-
quent manuscript.
13m
20%*
ND
* % inhibition at 0.3 µM, average of n=2,3
** % inhibition at concentration, average of n=2,3
We also surveyed the C4 position extensively keeping the C2
pyrimidine constant, including positional isomers of the pyri-
dine, as well as extensive library synthesis at C2 (not shown)
however, we did not identify compounds with increased Kv
1.5 potency. We subsequently combined substitution on the
phenyl group at the C5 position keeping the C4 ami-
nomethylpyridine and the C2 pyrimidine in place using the
chemistry described in Schemes 5 (Compounds 14a-14d).
Modification at C5 did not result in compounds with im-
proved potency or selectivity profiles, thus compound 13k was
selected as the lead compound for further in vivo evaluation.
Compound 6a (i.v.
2 mg/Kg p.o. 5
mg/Kg)
Compound 13k
(i.v. 2 mg/Kg p.o. 5
mg/Kg)
Clearance
(mL/min/Kg)
8.2 2.6
NC
4.6 1.8
NC
ACS Paragon Plus Environment

ACS Medicinal Chemistry Letters
Page 4 of 5
Vss (L/Kg)
T1/2 (h)
2.3 1.7
7.3 0.6
NC
5.2 3.2
NC
4. Hohnloser, S.H.; Crijns, H.J.G.M.; van Eickels, M.; Gaudin, C.;
Page, R.L.; Torp-Pedersen, C.; Connolly, S.J. Effect of droneda-
1
2
3
4
5
6
7
8
rone on cardiovascular events in atrial fibrillation N. Engl. .J
Med., 2009, 360, 668-678.
5. Sun, W.; Sarma, J.S.; Singh, B.N. Electrophysiological Effects
of Dronedarone (SR33589), a Noniodinated Benzofuran Deriva-
tive, in the Rabbit Heart: Comparison With Amiodarone Circu-
lation, 1999, 100 (22), 2276-2281.
6. De Bruin, M. L.; Hoes, A. W.; Leufkens, H. G.
QTc-prolonging drugs and hospitalizations for cardiac
arrhythmias Am. J. Cardiol. 2003, 91, 59-62.
7. Ford, J. W.; Milnes, J. T. New Drugs Targeting the Cardiac
Ultra-Rapid Delayed-Rectifier Current (IKur): Rationale, Phar-
macology and Evidence for Potential Therapeutic Value J. Car-
diovasc. Pharmacol. 2008, 52 (2), 105-120.
1.9 1.3
15 3.9
NC
3.5 1.3
Bioavailability
(%)
NC
10
6.3
TABLE 1. Rat pharmacokinetic profile for Compounds 6a
and 13k. Sprague Dawley rats, male, approximate weight
250g, isofluorene anesthesia, i.v. dosed in PEG-
400/PG/ethanol (50/40/10), collection from the jugular vein at
8 timepoints, n = 3. NC = not calculated.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
8. Nattel, S. Nature New ideas about atrial fibrillation 50 years on
2002, 415, 219-226.
Compound 6a
Compound 13k
9. Lloyd, J; Finlay, H. J.; Vacarro, W; Hyunh, T; Kover, A;
Bhandaru, R; Yan, L; Atwal, K; Conder, M; Jenkins-West, T;
Shi, Hong; Huang, C; Li, D; Sun, H; Levesque, P. Pyrrolidine
amides of pyrazolodihydropyrimidines as potent and selective
KV1.5 blockers Bioorg. Med. Chem. Lett. 2010, 20 (4), 1436-
1439.
10. Johnson, James A.; Xu, Ningning; Jeon, Yoon; Finlay, Heather
J.; Kover, Alexander; Conder, Mary L.; Sun, Huabin; Li,
Danshi; Levesque, Paul; Hsueh, Mei-Mann. Design, synthesis
and evaluation of phenethylaminoheterocycles as Kv1.5 inhibi-
tors Bioorg. Med. Chem. Lett. 2014, 24 (14), 3018-3022.
11. Lloyd, John; Finlay, Heather J.; Kover, Alexander; Johnson,
James; Pi, Zulan; Jiang, Ji; Neels, James; Cavallaro, Cullen;
Wexler, Ruth; Conder, Mary Lee. Pseudosaccharin amines as
potent and selective KV1.5 blockers Bioorg. Med. Chem. Lett.
2015, 25(21), 4983-4986.
12. Palmer, N.J.; Madge, John, D., Ford, J., Atherall, J.F. Prepara-
tion of thienopyridine derivatives as potassium channel inhibi-
tors for the treatment of arrhythmia and diabetes WO
2006061642 A1.
13. Atherall, F.J., Ford, J., Madge, D.; Palmer, N.J. Preparation of
furanopyrimidine derivatives effective as potassium channel in-
hibitors WO 2005121149 A1.
14. Harris, C.S.; Hennequin, L.; Morgentin, R.; Pasquet, G. Synthe-
sis and functionalization of 4-substituted quinazolines as kinase
templates Targets in Heterocyclic Systems 2010, 14, 315-350.
15. Stauffer, F.; Furet, P. Patent Application Preparation of 2,4-
substituted quinazolines as lipid kinase inhibitors WO
2008012326.
16. Synders, D.J.; Tamakun, M.N.; Bennett, P.B. A rapidly activat-
ing and slowly inactivating potassium channel cloned from hu-
man heart: functional analysis after stable mammalian cell cul-
ture expression. J. Gen. Physiol. 1993, 101, 513-543.
17. Weaver CD, Harden D, Dworetzky SI, Robertson B, Knox RJ. A
thallium-sensitive, fluorescence-based assay for detecting and
characterizing potassium channel modulators in mammalian
cells. J. Biomol Screen. 2004, 9(8), 671-7.
18. Zhou, Z.; Vorperian, V.R.; Gong, Q.; Zhang, S. and January,
C.T. Block of HERG potassium channels by the antihistamine
astemizole and its metabolites desmethylastemizole and
norastemizole. J. Cardiovasc. Electrophysiol., 1999, 10, (6),
836-843.
19. Carlsson, L. The anaesthetised methoxamine-sensitised rabbit
model of torsades de pointes Pharmacol. Ther., 2008, 119(2),
160-167.
Vehicle
DMF
DMF
% AERP
increase
9 2.4
21.4 2.8
% change in
BP (systolic,
mean BP)
0.1 5.4, -1.0 4.9
-3.4 3.1, -3.8 4.0
% change in
Heart Rate
-3.2 4.1
9.1 1.1
-3.1 2.0
2.7 1.5
Plasma ex-
posure (µM)
TABLE 2. Rabbit pharmacodynamic profile for Com-
pounds 6a and 13k (3 mg/Kg infusion over 30 min, param-
eters at 20 min, n=3 or n = 4)
ASSOCIATED CONTENT
Supporting Information. Experimental procedures and analyti-
cal data for Compounds 4 to 14d is supplied as Supporting Infor-
mation. This material is available free of charge via the Internet at
http://pubs.acs.org.
ACKNOWLEDGMENT
The authors would like to acknowledge with thanks, Robert Lan-
guish for running the high resolution mass spectral analysis of all
final compounds.
ABBREVIATIONS
VERP, ventricular effective refractory period; AERP, atrial effec-
tive refractory period; AF, atrial fibrillation; NSR, normal sinus
rhythm.
REFERENCES
1. Zimetbaum, P. Antiarrhythmic drug therapy for atrial fibrillation
Circulation 2012, 125, 381-389.
2. Chugh, S.S.; Havmoeller, R.; Narayanan, K.; Singh, D.;
Rienstra, M.; Benjamin, E.J.; Gillum, R.F.; Kim, Y.; McAnulty,
J.H.; Zheng, Z.; Forouzanfar, M.H.; Naghavi, M.; Mensah, G.A.;
Ezzati, M.; Murray, C.J.L. Worldwide epidemiology of atrial fi-
brillation: a Global Burden of Disease 2010 Study Circulation
2014, 129, 837-847.
3. Bassand, J. Review of atrial fibrillation outcome trials of oral
anticoagulant and antiplatelet agents Europace, 2012, 14, 312-
324.
20. Vacher, H. Structure, Function, and Modulation of Neuronal
Voltage-Gated Ion Channels (2009), 127. Publisher: (John Wiley
& Sons, Inc., Hoboken, N. J)
ACS Paragon Plus Environment

Page 5 of 5
For Table of Contents Only
ACS Medicinal Chemistry Letters
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5
ACS Paragon Plus Environment