Discovery of aminoquinazoline derivatives as human A2A adenosine receptor antagonists

Article abstract of DOI:10.1016/j.bmcl.2015.11.048

Novel bicyclic adenosine A_2A antagonists with an aminoquinazoline moiety were designed and synthesized. The optimization of the initial lead compound based on in vitro and in vivo activity has led to the discovery of a potent and selective class of adenosine A_2A antagonists. The structure-activity relationships of this novel series of bicyclic aminoquinazoline derivatives as adenosine A_2A antagonists are described in detail.

Full text of DOI:10.1016/j.bmcl.2015.11.048

Accepted Manuscript
Discovery of Aminoquinazoline Derivatives as Human A2A Adenosine Receptor
Antagonists
Gang Zhou, Amjad Ali, Robert Aslanian, Gioconda Gallo, Timothy Henderson,
Tanweer Khan, Rongze Kuang, Guoqing Li, Yeon-hee Lim, Michael Lo, Biju
Purakkattle, Manuel De Ruiz, Andrew Stamford, Pauline Ting, Heping Wu,
Hongwu Wang, Dong Xiao, Tao Yu, Yonglian Zhang
PII:
S0960-894X(15)30256-0
DOI:
http://dx.doi.org/10.1016/j.bmcl.2015.11.048
BMCL 23304
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
13 July 2015
12 November 2015
16 November 2015
Please cite this article as: Zhou, G., Ali, A., Aslanian, R., Gallo, G., Henderson, T., Khan, T., Kuang, R., Li, G.,
Lim, Y-h., Lo, M., Purakkattle, B., Ruiz, M.D., Stamford, A., Ting, P., Wu, H., Wang, H., Xiao, D., Yu, T., Zhang,
Y., Discovery of Aminoquinazoline Derivatives as Human A2A Adenosine Receptor Antagonists, Bioorganic &
Medicinal Chemistry Letters (2015), doi: http://dx.doi.org/10.1016/j.bmcl.2015.11.048
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Graphical Abstract
Discovery of Aminoquinazoline Series as
Leave this area blank for abstract info.
Human A2A Adenosine Receptor Antagonists
Gang Zhou,* Amjad Ali, Robert Aslanian, Gioconda Gallo, Timothy Henderson, Tanweer Khan, Rongze
Kuang, Biju Purakkattle, Manuel De Ruiz, Andrew Stamford, Pauline Ting, Heping Wu, Hongwu Wang, Dong
Xiao, Tao Yu, Yonglian Zhang

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Bioorganic & Medicinal Chemistry Letters
Discovery of Aminoquinazoline Derivatives as Human A2A Adenosine Receptor
Antagonists
Gang Zhou,*a Amjad Ali,a Robert Aslanian,b Gioconda Gallo,a Timothy Henderson,a Tanweer Khan,b Rongze
Kuang,a Guoqing Li,b Yeon-hee Lim,a Michael Lo,a Biju Purakkattle,b Manuel De Ruiz,c Andrew Stamford, a Pauline
Ting,a Heping Wu,a Hongwu Wang,b Dong Xiao,b Tao Yu,a Yonglian Zhang a
a Department of Chemical Research, Merck Research Laboratories, 126 E. Lincoln Ave., Rahway, NJ 07065, USA
b Department of Chemical Research, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
c Department of Chemical Research, Merck Research Laboratories, 770 Sumneytown Pike, West Point, Pennsylvania 19486, USA
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
Novel bicyclic adenosine A2 antagonists with an aminoquinazoline moiety were designed and
synthesized. The optimization of the initial lead compound based on in vitro and in vivo activity
has led to the discovery of a potent and selective class of adenosine A2A antagonists. The
structure-activity relationships of this novel series of bicyclic aminoquinazoline derivatives as
adenosine A2A antagonists are described in detail.
Keywords:
Adenosine A2A receptor Antagonist
Aminoquinazoline
Parkinson’s disease
2014 Elsevier Ltd. All rights reserved.
with many of the side effects associated with current therapies.8
Parkinson’s disease (PD) is the most common movement
disorder and is characterized by motor abnormalities such as
bradykinesia, tremor, muscle rigidity, and postural instability.1
Non-motor symptoms such as cognitive impairment and
depression also occur in later stages of the disease. At the
neurochemical level, PD is caused by progressive degeneration of
dopamine (DA) neurons in key motor pathways such as the
nigrostriatal pathway.2 The standard of care is to increase
dopaminergic transmission through the enhancement of DA
release with the DA precursor L-Dopa or direct activation of DA
D2/D3 receptors.3 These agents are relatively effective, but are
often accompanied by serious side effects, including dyskinesia,
sedation and compulsive behavior. Moreover, the efficacy of
current medications progressively decreases after chronic use.4
Currently, there are no drugs that treat the non-motor symptoms
or block the progression of PD. There is evidence that A2A
antagonists could address these unmet needs since they have pro-
cognitive, anti-depressant and neuroprotective properties in
animal models.9 Collectively, these data indicate that a safe and
well-tolerated A2A receptor antagonist will be a significant
improvement over the current standard of PD care.
In recent years, adenosine A2A receptor have emerged as an
alternative target for potential treatment of PD.5 A1, A2A, A2B, and
A3 receptors belong to the family of G-protein-coupled receptors
(GPCRs). Subtype A2A receptor which is coupled to stimulation
of adenylyl cyclase activity and enhancement of the levels of
cAMP, is a high-affinity receptor found in large amounts in the
brain striatum.6 Preclinical and clinical data strongly support the
use of adenosine A2A receptor antagonists as a novel treatment of
the motor complications of PD, both as monotherapy and as
adjunctive therapy in combination with existing dopaminergic
agents.7 Clinical and preclinical evidence also suggests that
adenosine A2A receptor antagonists are unlikely to be associated
Figure 1. Selected examples of A2A receptor antagonists .
A2A antagonists have demonstrated efficacy in rodent and
primate models of PD, with significant improvement in the side-
effect profile related to both motor (e.g., dyskinesia) and non-
motor (e.g., hallucinations) disturbances. A number of drug
candidates from companies including Kyowa-Hakko, Merck
(Schering-Plough) and Biogen have been advanced into clinical
trials for treatment of PD; several representative examples are

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showed in Figure 1.10 The discovery of selective A2A receptor
antagonists has also been disclosed in numerous reviews and
publications.11
Pharmacophore modeling with this new lead was conducted
using conformational analysis and docking (Figure 3a).14 This
shows aminoquinazoline 4 has good alignment with tricyclic lead
1 in terms of hydrogen bond donor and acceptor features. Key
elements of the plausible pharmacophore-based binding area are
illustrated in a homology model (figure 3b); two key hydrogen
bonds were proposed between aminoquinazoline 4 and Asn253 to
form a hinge binding interaction. An intramolecular hydrogen
bond between the amide NH and the quinazoline nitrogen locks
the trans amide conformation. Further stabilization can be
rationalized from aromatic π-π stacking of the bicyclic
quinazoline core with Phe168 as well as possible cation-π
interaction between partial positive charged N3 of
aminoquinazoline with Phe186.
In our efforts to identify novel A2A receptor antagonists, a
screening campaign of our in house collection led to several hit
series. Among these hits was a series tricyclic leads exemplified
by compounds 1 and 2 (Figure 2). Compound 1 was the most
potent among its analogues, binding to the human A2A receptor
with a Ki value of 0.6 nM with good selectivity over the human
A1 receptor.12 Unfortunately, this series of compounds was
inactive in an in vivo rat catalepsy assay due to poor oral
pharmacokinetic (PK) properties.12 Also, poor solubility of
compounds in this series such as 1 and 2 made it difficult to
further characterize these compounds. Consequently, a hit-to-lead
optimization effort was undertaken with the aim of identifying a
suitable replacement for the rigid tricyclic scaffold to improve
water solubility, physicochemical properties and in vivo activity.
Table 1. Optimization of the Substitution on Aminoquinazoline 4a
rat
A2A
Ki
Rat catalapsy
1 h
AUC
(10mg/kg)
-74%
Human
A2A
Ki (nM)
human
A1
Ki (nM)
Cpd
#
R
(nM)
(10 mg/kg)
2.4uM.h
1.3
4.8
0.5
12
5
-39%
(10 mg/kg)
2.3uM.h
0.3
4.4
3.0
31
6
7
8
-55%
(10 mg/kg)
0.8uM.h
-35%
(30 mg/kg)
Figure 2. Lead structure design based on screening hits 1 and 2
346
213
8.7
2.9
Through a strategy of fragmentation of the phthalimide and
pyrrolidinone rings in structures 1 and 2, aminoquinoline
compound 3 was initially proposed to probe the effects of
structure simplification. This modification significantly
attenuated hA2A receptor affinity and selectivity versus the hA1
receptor, although solubility was slightly increased. We believe
the amide side chain in 3 might be positioned at wrong side for
A2A binding. In theory, incorporation of nitrogen into the
quinoline ring would restore the desired conformation of amide
side chain. As a result, it led to the identification of the
aminoquinazoline lead compound 4 which had good human and
rat A2A potency and moderate to good hA1, hA2B, hA3 selectivity.
Water solubility and pharmacokinetic properties were
dramatically improved with compound 4 (rat AUC = 1.6 uM.h
NT
0.7
3.1
10
33
NT
NT
NT
9
-23%
(10 mg/kg)
1.3 uM.h
0%
10
(30 mg/kg)
2.3
7.7
1299
132
57
12
11
12
NT
0%
(30 mg/kg)
8.9uM.h
@10 mg/kg, T1/2 = 0.5h, permeability = 40 x 10-6 cm/s, Clrat/hu
=
12.8 / 34.8 l /min/Mcells, non PGP substrate). Compound 4 also
demonstrated a clean ancillary profile except for time-dependent
inhibition (TDI) of 3A4 (3 fold at 30uM). Most importantly,
good in vivo anti-cataleptic efficacy was observed after an oral
dose of 4 in the haloperidol-induced catalepsy assay (−61% at 30
mg/kg @1h). 13
13
14
15
86
24
4743
337
6
302
NT
0.6
NT
NT
-31%
(30 mg/kg)
0.8uM.h
0.2
0%
(30 mg/kg)
NT
16
0.2
20
2.9
1035
160
6037
6300
NT
NT
NT
NT
17
18
a
b
Figure 3. (a) Pharmocophore model of lead compound 1(green) and
4(brown). (b) Homology model of pharmacophore-based binding of 4 and A2A
receptor.

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6.6
3.6
50
40
NT
NT
NT
NT
19
927
6.7
10000
84
26.7
15.0
78
78
37
39
38
40
20
a Assay values are the average of at least two independent determinations.
a Assay values are the average of at least two independent determinations.
SAR was focused on improving in vitro hA2A activity, in vivo
potency andPK properties. Initial investigations were carried out
by introducing substituents on the bicyclic quinazoline ring of 4.
Representative examples (5-20) for substitution on the bicyclic
core (boxed) are summarized in Table 1. First, fluoro-
substitutions at 6-, 7-, and 8- positions of quinazoline ring
showed similar A2A binding affinity and A1 selectivity (5-7).
Compound 5 demonstrated good anti-cataleptic activity at the
dose of 10 mg/kg (-74% @1h) and 10 fold lower dose (-30%
@1h), as well as no CYP TDI effect.
Results in Table 2 show that compounds with monocyclic
substituents (21-26) led to a substantial loss in hA2A receptor
affinity compared to the quinoline 5. Introduction of alkyl group
at the benzylic position showed differentiation towards A2A
receptor binding as depicted by compounds 27 and 28.
Replacement of the quinoline ring with naphthalene 29,
tetrahydroquinoline
30,
dihydrobenzodioxane
31,
or
benzomorpholine 32 resulted in reduced in vitro affinity. The
quinoline ring was also substituted by 5, 6-fused bicyclic rings
(33-36), in which certain ring replacements were tolerated with a
slight loss of hA2A receptor affinity and a drop in selectivity
versus the hA1 receptor as shown by benzoimidazole 34 and
isoindolinone 36. Furthermore, nitrogen-walking around the
quinoline ring (37-39) and changing the substitution pattern as
shown in compounds 40 failed to provide any improvement.
The challenge remained to achieve A1 selectivity in the
aminoquinazoline series. Comparison of the proposed binding
conformations to the A1 and A2A receptors of 5 and preladenant
were analyzed to achieve better understanding of A1 selectivity.
Structural modeling has shown that the majority of differences
between the A2A and A1 receptors are in the extracellular loop
(ECL) region (blue color in figure 3a).14 The ECL3 loop, where
the tail of preladenant is proposed to bind, is one residue shorter
in A1 than A2A, leading to a possible conformational difference in
this area. In addition, at the top of the ligand binding pocket,
there are three residue differences between the two receptors;
L167E, A265K and M271T in the A1 receptor (Figure 4a). On the
other hand, there is minimal difference at the lower half of the
ligand binding pocket. Therefore, structural modifications of
compound 5 designed to bind in a region corresponding to the
binding site of the extended tail of preladenent could have a
higher possibility of achieving A1 selectivity (Figure 3b).
Since 8-fluoro substituted aminoquinazoline
5 had an
improved profile, we investigated other substituents in place of
fluorine at the 8-position (8-18). The majority of these didn’t
show any advantage in terms of A2A affinity and selectivity
except analog 11, which was inactive in the rat catalepsy assay at
an oral dose of 30 mg/kg. Heteroaryl substituted analogs 17–18
had greatly decreased A2A affinity. Disubstituted compounds 19-
20 didn’t produce any further improvement over monosubstituted
analogs.
We also discovered that alkylation of the amide NH or the
aminoquinazoline NH2 led to a complete loss of affinity at hA2A
receptors (data not shown). Because the amide NH appeared to
be important to hA2A affinity our explorations were mainly
focused on optimization of the amide N-substituent to improve
potency and selectivity (Table 2).
Table 2. SAR on the amide moiety in aminoquinazoline seriesa
hA2A
Ki
hA1
Ki
hA2A
Ki
hA1
Ki
#
#
R
R
(nM)
(nM)
(nM)
(nM)
5.4
8.4
14
83
45.0
13.6
160
170
116
559
21
23
25
22
24
26
28
E
112
600
F
N
6.7
57
90
126
7.6
524
213
27
29
a
b
Figure 4. (a) Homology model of preladenant in the A2A (cyan) and A1
(brown) receptor binding pockets. (b) Homology model comparison of
aminoquinazoline 5 and preladanant.
30
10.1
Guided by this hypothesis, efforts to improve A1 selectivity
were therefore largely concentrated on extension of the quinoline
moiety in compound 5 to reach the ECL3 loop. A series of
targets with substitution at the 3 and 4 positions of quinoline ring
of 5 were synthesized, with the 3 position predicted to be the
preferred position based on modeling. Selected biological data
are collated in Table 3. To our disappointment, substitutions at
the 3-position were not well tolerated; A2a binding affinity was
significantly decreased as the substituent size increased as shown
by compounds 41-44. Subsequently, substitution was shifted to
the 4- position of the quinoline ring with an amide linker, as
shown by compounds 45 and 46, which led to a 10-fold loss of
hA2A receptor affinity and a slightly improvement in selectivity
20
103
21.5
135
31
32
34
25
281
54
3.1
1.8
24
33
35
8.2
5.4
36

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1.
2.
Ferre, S.; von Euler, G.; Johansson, B.; Fredholm, B. B.; Fuxe, K. Proc.
Natl. Acad. Sci. U.S.A. 1991, 88, 7238; (b) Schwarzschild, M. A. guest
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versus the hA1 receptor. Gratifyingly, bulkier and more extended
substituents exemplified by compounds 47-49 retained potent
A2A affinity and demonstrated moderately improved selectivity
over A1, revealing a promising trend towards improved A1
selectivity.
Table 3. SAR of substitution on quinoline moiety in lead 5a
3. (a) Jankovic, J. Chin. Med. J. 2001, 114, 227; (b) Jankovic, J. Mov.
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Cristalli, G.; Lambertucci, C.; Marucci, G.; Volpini, R.; Dal Ben, D.
Curr. Pharmaceutical Des. 2008, 14, 1525; (b) Yuzlenko, O.; Kiec-
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Today 2004, 1, 51.
Human A2A
Ki (nM)
Human A1
Ki (nM)
rat A2A
Ki (nM)
#
R
4-OMe
15.2
69
1.3
41
6. Ruiz, M. D.; Lim, Y-H.; Zheng, J. J. Med. Chem. 2014, 57, 3623.
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MT, Pinna A, Ferre´ S, Lanciego JL, Mu¨ller CE, Franco R. Pharmacol
Ther. 2011, 132, 280.
4-OEt
73.2
245
252
748
NT
NA
42
43
4-OBu
1536
6003
NT
44
9. (a) Shook B.C.; Jackson P.F. ACS Chem Neurosci. 2011, 2, 555; (b)
Kalda, A.; Yu, L.; Oztas, E.; Chen, J.-F. J. Neurol. Sci. 2006, 248, 9.
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Neustadt, B. R.; Hao, J.; Lindo, N.; Greenlee, W. J.; Stamford, A. W.;
Tulshian, D.;Ongini, E.; Hunter, J.; Monopoli, A.; Bertorelli, R.; Foster,
C.; Arik, L.; Lachowicz, J.; Ng, K.; Feng, K.-I. Bioorg. Med. Chem. Lett.
2006, 17, 1376; (d) Gillespie, R. J.; Bamford, S. J.; Botting, R.; Comer,
M.; Denny, S.; Gaur, S.; Griffin, M.; Jordan, A. M.; Knight, A. R.;
Lerpiniere, J.; Leonardi, S.; Lightowler, S.;McAteer, S.; Merrett, A.;
Misra, A.; Padfield, A.; Reece, M.; Saadi, M.; Selwood, D. L.; Stratton,
G. C.; Surry, D.; Todd, R.; Tong, X.; Ruston, V.; Upton, R.; Weiss, S. M.
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11. A number of recent reports on selective A2A receptor antagonists are
summarized in: (a) Shah, U.; Hodgson, R. Curr. Opin. Drug Discov.
Devel. 2010,13, 466; (b) Neustadt, B. R.; Liu, H.; Hao, J.; Greenlee, W.
J.; Stamford, W.; Foster,C.; Arik, L.; Lachowicz, J.; Zhang, H.;
Bertorelli, R.; Fredduzzi, S.; Varty, G.;Cohen-Williams, M.; Ng, K.
Bioorg. Med. Chem. Lett. 2009, 19, 967; (c) Cole, A. G.; Stauffer, T. M.;
Rokosz, L. L.; Metzger, A.; Dillard, L. W.; Zeng, W.; Henderson, I.
Bioorg. Med. Chem. Lett. 2009, 19, 378; (d) Shao, Y.; Cole, A. G.;
Brescia, M.-R.; Qin, L.-Y.; Duo, J.; Stauffer, T. M.; Rokosz, L. L.;
McGuinness, B. F.; Henderson, I. Bioorg. Med. Chem. Lett. 2009, 19,
1399; (e) Lanier, M. C.; Moorjani, M.; Luo, Z.; Chen, Y.; Lin, E.;
Tellew, J. E.; Zhang, X.; Williams, J. P.; Gross, R. S.; Lechner, S. M.;
Markison, S.; Joswig, T.; Kargo, W.; Piercey, J.; Santos, M.; Malany, S.;
Zhao, M.; Petroski, R.; Crespo, M. I.; Diaz, J.-L.; Saunders, J.; Wen, J.;
O’Brien, Z.; Jalali, K.; Madan, A.; Slee, D. H. J. Med. Chem. 2009, 52,
709; (f) Gillespie, R. J.; Bamford, S. J.; Gaur, S.; Jordan, A. M.;
Lerpiniere, J.; Mansell, H. L.; Stratton, G. C. Bioorg. Med. Chem. Lett.
2009, 19, 2664; (g) Shah, U.; Boyle, C. D.; Chackalamannil, S.;
Neustadt, B. R.; Lindo, N.; Greenlee, W. J.; Foster, C.; Arik, L.; Zhai, Y.;
Lachowicz, J. E.; Ng, K.; Wang, S.; Monopoli, A. Bioorg. Med. Chem.
Lett. 2008, 18, 4199.
12.0
6.9
210
160
NT
NT
45
46
4.4
160
NT
47
4.8
2.7
120
110
11.4
12.5
48
49
a Assay values are the average of at least two independent determinations.
The general synthesis of aminoquinazoline compounds 4-49
from the readily available bicyclic isatin intermediate 50 is
outlined in Scheme 1. Under basic condition, isatin 50 was
hydrolyzed to amino acid potassium salt 51, which were then
subjected to a cyclization reaction with guanidine to generate
aminoquinazoline carboxylic acid 52. Standard amide formation
with the corresponding amine yielded the final products 4-49.
12. A detailed description of the adenosine receptor binding assay is provided
in Bioorg. Med. Chem. Lett. 2005, 15, 1333.
Scheme 1. Reagents and conditions: (a) K2CO3, H2O-CH3CN, 40oC; (b)
13. The rat catalepsy in vivo assay uses rat Male Sprague-Dawley rats
(Charles River, Calco, Italy) weighing 175-200 g are used. The cataleptic
state is induced by the subcutaneous administration of the dopamine
receptor antagonist haloperidol (1 mg/kg, sc), 90 min before testing the
animals on the vertical grid test. For this test, the rats are placed on the
wire mesh cover of a 25x43 plexiglass cage placed at an angle of about
70 degrees with the bench table. The rat is placed on the grid with all four
legs abducted and extended ("frog posture"). The use of such an
unnatural posture is essential for the specificity of this test for catalepsy.
The time span from placement of the paws until the first complete
removal of one paw (descent latency) is measured maximally for 120
sec.The selective A2A adenosine antagonists under evaluation are
administered orally at doses ranging between 1 and 30 mg/kg, 1 and 4 h
before scoring the animals. Normally >30%inhibition of haloperidol-
induced catalepsy is considered to be active in this assay.
guanidine, NaOEt, MeOH, heat; (c) amine, HATU, DIPEA, CH2Cl2 or DMF.
In conclusion, novel bicyclic adenosine A2A antagonists with
an aminoquinazoline core have been discovered. Systematic SAR
investigations have optimized the original lead compound 1 into
compound 5.15 Compound 5 exhibit much improved solubility,
excellent in vitro activity and moderate selectivity over A1
receptors, was active in an in vivo rat catalepsy assay at a low
dose with minimal off-target issues. As a general tendency, these
series of compounds displayed low selectivity toward the hA1
receptor; however, it was possible to identify compounds with
selectivity over the hA1 receptor based on a modeling analysis.
Further research results of this series will be disclosed in the
future.
14. (a) Zhukov, A.; Andrew S. P.; Errey, J. C.; Robertson, N.; Tehan, B.;
Mason, J. S.; Marshall, F. H.; Weir, M.; Congreve, M. J. Med. Chem.
2011, 54, 4312; (b) Kim, S-K.; Gao, Z.; Van Rompaey, P.; Gross, A. S.;
Chen, A.; Van Calenbergh, S.; Jacobson, K. A. J. Med. Chem. 2003, 46,
4847; (c)Warne, T.; Serrano-Vega,M. J.; Baker, J. G.; Moukhametzianov,
References and notes

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15. Compound 5: 1H NMR (CDCl3, 400 MHz)  9.38 (m, 1H), 9.01(m, 1H),
8.44 (d, J=3.2 Hz, 1H), 8.03 (d, J=6.4 Hz, 1H), 7.94 (d, J=6.4 Hz, 1H),
7.77 (d, J=3.2 Hz, 1H), 7.57 (m, 2H), 7.17 (m,1H), 5.17(d, J=5.8Hz, 2H);
MS (ESI) [M+1]+ 347.9.