2-Aminothiazole based P2Y1 antagonists as novel antiplatelet agents

Article abstract of DOI:10.1016/j.bmcl.2013.05.025

ADP receptors, P2Y₁ and P2Y₁₂ have been recognized as potential targets for antithrombotic drugs. A series of P2Y₁ antagonists that contain 2-aminothiazoles as urea surrogates were discovered. Extensive SAR of the thiazole

Full text of DOI:10.1016/j.bmcl.2013.05.025

Bioorganic & Medicinal Chemistry Letters 23 (2013) 4206–4209
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
2-Aminothiazole based P2Y1 antagonists as novel antiplatelet agents
⇑
Zulan Pi , James Sutton, John Lloyd, Ji Hua, Laura Price, Qimin Wu, Ming Chang, Joanna Zheng,
Robert Rehfuss, Christine S. Huang, Ruth R. Wexler, Patrick Y. S. Lam
Medicinal Chemistry, Molecular Sciences and Candidate Optimization, Bristol-Myers Squibb, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
ADP receptors, P2Y1 and P2Y12 have been recognized as potential targets for antithrombotic drugs. A ser-
ies of P2Y1 antagonists that contain 2-aminothiazoles as urea surrogates were discovered. Extensive SAR
of the thiazole ring is described. The most potent compound 7j showed good P2Y1 binding (Ki = 12 nM),
Received 4 March 2013
Revised 1 May 2013
Accepted 7 May 2013
Available online 17 May 2013
moderate antagonism of platelet aggregation (PA IC50 = 5.2
l
M) and acceptable PK in rats.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
P2Y1 antagonists
Platelet aggregation
Antithrombotic
Aminothiazole as urea surrogates
Adenosine-50-diphosphate (ADP) released from platelets, red
blood cells and damaged blood vessels is a key activator of plate-
lets and plays a crucial role in generation of arterial thrombi at
the site of vascular injury.1 Two G-protein coupled receptors,
P2Y1 and P2Y12, are required for full ADP-induced platelet aggrega-
tion, but each of these receptors plays a different role in this pro-
cess.2 P2Y1 triggers a rapid and transient intracellular calcium
increase which causes platelet shape change and initiates the pro-
cess of platelet activation.3 P2Y12 mediates a slower and more sus-
tained decrease in cyclic adenosine monophosphate (cAMP), which
amplifies and consolidates ADP-driven platelet activation.4
Co-activation of both P2Y1 and P2Y12 is required for a complete
platelet response, however, blockade of either receptor signifi-
cantly decreases ADP-induced platelet aggregation and thrombosis
formation.5
These studies suggest that novel P2Y1 antagonists could provide
an alternative or complement to current antithrombotic strategies
and our efforts focused on the search for orally bioavailable P2Y1
antagonists for chronic treatment.12 This paper describes our initial
effort towards the design, synthesis, and biological evaluation of a
series of novel 2-aminothiazole based P2Y1 antagonists.13
Biarylurea 112d (Fig. 1) was identified by our lead discovery
group as a potent P2Y1 antagonist in vitro with a Ki of 6 nM. This
compound showed moderate antagonism in the platelet aggrega-
tion assay with a platelet aggregation (PA) IC50 of 2.1 lM using
2.5 lM ADP. In search of structurally distinct urea isosteres that
could act as P2Y1 antagonists, we designed aminooxazole 2,14
aminoimidazole 3 and aminothiazole 414 (Fig. 1) as potential urea
surrogates. Compared to biarylurea 1, aminooxazole analog 2
(P2Y1 Ki = 59 nM) showed a threefold decrease in binding while
Given their key roles in platelet aggregation, P2Y1 and P2Y12
receptors have drawn increasing attention as potential targets of
antithrombotic therapy. The P2Y12 receptor is a well-established
target of marketed antithrombotic drugs,6 for example, clopido-
grel7, prasugrel8 and ticagrelor.9 Recently the P2Y1 receptor has
emerged as a new target for novel antithrombotic agents.10 Mice
that either lacked the P2Y1 gene or had been treated with the selec-
tive P2Y1 antagonist, MRS-2500,11a demonstrated a significant
antagonism of ADP-induced platelet aggregation. MRS-2500
administered intravenously showed strong efficacy in a thrombosis
model with only a moderate prolongation of bleeding time.11b
2-aminoimidazole 3 (P2Y1 Ki > 23 lM) did not show significant
P2Y1 binding affinity. Aminothiazole
4
(P2Y1 Ki = 15 nM)
O
H
X
H
N
N
N
OCF3
HN
O
N
N
O
1
2
, X = O, P2Y1 Ki = 59 nM
P2Y1 Ki = 6 nM
PA IC50 = 2.1 µM
(2.5 µM ADP)
3, X = NH, P2Y1 Ki > 23 µM
4
, X = S, P2Y1 Ki = 15 nM
⇑
Corresponding author. Tel.: +1 609 818 5843; fax: +1 609 818 3331.
E-mail address: Zulan.Pi@bms.com (Z. Pi).
Figure 1. 2-Aminoheterocycles as P2Y1 antagonists.
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.05.025

Z. Pi et al. / Bioorg. Med. Chem. Lett. 23 (2013) 4206–4209
4207
Table 1
Table 3
In vitro P2Y1 activity of 5a–e versus 4
In vitro P2Y1 activity of 7a–j versus 5c
Ph
5
S
N
H
N
5
S
N
4
H
N
R
R
4
N
O
CF3
5a-e
N
O
7a-j
Entry
R
P2Y1 Ki (nM)a
PA %Ctrlb@ 10
lM
Entry
R
P2Y1 Ki (nM)a
PA %Ctrlb@ 10
lM
4
H
Et
15
12
31
7
207
186
87
78
86
61
89
5a
5b
5c
5d
5e
5c
7a
7b
7c
7d
7e
7f
7g
7h
7i
H
7
11
8
7
8
61
54
32
41
41
30
85
79
99
98
17
t-Bu
CF3
C(Me)2CH2CO2H
CONMe2
2-Me
4-Me
2-F
3-OMe
4-OMe
4-OCF3
4-CN
2-OH
3-OH
100
8
a
n = 2, variation in individual values <20%.
Platelet aggregation (PA) AUC% control (%Ctrl) was tested with 10 lM of drug
and 2.5 lM of ADP.
12
13
435
195
12
b
7j
3-O(CH2)C(Me)2CH2N(Me)2
a
Table 2
n = 2, variation in individual values <20%.
Platelet aggregation (PA) AUC% control (%Ctrl) was tested with 10 lM of drug
b
In vitro P2Y1 activity of 6a–e versus 5c
and 2.5
lM of ADP.
R
5
S
N
H
N
4
CF3
N
O
6a-e
NH2
O
NO2
O
NO2
F
a
b
N
N
N
Entry
R
P2Y1 Ki (nM)a
PA %Ctrlb@ 10
lM
5c
6a
6b
6c
Ph
Me
CO2Et
CN
7
11
5
61
96
50
8
9
10
NCS
O
21
101
O
N
c
d
6d
6e
6
56
––
N
2
N
CONH2
4850
a
n = 2, variation in individual values <20%.
Platelet aggregation (PA) AUC% control (%Ctrl) was tested with 10 lM of drug
b
11
and 2.5 lM of ADP.
Scheme 1. Reagents and conditions: (a) 2-t-butylphenol, K2CO3, DMF, 130 °C,
6 days, 76%; (b) H2, 10% Pd/C, MeOH/THF, 95%; (c) di(1H-imidazol-1-yl)methan-
ethione, DCM, rt, 1 h, 80%; (d) 2-azido-1-phenylethanone, PPh3-resin, dioxane,
95 °C, 4 h, 64%.
maintained similar P2Y1 binding potency to that shown by 1.
However, compounds 2–4 did not show functional activity in a
human platelet aggregation assay.12d As described herein, we se-
lected aminothiazole 4 based on binding affinity to optimize fur-
ther for increased functional assay potency.
For initial optimization of compound 4 at the C4 position non-
polar ethyl (5a), t-butyl (5b) and trifluoromethyl (5c) analogs were
synthesized which maintained good P2Y1 binding affinity com-
pared to the parent compound 4 (Table 1). However, polar groups
such as carboxyl (5d) or amide (5e) at this position led to signifi-
cant loss of binding affinity compared to compound 4. Compounds
with P2Y1 Ki values less than 300 nM were tested for platelet
N
Boc
H
N
NH
H
N
a
HN Boc
10
b
NH2
c
N
O
3
N
O
12
13
aggregation at 10 lM with 2.5 lM ADP. In the C4 substituted ser-
ies, compound 5c (PA %Ctrl = 61) with a CF3 group was the most
potent showing a modest level of antagonism in the platelet aggre-
gation assay with an IC50 of 12 lM.
Scheme 2. Reagents and conditions: (a) N,N0-Di-Boc-S-methylisothiourea, HgCl2,
TEA, DMF, rt, 4 h, 77%; (b) TFA/DCM (1:1), rt, 2 h, 91%; (c) 2-bromo-1-phenyleth-
anone, TEA, DMF, 80 °C, 16 h, 26%.
Further optimization of 5c at the C5 position is shown in Table 2.
A variety of groups at the C5 position such as methyl (6a), ethoxy-
carbonyl (6b), cyano (6c), and oxadiazole (6d) maintained good
P2Y1 binding affinity. Ester 6b was equipotent in the platelet
aggregation assay (PA %Ctrl = 50%) to compound 5c. However, con-
verting the ethoxycarbonyl (6b) to the corresponding primary
amide (6e) resulted in significant loss of P2Y1 binding potency.
Since the phenyl substituent was well tolerated at C5, we
sought to improve the potency further by exploring phenyl group
substitutions. A number of small groups such as fluoro, methyl,
methoxy, trifluoromethoxy and cyano (7a–g) at different positions
on the phenyl ring were equipotent in P2Y1 binding affinity to 5c
(Table 3). However, both hydroxyl analogs 7h and 7i showed sig-
nificantly reduced binding affinity. Methoxy compounds 7d and
7e showed improved potency compared to 5c in the platelet aggre-
gation assay. We explored additional ether linked groups with

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Z. Pi et al. / Bioorg. Med. Chem. Lett. 23 (2013) 4206–4209
S
N
amine substituents to improve the physical chemical properties.
Compound 7j maintained strong binding and improved antago-
nism of platelet aggregation compared to compound 5c and dem-
H
N
b
a
CO2Et
14
N
O
onstrated an IC50 of 5.2 lM in the platelet aggregation assay.
Compound 7j was the most potent compound identified in this
series for platelet aggregation and was therefore advanced to a rat
pharmacokinetic study. Compound 7j demonstrated 27% oral bio-
availability, had a half-life (t1/2) of 2.1 h and a clearance of
6.7 mL/min/kg after intravenous dosing at 5 mg/kg in a solution
of EtOH/cremophor/water (1:1:8). This compound also showed a
high level of binding to human serum protein (99.9%).
The synthesis of 2-aminooxazole 2 is shown in Scheme 1. Com-
mercially available 2-fluoronitrobenzene 8 was treated with 2-t-
butylphenol and potassium carbonate in DMF at 130 °C to provide
9 which was hydrogenated to give the aniline intermediate 10.
Treatment of 10 with di(1H-imidazol-1-yl)methanethione in
dichloromethane at room temperature afforded the isothiocyanate
(11) in 80% yield. Intermediate 11 was treated with 2-azido-1-phe-
nylethanone in the presence of triphenyl phosphine resin in diox-
ane at 95 °C for 4 h to generate 2 in 64% yield.
17
Br
S
N
H
N
S
H
N
CO2Et
c, d
N
N
O
CO2H
N
O
18
5d
Scheme 4. Reagents and conditions: (a) ethyl 5-chloro-3,3-dimethyl-4-oxopent-
anoate, EtOH, 2,6-lutidine, 90 °C, 24 h, 95%; (b) NBS, HOAc, THF, rt, 83%; (c) phenyl
boronic acid, Pd(PPh3)4, 2 M Na2CO3, EtOH/toluene (1:2), 80 °C, 92%; (d) 1 N NaOH,
THF/MeOH (3:1), rt, 16 h, 55%.
Synthesis of 2-aminoimidazole 3 (Scheme 2) was accomplished
from intermediate 10 by treatment with N,N0-di-Boc-S-meth-
ylisothiourea, mercury (II) chloride and TEA to afford 12 which
was deprotected to give the guanidine intermediate 13. Cyclization
of 13 with 2-bromo-1-phenylethanone in DMF at 80 °C afforded 2-
aminoimidazole 3.
The aminothiazoles were synthesized from the amino interme-
diate 10. Intermediate 10 was condensed with benzoyl isothiocya-
nate and subsequently hydrolyzed to the thiourea 14 (Scheme 3).
ammonium hydroxide provided primary amide 6e which was then
dehydrated in the presence of trifluoroacetic anhydride and pyri-
dine to provide the nitrile (6c). Reaction of 6c with hydroxylamine
followed by cyclization in the presence of acetic acid, DIC and HOBt
afforded the oxadiazole analog 6d.
Coupling of 16c with the appropriately substituted phenyl
boronic acids in the presence of Pd(PPh3)4 and 2 M Na2CO3 at
95–100 °C yielded 5-phenyl analogs 7a–i (Scheme 6). Treatment
of 16c with Boc2O and DMAP in tetrahydrofuran gave the protected
aminothiazole 19. Coupling of 19 with 3-hydroxyphenylboronic
acid in the presence of Pd(PPh3)4 and 2 M Na2CO3 solution in 1:2
EtOH/toluene at 80 °C provided the phenol intermediate 20. Com-
pound 20 was treated with 3-(dimethylamino)-2,2-dimethylpro-
pan-1-ol, PPh3-resin and di-tert-butyl azodicarboxylate to yield
21 which was converted to 7j using 20% TFA in dichloromethane.
In summary, a novel series of 2-aminothiazole derivatives was
discovered with excellent P2Y1 binding activity. Several 4-trifluo-
romethyl-5-phenyl analogs demonstrated moderate antagonism
of platelet aggregation of which compound 7j was the most potent.
Compound 7j also showed acceptable oral bioavailability, clear-
ance and half-life in rats. However, high protein binding and low
solubility due to high lipophilicity may have contributed to the
moderate antagonism of platelet aggregation and this compound
was not advanced further. Further optimization of this series
including replacement of the thiazole with different heterocyclic
rings and modification of the t-butyl phenoxy group to improve
Compound 14 was then condensed with appropriate
a-bromoke-
tones or -bromoaldehydes in the presence of 2,6-lutidine at
a
90 °C to provide analogs 4, 6a and 15a–c. Bromination of 15a–c
with NBS in acetic acid generated the corresponding bromides
16a–c which were coupled with phenyl boronic acid in the pres-
ence of Pd(PPh3)4 and 2 M Na2CO3 at 95–100 °C to generate ana-
logs 5a–c.
The synthesis of 5d is illustrated in Scheme 4. Cyclization of the
thiourea 14 with ethyl 5-chloro-3,3-dimethyl-4-oxopentanoate in
the presence of 2,6-lutidine provided ester 17 which was treated
with NBS in acetic acid to give the bromide 18. Coupling of 18 with
phenyl boronic acid followed by subsequent hydrolysis provided
5d. The amide analog 5e was synthesized from 14 following a sim-
ilar procedure to that described for 5d using ethyl bromopyruvate.
Cyclization of 14 with ethyl 2-chloro-4,4,4-trifluoro-3-oxobut-
anoate at 90 °C in ethanol gave compound 6b (Scheme 5). Hydro-
lysis of 6b followed by treatment with thionyl chloride and
R'
S
H
S
H
N
N
a
NH2
10
b
N
R
N
O
N
O
4, R= H, R' = Ph
6a, R = CF3, R' = Me
15a, R =Et, R' = H
15b, R = t-Bu, R' = H
15c, R = CF3, R' = H
14
Ph
R
S
N
Br
R
S
N
H
N
H
N
c
d
15a-c
N
O
N
O
5a, R =Et
5b, R = t-Bu
5c, R = CF3
16a, R =Et
16b, R = t-Bu
16c, R = CF3
Scheme 3. Reagents and conditions: (a) i) Benzoyl isothiocyanate, DCM, 50 °C, 2 h, 97%; ii) 2 M LiOH, THF/MeOH (3:1), 50 °C, 2 h, 84%; (b) appropriate a-bromoketones or a-
bromoaldehydes, 2,6-lutidine, EtOH, 90 °C, 48–91%; (c) NBS, HOAc/THF (1:5), rt, 45-86%; (d) phenyl boronic acid, Pd(PPh3)4, 2 M NaCO3, toluene/ethanol (2:1), 95–100 °C,
24 h, 36–53%.

Z. Pi et al. / Bioorg. Med. Chem. Lett. 23 (2013) 4206–4209
4209
O
CO2Et
S
S
N
H
N
NH2
CF3
H
N
a
b, c
14
N
CF3
N
O
N
O
6e
6b
O
N
N
S
CN
H
N
S
N
H
N
e, f
N
CF3
d
CF3
N
O
N
O
6d
6c
Scheme 5. Reagents and conditions: (a) Ethyl 2-chloro-4,4,4-trifluoro-3-oxobutanoate, EtOH, 90 °C, 4 days, 77%; (b) 1 N NaOH, MeOH/THF (3:1), rt, 91%; (c) i) SOCl2, DCM, rt;
ii) 28% ammonium hydroxide, THF, rt, 88%; (d) trifluoroacetic anhydride (4 equiv), pyridine (6 equiv), THF, 0 °C-rt, 1 h, 76%; (e) hydroxylamine hydrochloride, DIPEA, EtOH,
60 °C, 5 h, 87%; (f) acetic acid, DIC, HOBt, CH3CN, 160 °C, microwave, 15 min, 37%.
Ann. Med. 2000, 32, 15; (d) Cattaneo, M.; Gachet, C. Arterioscler. Thromb. Vasc.
Biol. 1999, 19, 2281.
3. Wilde, J. I.; Retzer, M.; Siess, W.; Watson, S. P. Platelets 2000, 11, 286.
4. Gachet, C. Purinergic Signal. 2012, 8, 609.
S
H
N
R
a
5. (a) Hechler, B.; Gachet, C. Purinergic Signal. 2011, 7, 293; (b) Jacobson, K. A.;
Balasubramanian, R.; Deflorian, F.; Gao, Z.-G. Purinergic Signal. 2012, 8, 419; (c)
Wijeyeratne, Y. D.; Heptinstall, S. Br. J. Clin. Pharmacol. 2011, 72, 647; (d)
Gachet, C. Thromb. Haemost. 2008, 99, 466.
6. (a) Giorgi, M. A.; Arazi, H. C.; Gonzalez, C. D.; Di Girolamo, G. Expert Opin.
Pharmacother. 2011, 12, 1285. and references cited therein; (b) Fintel, D. J. Vasc.
Health Risk Manag. 2012, 8, 77. and references cited therein.
16c
N
CF3
7a-i
N
O
7. (a) Passacquale, G.; Ferro, A. Br. J. Med. 2011, 342, 1415; (b) Plosker, G. L.;
Lyseng-Williamson, K. A. Drugs 2007, 67, 613.
Br
Boc
S
Boc
OH
S
N
8. (a) Sugidachi, A.; Yamaguchi, S.; Jakubowski, J. A.; Ohno, K.; Tomizawa, A.;
Hashimoto, M.; Niitsu, Y. J. Cardiovasc. Pharmacol. 2011, 58, 329; (b) Angiolillo,
D. J.; Suryadevara, S.; Capranzano, P.; Bass, T. A. Expert Opin. Pharmacother.
2008, 9, 2893; (c) Jakubowski, J. A.; Winters, K. J.; Naganuma, H.; Wallentin, L.
Cardiovasc. Drug Rev. 2007, 25, 357.
9. (a) Sibbing, D.; Orban, M.; Massberg, S. Haemostaseologie 2013, 33, 12; (b) Di
Minno, M. N. D.; Momi, S.; Di Minno, A.; Russolillo, A. Curr. Drug Targets 2013,
14, 3.
10. (a) Thalji, R. K.; Aiyar, N.; Davenport, E. A.; Erhardt, J. A.; Kallal, L. A.; Morrow, D.
M.; Senadhi, S.; Burns-Kurtis, C. L.; Marino, J. P., Jr. Bioorg. Med. Chem. Lett.
2010, 20, 4104; (b) Pfefferkorn, J. A.; Choi, C.; Winters, T.; Kennedy, R.; Chi, L.;
Perrin, L. A.; Lu, G.; Ping, Y.-W.; McClanahan, T.; Schroeder, R.; Leininger, M. T.;
Geyer, A.; Schefzick, S.; Atherton, J. Bioorg. Med. Chem. Lett. 2008, 18, 3338; (c)
Morales-Ramos, A. I.; Mecom, J. S.; Kiesow, T. J.; Graybill, T. L.; Brown, G. D.;
Aiyar, N. V.; Davenport, E. A.; Kallal, L. A.; Knapp-Reed, B. A.; Li, P.; Londregan,
A. T.; Morrow, D. M.; Senadhi, S.; Thalji, R. K.; Zhao, S.; Burns-Kurtis, C. L.;
Marino, J.-P. Bioorg. Med. Chem. Lett. 2008, 18, 6222; (d) Houston, D.; Costanzi,
S.; Jacobson, K. A.; Harden, T. K. Comb. Chem. High Throughput Screening 2008,
11, 410.
N
N
b
N
CF3
c
16c
CF3
N
O
N
N
O
19
20
Boc
O
S
N
e
d
7j
N
CF3
N
O
11. (a) Houston, D.; Ohno, M.; Nicholas, R. A.; Jacobson, K. A.; Harden, T. K. Br. J.
Pharmacol. 2006, 147, 459; (b) Hechler, B.; Nonne, C.; Roh, E. J.; Cattaneo, M.;
Cazenave, J.-P.; Lanza, F.; Jacobson, K. A.; Gachet, C. J. Pharmacol. Exp. Ther.
2006, 316, 556. and references cited therein.
21
Scheme 6. Reagents and conditions: (a) appropriate boronic acid, Pd(PPh3)4, 2 M
Na2CO3, toluene/ethanol (2:1), 95–100 °C, 24 h, 55–96%; (b) Boc2O, DMAP, THF, rt,
87%; (c) 3-hydroxyphenylboronic acid, 2 M Na2CO3, Pd(PPh3)4, EtOH/toluene (1:2),
80 °C, 92%; (d) 3-(dimethylamino)-2,2-dimethylpropan-1-ol, PPh3-resin, DBAD,
THF, rt, 3 days, 81%; (e) 20% TFA/DCM, 1 h, 96%.
12. (a) Bird, J. E.; Wang, X.; Smith, P. L.; Barbera, F.; Huang, C.; Schumacher, W. A. J.
Thromb. Thrombolysis 2012, 34, 199; (b) Wong, P. C.; Crain, E. J.; Jiang, X.;
Bostwick, J. S.; Thibeault, C.; Ruel, R.; Rehfuss, R.; Schumacher, W. A.; Ogletree,
M. L. Circulation 2006, 114. II_248, abstract 1310; (c) Schumacher, W. A.;
Bostwick, J. S.; Ogletree, M. L.; Stewart, A.; Steinbacher, T. E.; Hua, J.; Price, L. A.;
Wong, P. C.; Rehfuss, R. J. Pharmacol. Exp. Ther. 2007, 322, 1; (d) Chao, H.; Turdi,
H.; Herpin, T. F.; Roberge, J. Y.; Liu, Y.; Schnur, D.; Poss, M. A.; Rehfuss, R.; Hua,
J.; Wu, Q.; Price, L. A.; Abell, L. M.; Schumacher, W. A.; Bostwick, J. S.;
Steinbacher, T. E.; Stewart, A. B.; Ogletree, M. R.; Huang, C. S.; Chang, M.;
Cacace, A. M.; Arcuri, M. J.; Celani, D.; Wexler, R. R.; Lawrence, R. M. J. Med.
Chem. 2013, 56, 1704.
13. The compounds reported herein were disclosed in: Sutton, J.; Pi, Z.; Ruel, R.;
L’Heureux, A.; Thibeault, C.; Lam, P.Y.S. US2006/0173002A1.
14. Ruel, R.; L’Heureux, A.; Thibeault, C.; Daris, J.-P.; Martel, A.; Price, L.; Wu, Q.;
Hua. J.; Wexler, R. R.; Rehfuss, R.; Lam, P.Y.S Bioorg. Med. Chem. Lett. 2013, 23,
3519.
the physical properties of these molecules will be reported in due
course.
References and notes
1. Murugappan, S.; Kunapuli, S. P. Front. Biosci. 2006, 11, 1977.
2. (a) Packham, M. A.; Mustard, J. F. Semin. Thromb. Hemost. 2005, 31, 129; (b)
Burnstock, G.; Williams, M. J. Pharmacol. Exp. Ther. 2000, 295, 862; (c) Gachet, C.