Optimization of ketone-based P2Y12 receptor antagonists as antithrombotic agents: Pharmacodynamics and receptor kinetics considerations

Article abstract of DOI:10.1016/j.bmcl.2014.04.001

Modification of a series of P2Y₁₂ receptor antagonists by replacement of the ester functionality was aimed at minimizing the risk of in vivo metabolic instability and pharmacokinetic variability. The resulting ketones were then optimized for their P2Y₁₂ antagonistic and anticoagulation effects in combination with their physicochemical and absorption profiles. The most promising compound showed very potent antiplatelet action in vivo. However, pharmacodynamic-pharmacokinetic analysis did not reveal a significant separation between its anti-platelet and bleeding effects. The relevance of receptor binding kinetics to the in vivo profile is described.

Full text of DOI:10.1016/j.bmcl.2014.04.001

Bioorganic & Medicinal Chemistry Letters xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Optimization of ketone-based P2Y12 receptor antagonists
as antithrombotic agents: Pharmacodynamics and receptor
kinetics considerations
a
a
a
a
Fabrizio Giordanetto a, , Peter Bach , Fredrik Zetterberg , Thomas Antonsson , Ruth Bylund ,
Johan Johansson a, Mikael Sellén a, David Brown a, Lotta Hideståhl a, Pia Berntsson b, Daniel Hovdal c,
Helen Zachrisson b, Jan-Arne Björkman b, J. J. J. van Giezen b
⇑
a Medicinal Chemistry, CVMD iMed, Pepparedsleden 1, SE-431 83 Mölndal, Sweden
b Bioscience, CVMD iMed, Pepparedsleden 1, SE-431 83 Mölndal, Sweden
c DMPK AstraZeneca R&D, CVMD iMed, Pepparedsleden 1, SE-431 83 Mölndal, Sweden
a r t i c l e i n f o
a b s t r a c t
Article history:
Modification of a series of P2Y12 receptor antagonists by replacement of the ester functionality was aimed
at minimizing the risk of in vivo metabolic instability and pharmacokinetic variability. The resulting
ketones were then optimized for their P2Y12 antagonistic and anticoagulation effects in combination with
their physicochemical and absorption profiles. The most promising compound showed very potent
antiplatelet action in vivo. However, pharmacodynamic–pharmacokinetic analysis did not reveal a
significant separation between its anti-platelet and bleeding effects. The relevance of receptor binding
kinetics to the in vivo profile is described.
Received 17 January 2014
Revised 31 March 2014
Accepted 1 April 2014
Available online xxxx
Keywords:
Acute coronary syndrome (ACS)
Acyl sulfonamides
Ketones
Ó 2014 Elsevier Ltd. All rights reserved.
Esters
P2Y12 receptor
Piperidinyl-pyridines
Platelet aggregation
Receptor kinetics
Thromboembolism
The P2 purinergic receptors are normally classified into two
families: metabotropic P2Y receptors (G-protein coupled recep-
tors) and ionotropic P2X receptors (ligand gated ion channels).1
Among the P2Y receptors described in humans, the P2Y1 and
P2Y12 receptors are expressed in platelets and are activated by
adenosine diphosphate (ADP),2 following platelet stimulation.
ADP is released from the platelet dense-granules and results in
increased concentration of cytosolic calcium via activation of
antagonists6 such as the thienopyridine derivative clopidogrel
(Fig. 1). Clopidogrel is a prodrug and exerts its pharmacological
effect through an active metabolite that binds irreversibly to the
P2Y12 receptor.7 Data suggests that reversible P2Y12 antagonism
results in a faster off-set of effect and could thus lead to a wider
therapeutic window, as defined by anti-thrombotic effect vs. risk
of bleeding.8,9 Comparative clinical studies have confirmed those
observations.10. The reversibly binding P2Y12 receptor antagonist
ticagrelor11 (Fig. 1) has been approved as an antiplatelet agent
for the treatment of patients with acute coronary syndrome (ACS).
We recently reported our discovery of novel reversible P2Y12
receptor antagonists,12,13 leading to the identification of 1, an
explorative clinical candidate with strong anti-thrombotic effect
and substantial therapeutic window in preclinical models.14 Given
the potential limitations imposed by the ester functionality of 1
(i.e., hydrolysis by esterases to give the corresponding nicotinic
acid derivative which showed limited intestinal absorption and
no anti-platelet effects), we set out to identify reversibly binding
P2Y12 antagonists devoid of such liabilities. Earlier in the program
P2Y1 and decreased concentration of cyclic adenosine monophos-
3
phate (cAMP) via activation of P2Y12
.
These combined actions
stabilize the formed platelet aggregates, which suggests a critical
role of P2Y12 in regulating platelet function, thereby offering
an opportunity for pharmacological intervention.4,5 Indeed,
common anti-platelet aggregation therapies include P2Y12 receptor
⇑
Corresponding author at present address: Medicinal Chemistry, Taros Chemi-
cals GmbH & Co. KG, Emil-Figge-Str. 76a, 44227 Dortmund, Germany. Tel.: +49
(0)231 9742 7224; fax: +49 (0)231 9742 7219.
E-mail address: fgiordanetto@tarosdiscovery.com (F. Giordanetto).
http://dx.doi.org/10.1016/j.bmcl.2014.04.001
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Giordanetto, F.; et al. Bioorg. Med. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.bmcl.2014.04.001

2
F. Giordanetto et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
O
HN
N
O
N
O
O
N
N
F
N
N
F
N
N
H
N
N
S
S
O
OH
S
Cl
clopidogrel
O
O
O
HO
OH
ticagrelor
1
Figure 1. Selected antagonists of the P2Y12 receptor.
we explored the potential for ester bioisosters, but overall no tan-
gible improvements were obtained.12,13 Based on the available
structure-activity relationships (SAR), we wanted to reevaluate
ketones, being the ester bioisosters with the highest steric and
electronic similarity to the parent ester compounds.
Despite still possessing the ability to accept hydrogen bonds
from the P2Y12 receptor, the propyl ketone analogue 2 (Scheme 1)
showed a decreased potency compared to the corresponding ethyl
ester 1, as previously reported13 (Table 1). Since 2 and 1 are equiv-
alent in size (as approximated by the number of heavy atoms) and
lipophilicity (based on logD measurements), this translated into
reduced ligand efficiencies for the ketone derivative 2 (Table 1).
In line with expectations, 2 displayed increased microsomal stabil-
ity but the permeability was somewhat reduced, as summarized in
Table 1. The overall results with 2 clearly indicated directions for
optimization. Specifically, we wanted to improve functional activ-
ity and maintain adequate physicochemical properties, in order to
assess whether non-ester containing P2Y12 antagonists in the
present series could show efficacy in vivo and be developed fur-
ther. Compound 2 demonstrated favorable microsomal stability
and solubility, but borderline permeability and suboptimal activity
at the P2Y12 receptor. These properties are normally affected by the
lipophilic character of molecules. We therefore hypothesized that
addition of small lipophilic substituents to structure 2 could give
sufficient increases in P2Y12 antagonism and permeability, while
retaining sufficient solubility and microsomal stability to warrant
in vivo testing. We thus explored chemical variations of the
pyridine 2-position and the benzylic substituents, respectively,
O
O
N
N
O
N
Cl
a,b,c
d
O
N
N
N
N
N
Cl
O
O
O
O
O
N
2:
R=benzyl
e,f
8-12: R=benzyl or substituted benzyl
13: R=1-methylbenzyl
N
N
H
14: R=1,1-cyclopropylbenzyl
N
R
S
O
O
O
Scheme 1. Reagents and conditions: (a) tert-butyl piperidine-4-carboxylate, TEA, MeCN, microwave oven, single node heating, 100 °C, 5 min (77%); (b) NaOH, water, 80 °C,
(98%); (c) (COCl)2, cat. DMF, DCM, 0 °C to rt, 20 min (98%); (d) n-PrMgBr, Fe(acac)3, THF, 0 °C, not isolated; (e) TFA, DCM (75%, 2 steps); (f) R-SO2NH2, PyBOP, DIPEA, DCM (25–
48%).
Table 1
Experimental profile for the initial ethyl ester—n-propyl ketone matched-pair
O
N
X
N
N
H
N
S
O
O
O
a
a
b
Compound
X
GTP
c
S IC50
(
lM)
RPC IC50
(
lM)
HLM T1/2 (min)
Caco-2 Papp (10À6 cm/s)c
LEd
LLEe
Log Df
1
2
O
C
0.025
0.100
3.2
7
60
>115
1
0.32
0.31
0.29
4.8
4.2
2.8
2.8
a
b
c
d
e
f
Results are mean of at least two experiments (Supplementary information).
Intrinsic clearance of test compounds after incubation for 30 min with human liver microsomes (HLM) (1 mg/mL) at 37 °C.
Permeability measured in Caco-2 cells in the apical to basolateral (A to B) direction, pH = 7.4 (Supplementary information).
Ligand efficiency, calculated as ÀRTln(GTP
c
S IC50)/heavy atoms count.
S pIC50—logD.
Lipophilic ligand efficiency, calculated as GTP
c
Experimental logD at pH = 7.4 using HPLC.15
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F. Giordanetto et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
3
O
N
O
N
O
O
O
a, b
c, d
e,f,g
O
R
N
N
R
O
O
R
N
H
O
R: n-Pr, CF, CF2
O
O
O
N
N
3: R = n-Pr
4: R = CF
5: R = CF2
h,i
R
N
N
R
N
N
H
N
O
S
O
O
O
O
Scheme 2. Reagents and conditions: (a) 1,1-dimethoxymethyl-N,N-dimethylmethanamine, EtOH, rt, over night; (b) NaOEt, 2-cyanoacetamide/EtOH rt, over night (41–56%);
(c) (COCl)2, DMF, DCM, 50 °C to reflux, over night (60–90%); (d) tert-butyl piperidine-4-carboxylate, TEA, MeCN, microwave oven, single node heating, 100 °C, 5 min; (e)
NaOH, water, 80 °C; (f) (COCl)2, cat. DMF, DCM, 0 °C to rt, 20 min; (g) n-PrMgBr, Fe(acac)3, THF, 0 °C, not isolated; (h) TFA, DCM. rt; (i) R-SO2NH2, PyBOP, DIPEA, DCM.
NH
O
O
N
HN
NC
b
c,d (X=S); e (X=O)
a
N
O
O
N
O
N
H
N
O
O
O
O
O
X
O
O
X
N
N
N
O
f,g,h
i,j
N
X
N
N
N
N
H
N
O
O
S
O
O
O
O
O
6: X=O
7: X=S
X= S,O
X= S,O
Scheme 3. Reagents and conditions: (a) ethyl 2-cyanoethanecarboximidate, DIPEA, EtOH, microwave oven, single node heating, 100 °C, 30 min, not isolated; (b) diethyl
(ethoxymethylene)malonate, rt, 16 h (32%, two steps); (c) Tf2O, TEA, DCM, 0 °C, 40 min, not isolated; (d) NaSMe THF, microwave oven, single node heating, 120 °C, 5 min, not
isolated; (e) MeI, Ag2CO3/DMSO, microwave oven, single node heating, 100 °C, 20 min (72%); (f) NaOH (1 M), THF, EtOH, microwave oven, single node heating, 120 °C, 5 min;
(g) cyanuric fluoride, pyridine, DCM, rt, 30 min, not isolated; (h) n-PrMgBr, Cu(I) iodide dimethylsulfide complex, 0 °C 20 min; (i) TFA, DCM, rt; (j) R-SO2NH2, PyBOP, DIPEA,
DCM, rt, 2.5 h (60–75%).
Table 2
Experimental profile for the variation set at the pyridyl-2-position
O
N
R
N
N
H
N
S
O
O
O
a
a
Compound
R
GTP
0.1
0.27
0.093
0.08
c
S IC50
(
lM)
RPC IC50
(lM)
Caco-2 Papp (10À6 cm/s)b
LEc
LLEd
LogDe
2
3
4
5
6
7
–Me
7
>30
8
11.5
10.3
1.4
0.3
1.2
<0.1
<0.1
NDf
0.3
0.29
0.26
0.28
0.28
0.29
0.31
4.2
2.9
4.3
4
4.1
4.7
2.8
3.7
2.7
3.1
3
–n-Pr
–CH2F
–CHF2
–OMe
–SMe
0.076
0.017
3.1
a
b
c
d
e
f
Results are mean of at least two experiments (Supplementary information).
Permeability was measured in human Caco-2 cells in the apical to basolateral (A to B) direction, pH = 7.4 (Supplementary information).
Calculated as ÀRTln(P2Y12 GTP S IC50)/HAC.
c
Calculated as P2Y12 GTPcS pIC50—logD
Experimental logD at pH = 7.4 using HPLC.15
Not determined.
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4
F. Giordanetto et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
and then combined the best identified modifications in a final set
for further profiling, as outlined below.
10.5 lM, respectively). Movement of the chlorine atom from the
para (9) to the ortho (10) position resulted in significantly reduced
A series of analogues with variation of the pyridine 2-substitu-
ent (3–7) was thus synthesized following Schemes 2 and 3. Table 2
summarizes the results for the pyridyl-2-substituent variation set
(3–7). Homologation of 2-methyl (2) to 2-n-propyl (3) increased
the lipophilicity and, in turn, the apparent permeability, but did
not result in increased potency. Fluoromethyl (4) and difluoro-
methyl (5) 2-substituents led to retained functional activity at
the P2Y12 receptor, but both compounds showed a further reduced
permeability (Papp <0.1 Â 10À6 cm/s) compared to 2. The 2-meth-
oxy derivative (6) did not afford any greater P2Y12 antagonism
than expected from its size and lipophilic contribution (cf. ligand
efficiency (LE) and ligand lipophilicity efficiency (LLE)). Interest-
ingly, compared to 2 and 6, the methylthio substituent (7) resulted
in a significant improvement in functional P2Y12 antagonism
activity (Table 3). Disubstitution, as exemplified by 11 and 12, or
introduction of substituents at the benzylic
a-position (13, 14)
did not offer any advantage over the unsubstituted parent
molecule (2). However, the cyclopropyl derivative 14, due to its
higher lipophilicity, showed the highest passive diffusion (Papp
:
5.2 Â 10À6 cm/s) of all compounds, with retained high aqueous sol-
ubility (>100 lM) and microsomal stability (HLM T1/2 >115 min),
and was thus considered further.
From the findings above, we combined the pyridyl-2-methyl-
thio substituent and the 1-phenylcyclopropanesulfonamide side
chain into one molecule by synthesizing compound 15 (Supple-
mentary information) to verify any additive or synergistic SAR
effects. We were pleased to see that 15 maintained similar P2Y12
antagonism to 7 (GTP
but, more importantly, that it was a much more potent platelet
inactivator than 1 (RPC IC50: 0.64 M; WPA IC50: 0.001 M), as
summarized in Table 4. Additionally, 15 was stable in HLM (T1/2
>115 min), soluble in water (78 M) and reasonably permeable
cS IC50: 0.019 and 0.017 lM, respectively),
(GTPcS IC50: 0.017
lM), which also translated into a better platelet
inactivation in plasma (RPC IC50: 1.4
lM), as shown in Table 2.
l
l
Having identified the methylthio substituent as an appropriate
lipophilic addition leading to potent P2Y12 antagonism, high solu-
l
bility (>100
l
M) and metabolic stability (HLM T1/2 >115 min), var-
(Papp: 2 Â 10À6 cm/s), therefore being an attractive compound to
be evaluated in vivo. We were interested in benchmarking 15
against our initial clinical candidate 1 in terms of anti-platelet
effect and bleeding risk before embarking on further compound
optimization. Compound 15 was thus dosed to conscious dogs
(N = 2) to record its pharmacodynamic (PD) profile, as summarized
in Figure 2.
iation of the benzyl substituents was explored by synthesizing
compounds 8–14 following the procedure outlined in Scheme 1.
As detailed in Table 3, p-methyl (8) and p-chloro (9) analogues of
2 showed increased functional antagonism of the P2Y12 receptor
(GTPcS IC50-values of 0.059 and 0.057 lM, respectively), but no
improvement in platelet inactivation (RPC IC50-values of 11 and
Table 3
Effects on potency, permeability, and lipophilicity by variation of the benzyl substituent
O
N
N
N
H
N
R
S
O
O
O
a
a
Compound
R
P2Y12 GTP
c
S IC50
(lM)
RPC IC50
7
(l
M)
Caco-2 Papp (10À6 cm/s)b
LogDc
*
2
0.1
0.3
2.8
*
*
8
9
0.059
0.057
11
1.4
0.4
3.4
3.4
10.5
Cl
F
Cl
F
10
11
0.27
0.13
ND
ND
0.4
0.7
3.1
3.4
*
*
12
0.042
11
0.3
3
*
F
( )-13
0.19
0.16
28
20
1
3.3
3.9
*
*
14
5.2
a
b
c
Results are mean of at least two experiments (Supplementary information).
Permeability was measured in human Caco-2 cells in the apical to basolateral (A to B) direction, pH = 6.5 (Supplementary information).
Experimental logD at pH = 7.4 using HPLC.15
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F. Giordanetto et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
5
Table 4
Experimental profile comparison for the initial ester 1 and ketone derivatives 2, 15
O
X
N
R
N
N
H
N
Y
S
O
O
O
a
a
b
c
e
f
Compound
R
X
Y
GTP
c
S IC50
(
lM) RPC IC50
(lM) WPA IC50
(l lmol h/L)
M) HLM T1/2 (min) Caco-2 Papp (10À6 cm/s)d PPB Fu (%) T1/2 (h) AUCf (
1
7
15
Me
MeS
MeS
O
C
C
CH2 0.025
CH2 0.017
cPro 0.019
3.2
1.4
0.64
0.009
60
>115
>115
1
0.3
2
0.35
NDg
0.41
5.1
5.9
NDg
5.2
NDg
6.7
0.001
a
b
c
d
e
f
Results are mean of at least two experiments (Supplementary information).
Ref. 8.
Intrinsic clearance of test compounds after incubation for 30 min with human liver microsomes (HLM) (1 mg/mL) at 37 °C.
Permeability was measured in human Caco-2 cells in the apical to basolateral (A to B) direction, pH = 7.4 (Supplementary information).
% fraction unbound in Beagle male dogs plasma measured by equilibrium dialysis (18 h at 37 °C).
Pharmacokinetic parameters calculated from noncompartmental analysis concentrations in fasted Beagle male dogs (N >2; iv dose: 1 lmol/kg).
Not determined.
g
Compound 15 displayed a strong, dose-dependent platelet inhi-
bition action in dogs, with an estimated ID80 of 0.052
and is thus a more potent anti-thrombotic agent than 1 (ID80
0.44 mol/kg/min). However, infusion of 15 also resulted in a
marked increase in bleeding time at the highest dose (1.6 mol/
lmol/kg/min,
:
l
l
kg/min, 6.7-fold increase in bleeding time), as shown in Figure 2.
This finding was in stark contrast to 1, which did not show any sig-
nificant bleeding time prolongation in the tested dose range
(0.02 nmol/kg/min–8.7 lmol/kg/min). The PD results in conscious
dogs confirmed 15 as an effective antithrombotic agent, but also
indicated the risk for a narrow therapeutic window. In order to
fully characterize the risk profile of 15, we evaluated it in a modi-
fied Folt’s model of arterial thrombosis,9,16 as summarized in
Figure 3.
Figure 3. Platelet aggregation (% inhibition, solid lines) and bleeding time (fold
increase, dashed lines) profiles for increasing doses of 1 (black) and 15 (red),
measured in the Folt’s dog model of arterial thrombosis (N>2).
Disappointingly, the modified Folt’s model profile of 15 con-
firmed the result of the PK–PD experiment in conscious dogs.
Despite an evident, full anti-platelet effect (ID80: 0.005
min) following administration of 15 (0.001–0.15 mol/kg/min), a
sharp increase in bleeding time (ED3.5-fold: 0.015 mol/kg/min)
was also observed. Although 1 was confirmed to be a weaker (p
<0.05) inhibitor of platelet activation (ID80: 0.009 mol/kg/min),
its therapeutic window was far superior to 15, as no significant
increase in bleeding time was observed. The differences in bleeding
time prolongation observed for 1 and 15 in vivo could not be ratio-
nalized based on the in vitro potency and pharmacokinetic data
generated, as summarized in Table 4. Here, T1/2 and AUC values fol-
lowing intravenous administration to Beagle dogs (N = 2) were
comparable, lending support to the hypotheses that no hysteresis
lmol/kg/
or PK–PD disconnect confounded the results. Likewise, the main
metabolites of 1 and 15, originating from CYP450-mediated oxida-
tion of the benzyl ring, that were characterized in vitro were
devoid of P2Y12 antagonism, thus ruling out their direct contribu-
tion to the observed in vivo PD effects. 1 and 15 did not show
any significant binding to more than 100 different enzyme, recep-
l
l
l
tors and ion channels at 10 l
M compound concentration.17 These
included GPCRs known to be involved in platelet regulation such
as the P2Y1 receptor, the platelet activating factor receptor (PAFr)
and thromboxane A2 receptor (TxA2).18 This reduced the risk of
any non-P2Y12-mediated effects. We further evaluated the binding
profile of the two compounds to the P2Y12 receptor since binding
kinetics have been suggested to play a major role in differentiating
PD action.19
Our previously described P2Y12 radiometric binding assay8
served to monitor the ability of test compounds to inhibit binding
of a radio-ligand to the P2Y12 receptor. The assay was run at differ-
ent time points (10, 30 and 60 s) and the corresponding IC50 values
were then compared to the IC50 values using a normal 60 min incu-
bation time to reflect equilibrium conditions (Table 5). Although 15
showed a two-fold higher affinity than 1 in binding to the P2Y12
receptor at 60 min (IC50-values: 4 1 and 9 1 nM, respectively),
it is significantly weaker than 1 at 10, 30 and 60 s, as summarized
in Table 5. Additionally, both 1 and 15 displayed time-dependent
binding profiles, with increasing binding affinities as function of
the incubation time. Taken together, these results indicate that,
under the tested in vitro conditions, 15 is a slow P2Y12 binder
and significantly slower than 1, as illustrated in Figure 4.
Figure 2. Platelet aggregation (% inhibition, solid lines) and bleeding time (fold
increase, dashed lines) profiles for increasing doses of 1 (black) and 15 (red),
measured in conscious dogs (N = 2).
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F. Giordanetto et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
Table 5
Supplementary data
Time-dependent binding of compounds 1 and 15 (N >4) to the P2Y12 receptor
Time
P2Y12 IC50 ( SD) (nM)
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.bmcl.2014.
04.001.
10 s
30 s
60 s
60 min
1
15
44 ( 5)
126 ( 33)
22 ( 3)
41 ( 5)
14 ( 2)
23 ( 3)
9 ( 1)
4 ( 1)
References and notes
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expressing the human P2Y12 receptor.8
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Figure 4. Ratio between P2Y12 binding IC50-values at a given incubation time (i.e.,
10, 30 and 60 s) over the corresponding IC50-values at 60 min (Table 5) for
compounds 15 (red circles) and 1 (black squares), respectively. Standard deviations
(N >4) are displayed.
The relevance of the observed kinetic profile for compound 15
to functional, in vivo P2Y12 antagonism needs to be further inves-
tigated. However, it is tempting to speculate that in order to suffi-
ciently separate anti-platelet effect from bleeding complications,
prolonged P2Y12 antagonism might not be desirable, as already
demonstrated with examples of irreversibly binding P2Y12 antago-
nists and a reversibly binding P2Y12 antagonist with rapid receptor
kinetics.6,8,10,20
In summary, we have developed ketone analogs of our ester-
based lead series with the aim to reduce PK/PD variability in a clin-
ical setting. Judicious addition of lipophilic substituents served to
increase antagonism of the P2Y12 receptor and anticoagulation
effects, while maintaining favourable physicochemical and pharma-
cokinetic properties. The best compound (15) identified by this
approach showed effective inhibition of platelet aggregation
in vivo, but also a marked prolongation of bleeding time. The differ-
ence in bleeding time between compounds 15 and 1 was possibly
the result of their different kinetic profiles in binding to the P2Y12
receptor. Based on the narrow therapeutic window of 15 and the
anticipated difficult balance between lipophilicity and compound
developability, namely metabolic stability and oral absorption, we
decided to cease any further optimisation of the series.
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Please cite this article in press as: Giordanetto, F.; et al. Bioorg. Med. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.bmcl.2014.04.001