Selective IKur Inhibitors for the Potential Treatment of Atrial Fibrillation: Optimization of the Phenyl Quinazoline Series Leading to Clinical Candidate 5-[5-Phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl]pyridine-3-sulfonamide

Article abstract of DOI:10.1021/acs.jmedchem.6b01889

We have recently disclosed 5-phenyl-N-(pyridin-2-ylmethyl)-2-(pyrimidin-5-yl)quinazolin-4-amine 1 as a potent I_Kur current blocker with selectivity versus hERG, Na and Ca channels, and an acceptable preclinical PK profile. Upon further characterization in vivo, compound 1 demonstrated an unacceptable level of brain penetration. In an effort to reduce the level of brain penetration while maintaining the overall profile, SAR was developed at the C2′ position for a series of close analogues by employing hydrogen bond donors. As a result, 5-[5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl]pyridine-3-sulfonamide (25) was identified as the lead compound in this series. Compound 25 showed robust effects in rabbit and canine pharmacodynamic models and an acceptable cross-species pharmacokinetic profile and was advanced as the clinical candidate. Further optimization of 25 to mitigate pH-dependent absorption resulted in identification of the corresponding phosphoramide prodrug (29) with an improved solubility and pharmacokinetic profile.

Full text of DOI:10.1021/acs.jmedchem.6b01889

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Article
Kur
Selective I Inhibitors for the Potential Treatment of Atrial Fibrillation:
Optimization of the Phenyl Quinazoline Series Leading to Clinical Candidate
5-(5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl)pyridine-3-sulfonamide.
Prashantha Gunaga, John L. Lloyd, Somanadham Mummadi, Abhisek Banerjee, Naveen Kumar Dhondi,
James K. Hennan, Veena Subray, Ramya Jayaram, Nagendra Rajugowda, Umamaheshwar Reddy,
Duraimurugan Kumaraguru, Umasankar Mandal, Dasthagiri Beldona, Ashok Kumar Adisechan, Navnath
Yadav, Jayakumar Warrier, James A. Johnson, Harinath Sale, Siva Prasad Putlur, Ajay Saxena, Anjaneya
Chimalakonda, Sandhya Mandlekar, Mary Lee Conder, Dezhi Xing, Arun Kumar Gupta, Anuradha
Gupta, Richard A. Rampulla, Arvind Mathur, Paul C. Levesque, Ruth R. Wexler, and Heather J. Finlay
J. Med. Chem., Just Accepted Manuscript • Publication Date (Web): 18 Apr 2017
Downloaded from http://pubs.acs.org on April 18, 2017
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Journal of Medicinal Chemistry is published by the American Chemical Society. 1155
Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
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Conder, Mary Lee; Bristol-Myers Squibb
Xing, Dezhi; Bristol-Myers Squibb
Gupta, Arun; Biocon Bristol-Myers Squibb Research and Development
Center
Gupta, Anuradha; Syngene International Pvt Ltd, Biocon BMS Research
Center
Rampulla, Richard; Bristol-Myers Squibb Pharmaceutical Research and
Development, Discovery Chemistry
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Mathur, Arvind; Bristol-Myers Squibb Co
Levesque, Paul; Bristol-Myers Squibb,
Wexler, Ruth; Bristol-Myers Squibb PRI,
Finlay, Heather; Bristol Myers Squibb,
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Selective IKur Inhibitors for the Potential Treatment
of Atrial Fibrillation: Optimization of the Phenyl
Quinazoline Series Leading to Clinical Candidate 5ꢀ
(5ꢀphenylꢀ4ꢀ(pyridinꢀ2ꢀylmethylamino)quinazolinꢀ2ꢀ
yl)pyridineꢀ3ꢀsulfonamide.
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Prashantha Gunaga,*† † John Lloyd,† Somanadham Mummadi,† † Abhisek Banerjee,† † Naveen
Kumar Dhondi,† † James Hennan,‡ Veena Subray,† † Ramya Jayaram,† † Nagendra Rajugowda,††
Umamaheshwar Reddy,† † Duraimurugan Kumaraguru,† † Umasankar Mandal,† † Dasthagiri
Beldona, † † Ashok Kumar Adisechen,† † Navnath Yadav, † † Jayakumar Warrier, † † James A.
Johnson,† Harinath Sale,‡‡ Siva Prasad Putlur, ## Ajay Saxena, + Anjaneya Chimalakonda,#
Sandhya Mandlekar, ### MaryLee Conder, ‡ Dezhi Xing, ‡ Arun Kumar Gupta, † † Anuradha
Gupta, † † Richard Rampulla, † Arvind Mathur, † Paul Levesque, ‡ Ruth R. Wexler, † Heather J.
Finlay.*†
†Departments of Discovery Chemistry, ‡Biology and # Pharmaceutical Candidate Optimization,
BristolꢀMyers Squibb, Research and Development, P.O. Box 5400, Princeton, New Jersey
08543ꢀ5400.
Departments of ††Discovery Chemistry, ‡‡Biology, +Biopharmaceutics, ## Pharmaceutical
Candidate Optimization, Biocon BMS R&D Center, Syngene International Ltd., ###BMS India
Pvt. Ltd., Biocon Park, Jigani Link Road, Bommasandra IV, Bangalore 560099, India,
Bangalore, India
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ABSTRACT
We have recently disclosed 5ꢀphenylꢀNꢀ(pyridinꢀ2ꢀylmethyl)ꢀ2ꢀ(pyrimidinꢀ5ꢀyl)quinazolinꢀ4ꢀ
amine 1 as a potent IKur current blocker with selectivity versus hERG, Na and Ca channels and an
acceptable preclinical PK profile. On further characterization in vivo, Compound 1 demonstrated
an unacceptable level of brain penetration. In an effort to reduce the level of brain penetration
while maintaining the overall profile, SAR was developed at the C2’ position for a series of close
analogs by employing hydrogen bond donors. As a result, 5ꢀ(5ꢀphenylꢀ4ꢀ(pyridinꢀ2ꢀ
ylmethylamino)quinazolinꢀ2ꢀyl)pyridineꢀ3ꢀsulfonamide (25) was identified as the lead
compound in this series. Compound 25 showed robust effects in rabbit and canine
pharmacodynamic models and an acceptable crossꢀspecies pharmacokinetic profile and was
advanced as the clinical candidate. Further optimization of 25 to mitigate pH dependent
absorption resulted in identification of the corresponding phosphoramide prodrug (29) with an
improved solubility and pharmacokinetic profile.
INTRODUCTION
Atrial fibrillation (AF) is a condition defined by abnormal sinus rhythm resulting from irregular
electrical activity in the atrium. AF has an associated higher risk of stroke due to
thromboembolism and patients have a reduced quality of life.1,2 Electrical cardioversion is the
standard of care for conversion to normal sinus rhythm (NSR) and pharmacologic intervention,
along with ablation are the current standards of care for maintenance of normal sinus rhythm.
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Antiarrhythmic therapy is recommended for patients with symptomatic paroxysmal AF.3,4
Antiarrhythmic agents maintain normal sinus rhythm or control the heart rate (HR) and are
targeted for combination with anticoagulation therapy indicated for AF. Currently available
antiarrhythmic drugs for the treatment of AF inhibit multiple cardiac ion channels which are
expressed in both atria and ventricles, in addition to having antiadrenergic properties for
example, amiodarone and dronedarone.5 Prolonging ventricular effective refractory period can
lead to the potentially fatal ventricular arrhythmia, torsade de pointes. Therefore, targeting
inhibition of atrial specific ion channels may provide a potentially safer treatment for
maintenance of NSR.
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IKur is the ultraꢀrapid delayed rectifier potassium current encoded by the KCNA5 (KV1.5) gene in
humans and is functionally expressed in human atrium and not in the ventricle.6 Selective
inhibition of IKur is expected to prolong atrial action potential duration (APD) without QT
prolongation as the ventricular effective refractory period remains unchanged.7 Thus, compounds
which selectively inhibit IKur are expected to have a low potential for ventricular proarrhythmia
along with an improved safety profile.8ꢀ11
Our recent disclosure12 in the phenylquinazoline series details the discovery of 5ꢀphenylꢀNꢀ
(pyridinꢀ2ꢀylmethyl)ꢀ2ꢀ(pyrimidinꢀ5ꢀyl)quinazolinꢀ4ꢀamine (1) as a potent (KV1.5 IC50 = 90 nM)
and selective IKur inhibitor that demonstrated robust effects in both rat and rabbit
pharmacodynamic models. However, a high brain to plasma ratio (B/P) of 2.8, with the potential
for CNS side effects, precluded progression of this compound. The blood brain barrier has been
shown to express efflux transporters such as Pꢀglycoprotein that exclude a variety of substrates
and the brain itself is shielded from molecules circulating in the periphery by a network of
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capillaries that are lined with endothelial cells. Permeability of molecules across the blood brain
barrier is determined by physicochemical properties such as size, polar surface area,
lipophilicity, hydrogen bonding potential, charge and conformation.13 Compounds in the
phenylquinazoline series had high plasma protein binding12 in rat and human in addition to low
solubility at pH7.4 which led to recovery issues in the high throughput PAMPA and Caco
permeability assays. Therefore, the in vitro permeability or efflux data could not be routinely
used for SAR development or assessment of Pꢀgp efflux. To reduce brain penetration observed in
this series further, we targeted analogs with (1) increased number of hydrogen bond donors, (2)
increased rotatable bonds, (3) increased polarity, and (4) increased polar surface area.14,15
We first focused on introducing polar groups and hydrogen bond donors at the C2, C4 and C5
positions to target B/P ≤ 0.1 in a molecule with acceptable potency and selectivity.
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Figure 1. Compound 1, 5ꢀphenylꢀNꢀ(pyridinꢀ2ꢀylmethyl)ꢀ2ꢀ(pyrimidinꢀ5ꢀyl)quinazolinꢀ4ꢀamine;
a potent KV1.5 inhibitor with unacceptable brain penetration (B/P 2.8) in rats.
RESULTS AND DISCUSSION
All compounds described were assayed for block of IKur current in patch clamped mammalian Lꢀ
929 cells which were transfected with human KV1.5 and stably expressed IKur protein.16
Inhibition data for compounds 3 to 28 are shown in Tables 1 to 4. Compounds which were potent
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for KV1.5 were also evaluated for selectivity versus the hERG channel in an in vitro
5
6
electrophysiology assay.17ꢀ19
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Phenylquinazoline analogs 3 to 28 were obtained utilizing the general sequence described
previously12 (Scheme 1). Dichloroquinazoline, 2 was a versatile intermediate to explore the SAR
at the C2 and C4 positions. To further explore diversity at the C4 position, a library approach
was used to incorporate polar groups and functional groups with hydrogen bond donors (Table
1). Intermediate 2 underwent selective C4 chloro displacement to yield the corresponding C4
amines and the respective amines were subsequently converted to C2 heteroaryl analogues via
transition metal cross coupling (Scheme 1). Utilizing compounds, 3 and 4, corresponding
analogs 5 and 6 were prepared and utilizing aminoꢀmethylꢀ2ꢀpyridine for the displacement at C4,
corresponding analogs 7 – 28 were prepared.
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Scheme 1. Synthetic route for compounds 3ꢀ28
Reagents and conditions:
a) Compound 3: DIPEA, THF, 4ꢀ(2ꢀaminoethyl)benzenesulfonamide, RT 14h (57% yield),
compound 4: NaH, 3ꢀ(morpholinosulfonyl)aniline, DMF, 0ꢀ75 ºC 14h, (9% yield) b) Cross
coupling conditions, yields and subsequent synthetic steps are included in the supplemental
information (4ꢀ68% yield for 2ꢀ3 steps).
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Table 1. C4 position analogs with polar groups
hERG flux
B/P Ratioc
KV1.5 IC50 (ꢀM)
or inh at 0.3 µMa,b
73%
Example
3
R1
R
IC50 (µM)
Cl
Cl
24
0.6
3.0
0.21
ND
4
15%
0.08
5.6
ND
2.4
5
6
ND
aInhibition is measured in duplicate at three concentrations and the mean values used to calculate IC50
values. bPercent inhibition of current in Lꢀ929 cells at 0.3µM, 2ꢀ4 point determinations.16 cBrain to plasma
ratio in rat is measured at a single timeꢀpoint following an intravenous infusion of compounds as per the
protocol described in supporting information.
We were encouraged to find that sulfonamide 3 retained KV1.5 potency and selectivity versus
hERG and was the first compound in the series to demonstrate B/P ratio of <1 in the rat
pharmacodynamic model. Compound 3 was not advanced due to low metabolic stability (68%
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remaining, 10 min incubation with NADPH supplemented in human liver microsomes). Utilizing
SAR at the C2 position described in our earlier work,12 the corresponding pyrimidines 5 and 6
were prepared. Compounds 4 and 6 also retained Kv1.5 potency, but demonstrated equally high
brain penetration compared to compound 1. Compound 5 was significantly less potent and less
selective versus hERG than 3 demonstrating the narrow balance of SAR between the C2 and C4
positions for target potency and selectivity. Low metabolic stability was also observed for
compound 6 and continued to be an issue in this series. These observations together with our
earlier optimization for metabolic stability at the C4 position12 prompted us to incorporate
aminomethyl 2ꢀpyridine and focus on exploring substitution at the C5 and the C2 positions to
introduce polar functionality with the goal of reducing brain penetration and increasing
metabolic stability.
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Polar groups and groups with Hꢀbond donors were incorporated at various positions on the C5
phenyl group, (compounds 7ꢀ10) following the general sequence described previously12 and in
Scheme 1.
N
Ar HN
C5
N
N
N
N
Table 2. Modification of C5 phenyl with polar group substitutents
hERG IC50 (µM)
B/P Ratioc
KV1.5 IC50 (ꢀM) or
Example
Ar
inh at 0.3 µMa,b
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Phenyl
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50%
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0.33
8%
>80 (Flux)
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9
0.2
2%
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0.3
10
aInhibition is measured in duplicate at three concentrations and the mean values used to calculate IC50
values. bPercent inhibition of current in Lꢀ929 cells at 0.3 µM, 2ꢀ4 point determinations.16
cBrain to plasma ratio in rat is measured as per the protocol described in supporting information.
With few exceptions, polar substituents on the C5 phenyl ring resulted in reduced KV1.5 potency
compared to the unsubstituted phenyl compound 1. The dimethylamino analog 8, maintained
KV1.5 potency (albeit less potent than compound 1) and hERG selectivity, however had low
metabolic stability across species (<3% remaining with human liver microsomes after 10 min
incubation) and was not evaluated for brain penetration. Compounds 9 and 10 were not potent
for KV1.5 and were significantly less selective versus hERG. Interestingly, compounds with Hꢀ
bond donors such as amides 9 and 10 had increased metabolic stability and significantly lower
brain penetration. While 9 and 10 were not profiled further, the lower brain to plasma ratio for
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these amide analogs directed us to target compounds with polar substituents at the C2’position to
maintain potency, increase metabolic stability and reduce B/P levels.
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9
As a starting point for optimization at the C2’ position, we explored SAR in the C2 pyrimidine
series (compound 1). Compounds 11 – 13 were prepared from commercially available boronic
acids as shown in Scheme 1. The SAR for potency for the substituted pyrimidines was narrow.
2’ꢀCyanopyrimidine (11) was less potent, while the corresponding 2’ꢀaminopyrimidine (12) and
2’ꢀmethoxypyrimidine (13) retained KV1.5 potency and selectivity versus hERG, however, brain
penetration remained high (B/P ratio 3.0 and 2.5 respectively) with C2 pyrimidine analogues.
We continued to explore alternate heterocycles at C2 including the pyridine moiety (compound
14), which demonstrated acceptable potency and hERG selectivity. However, further in vitro
profiling indicated that compound 14 was a potent CYP P450 inhibitor (IC50 for 2C19, 1A2, 2C8
and 2C9 < 10 ꢀM). In an effort to incorporate a polar substituent and to reduce basicity of the C2
pyridine nitrogen to reduce CYP P450 inhibition, we synthesized the corresponding C2 pyridone,
15. This compound was potent, with an improved CYP P450 profile and lower brain penetration,
but we were unable to balance selectivity for hERG, therefore 15 was not advanced. These
observations led us to target analogs in the potent C2 pyridine series with Hꢀbonding substituents
that would attenuate the pyridine nitrogen basicity and lead to an overall improved in vitro
potency and selectivity profile while maintaining lower brain penetration (Table 4).
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Table 3. C2 heteroaryl substitutions with polar groups to prevent the brain penetration
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B/P Ratioc
hERG flux IC50 (µM)
Example
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R1
inh at 0.3 µMa,b
or inh at 10 µM
Phenyl
0.09
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3.0
3.0
2.5
43% at 10 µM
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64%
95%
0.10
ꢀ
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13
80
66
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ꢀ
20
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15
1.0
0.5
aInhibition is measured in duplicate at three concentrations and the mean values used to calculate IC50
values. bPercent inhibition of current in Lꢀ929 cells at 0.3 µM, 2ꢀ4 point determinations.16
cBrain to plasma ratio in rat is measured as per the protocol described in supporting information.
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Table 4. C2 Pyridyl analogues with polar groups to reduce brain penetrationa,b
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6
7
8
B/P Ratioc
hERG d
KV1.5 IC50 (ꢀM)
or inh at 0.3
µMa,b
IC50 (µM) or inh
Example
R1
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0.10
3.0
1.0
2.0
0.4
0.3
4.6
4.8
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20
79%
80%
92%
89%
>80 (Flux)
85% at 1 ꢀM
26% at 1 ꢀM
1.9
91%
99%
0.10
87%
0.04
0.04
0.08
0.07
21
22
23
24
0.8
2.0
94% at 10 µM
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0.05
48%
0.1
1.9
25
26
ND
>80 (Flux)
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20%
87%
ND
36 (Flux)
27
28
O
N
S
O
NH2
ND
94% at10 µM
a Inhibition is measured in duplicate at three concentrations and the mean values used to calculate IC50
values. bPercent inhibition of current in Lꢀ929 cells at 0.3 µM, 2ꢀ4 point determinations.16
d
cBrain to plasma ratio in rat is measured as per the protocol described in supporting information. hERG
IC50 or % inhibition at concentration indicated as determined by patch clamp.17ꢀ19 or hERG flux
IC50 (ꢀM) as noted.
We synthesized orthoꢀamide and urea substituted compounds 16 to 18 and were surprised to
observe that brain penetration remained high despite incorporating groups with Hꢀbond donors.
As we explored SAR at this position further, we observed that sulfonamide, 19, had a
significantly reduced B/P ratio of 0.4 compared to the amides 16 and 18 and the urea, 17. We
also observed that the corresponding regioisomeric metaꢀsubstituted analogs in the pyridine
series (compounds 20 to 25 compared to 16 to 19), maintained potency and demonstrated
significantly reduced brain penetration. Compounds 21 and 22 had good potency, low brain
penetration, and selectivity versus hERG, however, solubility was low and dose limiting in the
vehicle required for intravenous formulation. Compounds 23 and 24 were not progressed further
due to low selectivity versus hERG inhibition, despite having good potency and low brain
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penetration. To followꢀup on pyridyl sulfonamide 24, a sulfonamide walk around the pyridyl ring
gave rise to compounds 25ꢀ28. Compound 25 proved to be the most potent of the isomeric
pyridyl sulfonamides. We were gratified to see that compound 25 showed good selectivity over
hERG (IC50 = 1.9 uM) and reduced brain penetration with a brain to plasma ratio of 0.1.
According to the free drug hypothesis, the Kpu,u, or the partition coefficient between unbound
tissue and unbound plasma concentration is the best measure of pharmacodynamic activity.20
For many compounds exemplified in the current manuscript, the plasma protein binding in
human and rat was very high (Compounds 6, 10, 12 and 17 to 24 > 99.5%, or free fraction fu less
than 0.5% and Compounds 9, 16 and 25 were >99%, or fu less than 1%), resulting in low
unbound plasma concentration (Cu,pl = Ct,pl* fu). The brain unbound concentrations, however,
were not determined. Instead, we relied on total brain and total plasma concentration in vivo, to
drive the SAR for brain penetration. The in vivo studies also allowed us to make cageꢀside
behavioral observations of any potential CNS sideꢀeffects owing to high brain penetration.
Compound 25 was chosen for further evaluation as it had the balance of potency, selectivity, low
brain penetration, adequate solubility, acceptable CYP profile and metabolic stability.
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Compound 25 was evaluated against a panel of additional ion channels and was shown to have
excellent selectivity across the panel (see Table 5). The pharmacokinetics of compound 25 was
evaluated in mouse, rat, monkey and dog and high oral bioavailability was observed across
species. Compound 25 had very low clearance and a long halfꢀlife of 51 hours in dogs. (Tableꢀ6).
Based on this excellent overall profile, Compound 25, also known as BMSꢀ919373, (5ꢀ(5ꢀ
phenylꢀ4ꢀ(pyridinꢀ2ꢀylmethylamino)quinazolinꢀ2ꢀyl)pyridineꢀ3ꢀsulfonamide)21 was progressed
into in vivo efficacy studies.
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Table 5. Cardiac ion channel inhibition for compound 25
5
6
7
8
Fold over KV1.5
Channel/current
IC50 (ꢁM)
0.046
1.9
1
KV1.5
hERG
ICaL
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
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51
52
53
54
55
56
57
58
59
60
40
>10
>200
>200
>200
>10
IKs
>10
INa
Table 6. PK parameters for compound 25.
mouse
i.v. (2
mg/kg)
p.o. (5
mg/kg)
10.6
1.8
Rat
Cynomolgus
monkey
Dog
i.v. (2
mg/kg)
p.o. (5
mg/kg)
3.3
i.v. (0.1 mg/kg)
i.v. (1 mg/kg)
p.o. (1 mg/kg)
p.o. (1 mg/kg)
3.2
0.05
0.2
51
Cl (mL/min/kg)
Vss (L/kg)
T1/2 (h)
0.9
1.2
2
3.2
4.6
4
7.9
0.9
7.8
Cmax (ꢁM)
0.5
2.6
4.9
T
max (h)
21
49
11
590
64
AUC (ꢁM.h)
%F
100
100 (35) *
100 (54) *
Vehicle = EtOH:PG:PEG400, 1:4:5. *F% with micronized crystalline suspension
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The pharmacodynamic effects of 25 were evaluated in the anesthetized slow infusion rabbit PD
model.22 Compound 25 was dosed at 3 mg/kg (Figure 2) and the compound prolonged AERP by
~22 % at the end of the 30 min infusion at a plasma concentration of 3.3 µM. The maximal
increase in AERP corresponded to the maximal plasma concentration. There was no significant
effect on VERP at this dose (Table 4).
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Figure 2. At 1 mg/kg IV, AERP was prolonged 10.6 and 10.7% at the 20 and 30 min time
points. Changes in AERP were positively and significantly correlated to Compound 25 plasma
concentration which was 1.1 and 1.3 µM at the 20 and 30 min time points, respectively. At 3
mg/kg IV, AERP was prolonged by 10.8, 16.2 and 21.6% at the 10, 20 and 30 min time points,
which correlated with plasma concentrations of 2.3, 3.6 and 3.3 µM respectively.
Compound 25 was subsequently evaluated at lower doses to determine the minimal efficacious
dose that increased AERP by 10%, (Figure 3) as an AERP increase of 10% (in humans) is
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clinically relevant8. This was observed at a steady state concentration of ~0.15 µM in the rabbit
model.
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Figure 3. Compound 25 in DMF (0.17 mg/mL). Data are Mean ±SE, AERP data was normalized
with DMF. Time was counted from infusion of 0.17 mg/kg (maintenance dose). Tissues were
collected post 30 min, N=3 rabbits.
Compound 25 was also progressed into the simultaneous atrioꢀventricular pacing dog model, a
clinically relevant pharmacodynamic model for atrial arrhythmia,23 to measure AF inducibility
(0.1 mg/kg or 0.3 mg/kg, dosed orally in a 10% EtOH; 40% propylene glycol; 50% PEG 400: PO
vehicle). Compound 25 reduced the mean number of AF inductions and total AF duration in the
absence of any effect on QTc interval at the doses of 0.1 mg/kg (plasma concentration, 0.47 µM)
and 0.3 mg/kg (plasma concentration, 1.84 µM) (Figure 4).
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7000
6000
5000
4000
3000
2000
1000
0
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Vehicle
0.1 mg/kg
0.3 mg/kg
10
0
-10
-20
-30
-40
-50
-60
-70
-80
*
466 nM
Plasma Concentration
1841 nM
Figure 4. Effect of 25 on AF duration and total AF burden in a canine pharmacodynamic model
(n=7 control dogs, n=5 dogs at 0.1 mg/kg and n=6 dogs at 0.3 mg/kg)
The target efficacious human exposure at Ctrough was calculated to be between 150 and 400 nM
based on the rabbit and dog pharmacodynamic studies, respectively. The human PK parameters
were projected based on allometric scaling of PK in preclinical species, except dog. The
projected human dose of 25 was 30 ꢀ 80 mg, BID.
Compound 25 was negative in the AMES and micronucleus assay, suggesting a low potential for
mutagenicity. Based on further in vivo toxicological studies and overall profile, compound 25
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was selected as the clinical candidate. Compound 25 demonstrated pH dependent solubility
(Figure 5) and further evaluation of the pharmacokinetic profile in the monkey famotidine model
showed that 25 demonstrated pHꢀdependent absorption at 10 mg/kg. Based on these
observations, compound 25 had the potential to demonstrate pH dependent absorption in humans
and an increased probability of food effects and drugꢀdrug interactions with coꢀadministration of
compounds that affect the stomach or intestinal pH. A prodrug strategy was employed to
improve the solubility profile and mitigate the potential issues associated with pH dependent
absorption. Several prodrugs attached through the sulfonamide group were evaluated in vivo for
(i) cleavage to compound 25, (ii) concentration of circulating prodrug and (iii) the absorption
profile. The prodrug with the best overall profile was the phosphoramide 29. Compound 29 had
an improved solubility profile (Figure 5) and mitigated pH dependent absorption in the monkey
famotidine model likely due to efficient hydrolysis at the intestinal brush border followed by
rapid absorption of compound 25. No circulating prodrug was observed in vivo.
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Figure 5. pH dependent solubility of 25 and corresponding prodrug 29.
CONCLUSIONS
We have further optimized the phenylquinazoline series of selective IKur inhibitors to
reduce brain penetration and have identified 25 as the lead compound in this series. Compound
25 had an acceptable in vitro selectivity and liability profile and a good pharmacokinetic profile
across species. Compound 25 was advanced to rabbit and dog pharmacodynamic models of
arrhythmia and demonstrated robust and dose dependent effects in these models. An acceptable
human projected dose and in vivo safety profile in toxicology studies led to selection of
compound 25 as our clinical candidate. The physicochemical properties of 25 were further
improved by preparation of the phosphoramide prodrug 29 as a backup candidate if needed.
Clinical data for compound 25 will be disclosed in due course.
EXPERIMENTAL SECTION
All reactions were carried out under a static atmosphere of argon or nitrogen and stirred
1
magnetically unless otherwise stated. All reagents used were of commercial quality. H NMR
spectra were obtained with Bruker or JEOL FOURIER® transform spectrometers operating at
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frequencies as follows: H NMR: 400 MHz (Bruker or JEOL) or 500MHz (JEOL). C NMR:
100 MHz (Bruker or JEOL). Spectral data are reported in the format: chemical shift (multiplicity,
coupling constants, and number of hydrogens). Chemical shifts are specified in ppm downfield
of a tetramethylsilane internal standard (δ units, tetramethylsilane = 0 ppm) and/or referenced to
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1
solvent peaks, which in H NMR spectra appear at 2.49 ppm for CD2HSOCD3, 3.30 ppm for
CD2HOD, and 7.24 ppm for CHCl3, and which in 13C NMR spectra appear at 39.7 ppm for
13
CD3SOCD3, 49.0 ppm for CD3OD, and 77.0 ppm for CDCl3. All C NMR spectra were proton
decoupled. 15N chemical shifts are referenced to (aq.) 15NH4Cl at 27.3 ppm. Reverse phase
analytical HPLC/MS was performed on Agilent 1200 Series, Single Quadrapole instrument.
Waters Aquity system coupled with a Waters Micromass SQ Mass Spectrometer. Chiral
analytical LC was performed on a Waters SFC instrument. Methods used for the experiments are
listed below (Method 1ꢀ9).
Method 1: Linear gradient of 0 to 100 % B over 2 min; UV visualization at 220 nm; Column:
PHENOMENEX® Luna C18 4.6 x 30 mm; Flow rate: 5 mL/min; Solvent A: 10 mM ammonium
acetate, 90 % water, 10 % methanol; Solvent B: 10 mM ammonium acetate, 90 % methanol,
10% water.
Method 2: Linear gradient of 0 to 100 % B over 2 min; UV visualization at 220 nm; Column:
CHROMOLITH® SpeedROD C18 4.6 x 30 mm; Flow rate: 5 mL/min; Solvent A: 0.1 % TFA,
90% water, 10 % methanol; Solvent B: 0.1 % TFA, 90 % methanol, 10 % water.
Method 3: Linear gradient: T/%B: 0/10, 12/100, 15/100, 18/10, 23/10; UV visualization at 220 &
254 nm; Waters Sun fire C18 (4.6 x 150 mm, 3.5u); Flow rate: 1 mL/min; Buffer: 0.05 % TFA in
water pH adjusted to 2.5 with dilute ammonia; Mobile Phase A: Buffer: acetonitrile /95:05;
Mobile Phase B: Buffer: Acetonitrile /05:95
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Method 4: Linear gradient: T/%B: 0/10, 12/100, 15/100, 18/10, 23/10; UV visualization at 220 &
254 nm; Waters XBridge Phenyl (4.6 x 150 mm, 3.5u); Flow rate: 1 mL/min; Buffer: 0.05 %
TFA in water pH adjusted to 2.5 with dilute ammonia; Mobile Phase A: Buffer:
Acetonitrile/95:05; Mobile Phase B: Buffer: Acetonitrile /05:95
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Method 5: Linear gradient of 10 to 100 % B over 15 min, with 12 min hold at 100% B; UV
visualization at 220 nm; Column: XBridge phenyl (4.6 x 150 mm) 3.5 micron SC/ 1072; Flow
rate: 1 mL/min; Buffer: 0.05 % TFA in water pH 2.5. Mobile Phase A: Buffer:acetonitrile/95:5;
Mobile Phase B: acetonitrile:Buffer/95:5.
Method 6: Linear Gradient: T(min)/%B: 0/0, 12/100, 15/100 ; Column: Xbridge Phenyl, 3.5 ꢁ x
150mm (L) x 4.6 mm, Flow rate: 1.0 mL/min; Mobile phase A: 0.05 %TFA in water pH adjusted
to 2.5 using dilute NH3 : ACN (95:5); Mobile phase B: 0.05 % TFA in water pH adjusted to 2.5
using dilute NH3: ACN (5:95).
Method 7: Linear Gradient: T(min)/%B: 0/20, 4/100, 4.6/100, 4.7/20 ; ColumnꢀKinetex XBꢀC18
(75X3mmꢀ2.6ꢁm ); Flow rate: 1.0 mL/min; Mobile phase A: 10 mM ammonium formate in
water:ACN (98:02); Mobile phase B: 10 mM ammonium formate in water:ACN (02:98).
Method 8: Linear Gradient: T(min)/%B: 0/0%, 15/50%, 18/100%, 23/100; Column: Xbridge
Phenyl, 3.5 ꢁ x 150mm (L) x 4.6 mm, Flow rate: 1.0 mL/min; Mobile phase A: 0.05 %TFA in
water pH adjusted to 2.5 using dilute NH3 : ACN (95:5); Mobile phase B: 0.05% TFA in water
pH adjusted to 2.5 using dilute NH3: ACN (5:95).
Method 9: Linear gradient: T/%B: 0/0, 15/50, 18/100, 23/100; UV visualization at 220 & 254
nm; Waters Sunfire C18 (4.6 x 150 mm,3.5u); Flow rate: 1 mL/min; Buffer: 0.05 % TFA in
water pH adjusted to 2.5 with dilute ammonia; Mobile Phase A: Buffer:acetonitrile/95:05;
Mobile Phase B: Buffer:Acetonitrile/05:95.
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Purity for compounds was measured by HPLC analysis using the conditions listed for the
methods above and determined to be ≥95%.
7
8
9
5ꢀ(5ꢀPhenylꢀ4ꢀ(pyridinꢀ2ꢀylmethylamino)quinazolinꢀ2ꢀyl)pyridineꢀ3ꢀsulfonamide (25).
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25
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A mixture of pyridineꢀ3ꢀsulfonic acid (10.30 g, 64.80 mmol), phosphorous pentachloride (20.82
o
g, 100.0 mmol) and phosphorous oxychloride (10 mL, 110 mmol) were heated at 120 C for 4 h.
The reaction mixture was allowed to cool to room temperature and was evaporated to dryness
under reduced pressure to yield a residue. The residue was treated with bromine (6.00 mL, 116
o
mmol) and heated to reflux at 80 C for 14 h. The reaction mixture was cooled to 0 °C and a
saturated solution of NH4OH in H2O (40 mL) was slowly added. The resulting reaction mixture
was allowed to warm to room temperature while stirring, filtered and the filter cake was washed
with hexane to afford 5ꢀbromopyridineꢀ3ꢀsulfonamide (6.0 g, 58 %) as an offꢀwhite solid. The
compound was used without further purification. LCMS Method 1: retention time 0.75 min;
[M+1] = 237.0. HPLC Method 8: purity 94.8 %, retention time = 8.93 min. HPLC Method 9:
1
purity 94.6 %, retention time = 5.49 min. H NMR (400 MHz, DMSOꢀd6) δ (ppm): 7.73 (s, 2H),
8.39 (t, J = 2.4 Hz, 1H), 8.95 (dd, J = 2.4, 6.4 Hz, 2H). 13C NMR (126 MHz, DMSOꢀd6) δ (ppm):
120.14, 135.84, 141.28, 144.69, 153.31.
Pyridineꢀ3ꢀsulfonamideꢀ5ꢀylboronic acid pinacol ester
A solution of 5ꢀbromopyridineꢀ3ꢀsulfonamide (1.50 g, 6.33 mmol), bis(pinacolato)diboron (2.41
g, 9.50 mmol) and potassium acetate (1.86 g, 19.0 mmol) in 1,4ꢀdioxane (15 mL) was degassed
with nitrogen for 15 min then (1,1′ꢀbis(diphenylphosphino)ꢀferrocene)palladium (II) chloride
dichloromethane complex (0.232 g, 0.317 mmol) was added and the resulting mixture was
degassed further with nitrogen for 10 min. The reaction mixture was heated in a microwave
reactor at 120 °C for 45 min, allowed to cool, filtered through CELITE® and the filtrate
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concentrated under reduced pressure to provide pyridineꢀ3ꢀsulfonamideꢀ5ꢀylboronic acid pinacol
ester (0.740 g, 41.3 %) as a brown solid. The compound was used without further purification.
7
8
1
LCMS Method 7: retention time 0.36 min; [M+1] = 285.2. H NMR (400 MHz, DMSOꢀd6) δ
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(ppm): 8.83 (s, 1H), 8.80 (s, 1H), 8.26 (s, 1H), 7.56ꢀ7.74 (bs, 2H), 1.17 (s, 12H). HRMS: [M + 1]
obs 285.1071 calc 285.1075.
5ꢀ(5ꢀPhenylꢀ4ꢀ(pyridinꢀ2ꢀylmethylamino)quinazolinꢀ2ꢀyl)pyridineꢀ3ꢀsulfonamide (25). To a
solution of 2ꢀchloroꢀ5ꢀphenylꢀNꢀ(pyridinꢀ2ꢀylmethyl)quinazolinꢀ4ꢀamine (0.150 g, 0.430 mmol)
in 1,4ꢀdioxane (6 mL) and H2O (1 mL) under nitrogen was added pyridineꢀ3ꢀsulfonamideꢀ5ꢀ
ylboronic acid pinacol ester (0.185 g, 0.650 mmol), and potassium carbonate (0.119 g, 0.860
mmol). The reaction mixture was degassed with nitrogen for 15 minutes and (1,1′ꢀ
bis(diphenylphosphino)ferrocene)palladium (II) chloride dichloromethane complex (0.0031 g,
0.043 mmol) was added. The resulting mixture was degassed with nitrogen for 10 min and
heated to 90 °C for 16 h. The reaction mixture was allowed to cool to room temperature and
quenched by the addition of water and then transferred to a separation funnel. The aqueous layer
was extracted with ethyl acetate. The combined organic layers were washed with water and
saturated NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure. The
resulting concentrate was purified by preparative TLC using 5 % methanol in dichloromethane to
afford Example 25 (0.050 g, 20 %) as a brown solid. LCMS Method 2: retention time 1.49 min;
[M+1] = 469.0. HPLC Method 3: purity 96.5 %, retention time = 9.19 min. HPLC Method 4:
1
purity 96.6 %, retention time = 8.89 min. H NMR (400 MHz, DMSOꢀd6) δ (ppm): 9.81 (d,
J=1.93 Hz, 1H), 9.18 (t, J=2.20 Hz, 1H), 9.10 (d, J=2.20 Hz, 1H), 8.24 (d, J=4.95 Hz, 1H), 7.93
(d, J=8.25 Hz, 1H), 7.86 (m, 1H), 7.77 (br.s., 2H), 7.73 (t, J=7.70 Hz, 1H), 7.55 (m, 2H), 7.55
(m, 2H), 7.55 (m, 1H), 7.33 (d, J=7.29 Hz, 1H), 7.33 (d, J=7.29 Hz, 1H), 7.24 (t, J=6.05 Hz,
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1H), 6.95 (t, J=3.85 Hz, 1H), 4.76 (d, J=3.30 Hz, 2H). 13C NMR (126 MHz, DMSOꢀd6) δ (ppm):
46.04, 111.66, 121.60, 122.14, 127.87, 128.41, 129.06, 129.08, 129.43, 132.20, 132.29, 133.68,
136.69, 138.94, 139.72, 140.17, 147.48, 148.18, 150.76, 151.81, 155.26, 156.06, 158.97. 15N
NMR 400 Hz, DMSOꢀd6) δ (ppm): 96.1, 100.2, 224.1, 243.5, 305.0, 317.9. Elemental analysis:
MF C25H20N6O2S, Calculated C, 64.09; H, 4.30; N, 17.94; O, 6.83; S, 6.84. Found C, 63.34; H,
4.24; N, 17.29; S, ND; H2O, ND; IR peak assignments (KBr film): 3361cmꢀ1, 3341cmꢀ1, NꢀH
stretches; 1356cmꢀ1, 1162cmꢀ1, sulfur dioxide stretches. HRMS: [M + 1] obs 469.1432 calc
469.1441.
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5ꢀ(5ꢀphenylꢀ4ꢀ(pyridinꢀ2ꢀylmethylamino)quinazolinꢀ2ꢀyl)pyridinꢀ3ꢀ
ylsulfonylphosphoramidic acid (29)
To
a
solution of 5ꢀ(5ꢀphenylꢀ4ꢀ((pyridinꢀ2ꢀylmethyl)amino)quinazolinꢀ2ꢀyl)pyridineꢀ3ꢀ
sulfonamide (25) (3.0 g, 6.4 mmol) in DCM (50 mL) was added DIPEA (2.237 mL, 12.81
mmol). The reaction mixture was stirred for 20 min, cooled to 0 °C and POCl3 (2.39 mL, 25.6
mmol) was added and the reaction mixture was stirred for 4 h. DCM and excess POCl3 were
removed under reduced pressure and the residue was dissolved in 100 mL of water and stirred
for 1 h. The resulting solid was filtered and the solid washed with excess water then dried under
reduced pressure to yield 5ꢀ(5ꢀphenylꢀ4ꢀ(pyridinꢀ2ꢀylmethylamino)quinazolinꢀ2ꢀyl)pyridinꢀ3ꢀ
ylsulfonylphosphoramidic acid (30) (2.50 g, 71.0 %) as an offꢀwhite solid.
To a solution of amorphous ((5ꢀ(5ꢀphenylꢀ4ꢀ((pyridinꢀ2ꢀylmethyl)amino)quinazolinꢀ2 yl)pyridinꢀ
3ꢀyl)sulfonyl)phosphoramidic acid (30) (6.00 g, 10.9 mmol) (HPLC Purity 97%) in DMSO (100
mL) was added water (40 mL) and the suspension stirred for 1 h. The resulting solid was filtered
and washed with water (10 mL) and dried under reduced pressure to yield crystalline ((5ꢀ(5ꢀ
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phenylꢀ4ꢀ((pyridinꢀ2ꢀylmethyl)amino)quinazolinꢀ2ꢀyl)pyridinꢀ3ꢀyl)sulfonyl)phosphoramidic acid
5
6
(29) (4.60 g, 77.1 %).
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9
LCMS Method 6: retention time 6.19 min; [M+1] = 549.1. HPLC Method 5: purity 99.3 %,
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1
retention time = 6.30 min. H NMR (400 MHz, DMSOꢀd6) δ (ppm): 4.78 (d, J =4 Hz, 2H), 6.91
(t, J =4 Hz, 1H), 7.30ꢀ7.36 (m, 2H), 7.40 (d, J =8 Hz, 1H), 7.53ꢀ7.58 (m, 5H), 7.81 (ddd, J =13.6
Hz, 7.6 Hz, 1.6 Hz, 1H), 7.86 (t, J =8.4 Hz, 1H), 7.94 (dd, J =8.4 Hz, 1.2 Hz, 1H), 8.35 (d, J =
13
4.4 Hz, 1H), 9.09 (d, J = 2.4 Hz, 1H), 9.28 (t, J = 2 Hz, 1H), 9.75 (d, J = 2 Hz, 1H). C NMR
(400 MHz, DMSOꢀd6) δ (ppm): 159.429, 156.404, 155.804, 152.351, 151.061, 148.554, 147.659,
140.087, 139.540, 139.394, 138.517, 134.042, 133.818, 132.799, 130.009, 129.630, 129.548,
128.977, 128.171, 123.061, 122.610, 111.997, 46.022. Elemental analysis: MF
C25H21N6O5PS.4H2O, Calculated C, 48.57; H, 4.69; N, 13.53; S, 5.46; H2O, 11.53; Found C,
48.26; H, 4.80; N, 13.19; S, 5.53; H2O, 12.42;
SUPPORTING INFORMATION AVAILABLE
Experimental details for synthesis and analysis of Compounds 6 to 24 and 26 to 29 can be found
in the supporting information.
AUTHOR INFORMATION
To whom correspondence should be addressed: Heather Finlay Phone: 609ꢀ466ꢀ5038. Fax: 609ꢀ
818ꢀ3550. Eꢀmail: heather.finlay@bms.com. Prashantha Gunaga Phone: +91 9900150718. Eꢀ
mail: prashantha.gunaga@syngeneintl.com
ACKNOWLEDGMENTS
We wish to acknowledge the following collaborators for their contributions as follows:
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Kavitha Govindrajulu and Shreelalitha Badagi for synthesis of closely related analogues in this
series. Amrita Roy at BBRC for library synthesis of the C4 analogs, Lokesh Babu,
Nanjundaswamy K C, Thirupala Reddy, Indasi Gopi Kumar and Sridharan Ramalingamfor their
contributions to scale up of intermediate 2.
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ABREVIATIONS
AERP, atrial effective refractory period; VERP, ventricular effective refractory period; AF, atrial
fibrillation.
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