Carbamate substituted 2-amino-4,6-diphenylpyrimidines as adenosine receptor antagonists

Article abstract of DOI:10.1016/j.bmcl.2016.01.004

A novel series of carbamate substituted 2-amino-4,6-diphenylpyrimidines was evaluated as potential dual adenosine A₁and A_2Areceptor antagonists. The majority of the synthesised compounds exhibited promising dual affinities, with A

Full text of DOI:10.1016/j.bmcl.2016.01.004

Bioorganic & Medicinal Chemistry Letters xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Carbamate substituted 2-amino-4,6-diphenylpyrimidines as
adenosine receptor antagonists
Sarel J. Robinson a,b, Jacobus P. Petzer a,b, Amanda L. Rousseau c, Gisella Terre’Blanche a,b, Anél Petzer b,
Anna C. U. Lourens a,b,
⇑
a Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa
b Centre of Excellence for Pharmaceutical Sciences, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa
c Molecular Sciences Institute, School of Chemistry, University of the Witwatersrand, Private Bag 3, PO WITS 2050, South Africa
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel series of carbamate substituted 2-amino-4,6-diphenylpyrimidines was evaluated as potential
dual adenosine A1 and A2A receptor antagonists. The majority of the synthesised compounds exhibited
promising dual affinities, with A1Ki values ranging from 0.175 to 10.7 nM and A2AKi values ranging from
1.58 to 451 nM. The in vivo activity illustrated for 3-(2-amino-6-phenylpyrimidin-4-yl)phenyl morpho-
line-4-carboxylate (4c) is indicative of the potential of these compounds as therapeutic agents in the
treatment of Parkinson’s disease, although physicochemical properties may require optimisation.
Ó 2016 Elsevier Ltd. All rights reserved.
Received 18 November 2015
Revised 3 January 2016
Accepted 4 January 2016
Available online xxxx
Keywords:
2-Aminopyrimidine
Adenosine A1 and A2A receptor
Dual
Antagonist
Parkinson’s disease (PD) is a chronic neurodegenerative disease
that affects over 1% of the world population. PD is an age related
disease, and with life expectancy increasing worldwide, will con-
tinue to present a huge social and economic burden in the future.1
Patients with PD mainly suffer from a progressive loss of motor
function, but non-motor symptoms, such as cognitive impairment
and depression often occur.2 The motor symptoms of the disease
can be attributed to the deterioration of dopaminergic neurons in
the striatum, resulting in a significant loss of dopamine in this
region.3 There is still no cure for PD, but the dopaminergic thera-
pies used clinically are reasonably effective in managing the symp-
toms during the early stages of the disease. Long-term treatment
with dopaminergic therapies however, is associated with several
undesirable side effects such as loss of drug efficacy, dyskinesia
and depression.4
Adenosine is an endogenous ligand that acts as a neurotrans-
mitter in the brain through the activation of its G-protein coupled
receptors, namely the A1, A2A, A2B and A3 receptors.5 Recently, dual
targeted antagonism of adenosine A1 and A2A receptors has
emerged as a promising non-dopaminergic alternative for the
treatment of neurodegenerative diseases such as Parkinson’s dis-
ease.6,7 The appeal of adenosine A2A receptors as a target in move-
ment disorders is due to their distinct localisation in the striatum
as well as their unique integrative action with dopamine D2 recep-
tors.8 Adenosine A2A receptors and dopamine D2 receptors have a
mutual antagonistic interaction, which means that antagonism of
adenosine A2A receptors would lead to enhanced D2 signalling, pro-
viding a rationale for their use in the symptomatic treatment of
PD.9 The use of A2A antagonists adjunctive to current dopaminergic
therapy may be beneficial since the dosage of the dopaminergic
drugs administered could potentially be lowered.10 This may
reduce the occurrence of dyskinesia and other side effects associ-
ated with dopaminergic drugs.11 Furthermore, it has been sug-
gested that A2A antagonism may halt the progression of PD as
preclinical evidence exists of its possible neuroprotective
benefits.12,13 Depression is a co-morbidity that often decreases
quality of life in PD patients, especially in the later stages of the
disease. A recent study illustrated the antidepressant effect of
the known A2A antagonist, KW6002, indicating an additional
advantage of A2A antagonism.14
The brain distribution of the adenosine A1 receptor on the other
hand, is more widespread than that of the A2A receptor, with high
levels expressed in the striatum, hippocampus and neocortex.15
Similar to adenosine A2A antagonism, antagonism of A1 receptors
have been shown to result in activation of motor function in ani-
mals,16,17 and may thus decrease motor deficiencies experienced
in PD. It has also been reported that the antagonism of the A1
receptor may enhance cognitive ability,18–21 and since a decline
in cognition is often observed in PD patients over time,
⇑
Corresponding author. Tel.: +27 18 2992266; fax: +27 18 2994243.
E-mail address: arina.lourens@nwu.ac.za (A.C.U. Lourens).
http://dx.doi.org/10.1016/j.bmcl.2016.01.004
0960-894X/Ó 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Robinson, S. J.; et al. Bioorg. Med. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.bmcl.2016.01.004

2
S. J. Robinson et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
A1 antagonism may thus be advantageous.22 Dual antagonism of A1
and A2A receptors thus has the potential of addressing the multi-
factorial nature of PD symptoms with less dopaminergic side-
effects than generally experienced with current therapies.
The best known adenosine receptor antagonists are the xanthi-
nes, such as caffeine and theophylline, which as a chemical class,
have been reviewed extensively.18 Several heterocyclic compounds
have also progressed to clinical trials, and include compounds such
as preladenant (1) and tozadenant (2).23,24
commercially available carbamoyl chlorides to obtain carbamates
(9a–i).32 Cyclisation was carried out with guanidine hydrochloride
and sodium hydride in N,N-dimethylformamide yielding the
desired 2-aminopyrimidines (4a–i) in low yields.33 Initially, three
equivalents of sodium hydride were used in the cyclisation step,
but this resulted in cleavage of the carbamate group. This problem
was overcome by reducing the number of molar equivalents of
NaH used in the reaction. The structures of all synthesised com-
pounds (Table 1) were confirmed by nuclear magnetic resonance
O
O
CH3
OH
N
N
S
N
N
NH
N
OCH3
N
O
N
N
O
N
O
N
N
NH2
1
2
Of particular interest to our group was the fact that the 2-
aminopyrimidine motif often occurred in heterocycles with adeno-
sine A2A and/or A1 affinity.7,25–29 Based on the aforementioned
results, we set out to synthesise a small library of 2-aminopyrim-
idines to investigate the potential of these compounds as dual ade-
nosine A1 and A2A antagonists. In a preliminary study reported
recently, we synthesised amide derivative 3 which exhibited high
dual affinity (A1Ki = 9.54 nM; A2A Ki = 6.34 nM) and in vivo
activity.30
spectroscopy and mass spectrometry, while purity was assessed
by HPLC (see Supporting Information).
Radioligand binding assays were performed to assess the bind-
ing of synthesised compounds to adenosine receptors. The radioli-
gands used were 1,3-[3H]-dipropyl-8-cyclopentylxanthine ([3H]
DPCPX) for adenosine A1 receptors, and [3H]5’-N-ethylcarboxam-
ide-adenosine ([3H]NECA) for adenosine A2A receptors. Striata from
male Sprague–Dawley rats were used as receptor source for A2A
binding studies, while whole brains were utilised for A1 binding
NH2
NH2
N
N
N
N
O
O
O
O
N
O
N
N
O
NR2
3
4
5
In order to further investigate the affinities of this class of com-
pounds for adenosine receptors, we decided to synthesise a series
of carbamate substituted 2-amino-4,6-diphenylpyrimidines (4).
The carbamate moiety is often present in therapeutic agents, such
as rivastigmine (5), an acetylcholinesterase inhibitor, which is used
in the treatment of Alzheimer’s disease. This amide-ester hybrid
generally displays very good chemical and proteolytic stability
and may increase permeability across cellular membranes.31 The
addition of the extra oxygen in structures such as 4, alters the posi-
tion of both the carbonyl and nitrogen groups and has the potential
to change the hydrogen bonding between the compound and the
receptor binding site, thus changing the affinity and possibly the
selectivity of these compounds in comparison with the amide
derivatives (3). It was also decided to replace the methyl furan sub-
stituent on position 4 with a phenyl ring, as this simplified the syn-
thesis. Gratifyingly, preliminary results indicated that this change
did not alter affinity to a significant degree.
studies (Ethics number: NWU-0035-10-A5). IC50 values were
obtained from sigmoidal-dose response curves as generated by
the Prism 5 software package (GraphPad) and the Ki values were
calculated from the IC50 values using the Cheng–Prusoff equa-
tion.34 Results from the receptor binding studies are presented in
Table 1.
The results reveal that most of these compounds have potent
dual affinity for both receptor subtypes, although affinities are gen-
erally higher for the adenosine A1 receptor compared to the adeno-
sine A2A receptor. Compounds 4a, 4b and 4c are the most
promising candidates for dual antagonistic activity with both
A1Ki and A2AKi values below 10 nM and selectivity indices of 4.6,
0.8 and 1.3, respectively. Compounds 4f and 4g in particular exhi-
bit high affinities for the adenosine A1 receptors, with Ki values of
0.468 and 0.175 nM, respectively. As exemplified by compounds
4a, 4b and 4c, substitution with six-membered saturated cyclic
carbamate substituents appears to yield optimal A2A receptor affin-
ity. Interestingly, although compound 4i with diphenyl substitu-
tion still has high affinity for the adenosine A1 receptor
(Ki = 10.7 nM), its affinity for the adenosine A2A receptor is compar-
atively weak with a Ki value of 451 nM. The size of the carbamate
Nine carbamate substituted 2-amino-4,6-diphenylpyrimidines
(Table 1) were successfully synthesised as indicated in Scheme 1.
Firstly, 3-hydroxybenzaldehyde (6) was condensed with
acetophenone (7), yielding chalcone (8), which was reacted with
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S. J. Robinson et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
3
Table 1
O
O
O
7
Adenosine receptor affinities (Ki) of the synthesised carbamates 4a–4i
i
H
CH3
+
NH2
OH
OH
N
N
6
8
NH2
N
ii,iii
O
N
O
O
iv
R
O
O
NR2
O
O
a
a
Compound
R
A1
A2A
SIb
(A2A/A1)
Ki (nM)
Ki (nM)
NR2
4a-i
9a-i
4a
4b
1.95 0.278
8.94 0.259
4.6
0.8
N
Scheme 1. Synthesis. Reagents and conditions: (i) NaOH, 1 M (2 equiv), MeOH, 90 ⁰C,
5 days (60%); (ii) K2CO3 (2 equiv), CH3CN, rt, 30 min; (iii) carbamoyl chloride
(1.2 equiv), reflux, 90 °C, overnight (70–90%); (iv) Guanidine hydrochloride
(1.5 equiv), NaH (1.5 equiv), DMF, 110 °C, overnight (15–30%).
2.04 0.002
1.58 0.311
N
N
N
N
N
N
O
4c
4d
4e
4f
2.65 0.059
0.835 0.088
2.06 0.135
0.468 0.057
3.50 0.030
24.8 6.61
51.9 3.07
22.8 1.75
1.3
30
Phe168 for all compounds. Intermolecular hydrogen bonding inter-
actions were also present between the exocyclic amino group of
the pyrimidine ring and Glu169 as well as Asn253 (Fig. 1) for most
derivatives. These interactions are believed to be responsible for
anchoring the aminopyrimidine in the binding site and are similar
to binding interactions previously determined for other
2-aminopyrimidine antagonists.35 There was another noticeable
hydrogen bond interaction between Glu169 and the carbamate
carbonyl of most compounds. When ranking the compounds
according to C-DOCKER- and C-DOCKER-interaction energies, it
was observed that compound 4i exhibited the least favourable val-
ues. This corresponds with the results obtained in the radioligand
binding studies, where compound 4i also exhibited the weakest
affinity for the A2A receptor among the compounds synthesised
(Ki = 451 nM). Visual inspection of the lowest energy pose of com-
pound 4i reveals that the hydrogen bonding interactions with
Glu169 and Asn253 are absent and that it has docked ‘upside
down’ in the binding site when compared to the rest of the synthe-
sised compounds (Fig. 2A), as well as ZM241385 (Fig. 2B). This sup-
ports the theory that A2A receptor affinity is influenced by
molecular size, with the receptor binding site unable to accommo-
date this large compound (4i). These molecular docking results
provide, at least in part, some explanation for the results obtained
with the radioligand binding assays.
25
49
N
4g
4h
0.175 0.017
1.07 0.079
12.1 1.35
39.9 4.77
69
37
N
N
4i
10.7 0.431
8.48 0.302
451 143
42
CPAc
ZM241385d
1.20 0.387
a
b
c
All values are expressed as the mean SEM of duplicate determinations.
Selectivity index (A2AKi/A1Ki).
N6-Cyclopentyladenosine,
a known adenosine A1 agonist, used as positive
control for A1 receptor affinity – literature Ki = 7.9 nM.35
d
A known adenosine A2A receptor antagonist, used as positive control for A2A
affinity – literature Ki = 2 nM.18
substituent therefore appears to affect affinity to a greater degree
for A2A receptors, where substitution with groups that are either
too small (e.g., 4e) or too large (e.g., 4h and 4i) appears to be detri-
mental for affinity. By comparison, the A1 receptors are able to
accommodate larger carbamate substituents without loss of bind-
ing affinity.
Molecular modelling studies were performed in an attempt to
rationalise the results obtained with the radioligand binding
assays. The crystal structure of the human A2A receptor crystallised
with the known adenosine A2A antagonist ZM241385 (PDB code:
3EML) was used as protein model. All compounds were success-
fully docked into the binding site using the C-DOCKER function
Figure 1. Compound 4b docked in the binding site of the human A2A receptor.
Hydrophobic interactions are indicated in orange while intermolecular hydrogen
bonding are indicated in green.
of Discovery studio 3.1 (Accelrys). Hydrophobic (
p–p) interactions
were observed between the three-membered ring system and
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S. J. Robinson et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
A
B
Figure 2. A. Compounds 4i (in colour) and 4b (in yellow) docked in the binding site of the human A2A receptor. B. ZM241385 bound in the binding site of the human A2A
receptor.36 Hydrophobic interactions are indicated in orange while intermolecular hydrogen bondings are indicated in green.
150
100
50
150
100
50
3A
3B
*
*
0
0
e
l
g
kg
/
/k
2 mg
ro
nt
Co
2 mg/kg
4 mg
0.
Controle
0.4Dmgo/ksgage
Dosage
Figure 3. A. Graph illustrating no significant reduction of catalepsy for both concentrations of compound 4b. B. Graph illustrating a significant attenuation of catalepsy with
both concentrations of compound 4c. (⁄Indicates significant differences compared with the haloperidol + vehicle control group as determined by one-way ANOVA [F(2,24)
= 3.97 (p = 0.032) followed by Dunnet’s post test with p = 0.03–0.05).
The most promising dual affinity compounds (4b and 4c) were
subsequently selected for in vivo screening, using the reversal of
haloperidol induced catalepsy with the standard bar test as an
indication of the potential of these compounds to act as antago-
nists at A2A receptors.16 Drug naïve Sprague–Dawley rats were
divided into three groups each receiving intraperitoneal (i.p.) injec-
tions of haloperidol (5.0 mg/kg) to induce catalepsy. Thirty min-
utes later the animals from group 1 received DMSO (control
group) and the other two groups received 0.4 and 2 mg/kg of the
test compound, respectively. Catalepsy was measured 60 minutes
after the first injection.
The results obtained after i.p. administration of the two selected
compounds 4b and 4c are shown in Figure 3. Disappointingly, com-
pound 4b with the highest dual affinity in vitro, did not reverse
catalepsy and appeared to be inactive in vivo (Fig. 3A). Contrast-
ingly, after i.p. administration of compound 4c, a significant reduc-
tion in catalepsy was observed when compared to the control
group (Fig. 3B), which is indicative of adenosine A2A antagonism.
It is postulated that the negative results obtained with compound
4b are due to unfavourable physicochemical properties, such
as poor water solubility, resulting in the precipitation of the
compound upon i.p. injection.
To obtain support for this theory, solubility and log D values
were determined for compound 4b in order to assess its suitability
as a drug candidate. The octanol-buffer partition coefficient was
determined with the shake flask method, while water solubility
was determined by shaking an excessive amount of 4b in water
at 37 °C. For the Log D study potassium phosphate buffer (pH
7.4) was selected for the hydrophilic phase and n-octanol for the
hydrophobic phase. Results are shown in Table 2.
It is generally accepted that the ideal log D value for a drug
should be between 1 and 3,37 thus allowing solubility in blood
plasma while at the same time ensuring that the compound is lipo-
philic enough to cross the blood brain-barrier. A Log D value of 4.03
is thus rather lipophilic, and this combined with the low aqueous
solubility may, at least in part, explain the lack of in vivo activity
of 4b. Other physicochemical and pharmacokinetic properties
may however also contribute. For example, a high degree of plasma
Table 2
The Log D and solubility of compound 4b
Log D
4.03 0.197
Solubility (
lM)
0.22 0.072
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S. J. Robinson et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2016.01.
004.
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Please cite this article in press as: Robinson, S. J.; et al. Bioorg. Med. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.bmcl.2016.01.004