N6-Cycloalkyl-2-substituted adenosine derivatives as selective, high affinity adenosine A1 receptor agonists

Article abstract of DOI:10.1016/j.bmcl.2006.09.065

A series of new selective, high affinity A₁-AdoR agonists is reported. Compound 23 that incorporated a carboxylic acid functionality in the 4-position of the pyrazole ring displayed K_iL value of 1 nM for the A₁-AdoR and >5

Full text of DOI:10.1016/j.bmcl.2006.09.065

Bioorganic & Medicinal Chemistry Letters 17 (2007) 161–166
N6-Cycloalkyl-2-substituted adenosine derivatives as selective,
high affinity adenosine A1 receptor agonists
Elfatih Elzein,a,* Rao Kalla,a Xiaofen Li,a Thao Perry,a Tim Marquart,a
Mark Micklatcher,a Yuan Li,b Yuzhi Wu,b Dewan Zengb and Jeff Zablockia
aDepartment of Bioorganic Chemistry, CV Therapeutics Inc., 3172 Porter Drive, Palo Alto, CA 94304, USA
bDepartment of Drug Research and Pharmacological Sciences, CV Therapeutics Inc., 3172 Porter Drive, Palo Alto, CA 94304, USA
Received 31 August 2006; revised 19 September 2006; accepted 21 September 2006
Available online 11 October 2006
Abstract—A series of new selective, high affinity A1-AdoR agonists is reported. Compound 23 that incorporated a carboxylic acid
functionality in the 4-position of the pyrazole ring displayed KiL value of 1 nM for the A1-AdoR and >5000-fold selectivity over the
A3 and A2A-AdoRs. In addition, compound 19 that incorporated a carboxamide functionality in the 4-position of the pyrazole ring
displayed subnanomolar affinity for the A1-AdoR (KiL = 0.6 nM) and >600-fold selectivity over the A3 and A2A-AdoRs.
Ó 2006 Elsevier Ltd. All rights reserved.
Adenosine is an endogenous purine nucleoside that
modulates a variety of physiological functions as a result
of its activation of specific G protein-coupled receptors
defined as A1, A2A, A2B, and A3 adenosine receptors
(AdoRs).1 Physiological responses that are mediated
by the A1-AdoR include cardiac (negative inotropic,
negative chronotropic, and negative dromotropic ef-
fects) and antilipolytic effects.2 Therefore, A1-AdoR
agonists have received much attention as antiarrhythmic
and antilipolytic agents. In general, selective A1-AdoR
agonists were obtained by monosubstitution of the N6-
position of adenosine (e.g., CPA, CHA)3, whereas
substitution at the C-2 position of adenosine yielded
selective A2A-AdoR agonists (e.g., CVT-3146 (Regade-
noson), CGS21680).4,5 However, the selectivity of AdoR
agonists for the A1 receptor was challenged by the dis-
covery of the A3-AdoR. Consequently, a wide range of
N6-substituted adenosine derivatives originally thought
to be selective for the A1-AdoR later turned out to be
also active at the A3-AdoR and that represented a new
challenge to discover selective A1-AdoR agonists.6 Even
though CCPA is considered to be one of the most selec-
tive A1-AdoR agonists known to date, it displayed only
50-fold selectivity for the A1-AdoR over the A3-AdoR.7
Hence, more selective A1-AdoR agonists are needed.
Simultaneous substitution at the N6 and C-2 positions
of adenosine has resulted in compounds with different
activity and selectivity profiles and some of these disub-
stituted compounds have high affinity and selectivity for
the A1-AdoR.8,9
In previous communications, we have shown that intro-
ducing a methyl group into the N6 position of CVT-3146
induces an increase in the affinity for the human
A3-AdoR and simultaneously decreases the affinity for
the A1 and A2A-AdoRs, resulting in significant enhance-
ment in A3-AdoR selectivity.10 During that study, we
have also observed that increasing the size of the N6 sub-
stituent from methyl to ethyl and propyl resulted in a de-
crease in the A3-AdoR affinity and an increase in the
A1-AdoR affinity and selectivity. This prompted us to
explore the effect of introducing substituents that are
conducive to high A1-AdoR binding affinity (e.g., cyclo-
alkyls) into the N6 position of our 2-pyrazolyl adenosine
derivatives with the idea of enhancing A1-AdoR binding
affinity and selectivity. In addition to the N6-cyclopen-
tyl, N6-norbornyl, and N6-cyclohexyl substituents, we
elected to incorporate the R-tetrahydrofuran (R-THF)
group as our main N6-substituent (R-THF is the
N6-substituent in CVT-510, our agent in phase III clin-
ical trials as an antiarrhythmic agent, Fig. 1).
The synthesis of compounds 27–34 is outlined in Scheme
1. Treatment of commercially available 20,30,50-tri-O-ace-
tyl-2,6-dichloroadenosine with 3-(R)-aminotetrahydrofu-
Keyword: A1-Adenosine receptors.
*
Corresponding author. Tel.: +1 650 384 8217; fax: +1 650 858
0390; e-mail: elfatih.elzein@cvt.com
0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.09.065

162
E. Elzein et al. / Bioorg. Med. Chem. Lett. 17 (2007) 161–166
O
NH2
N
HN
N
HN
N
N
N
N
N
N
N
N
N
N
N
N
R
O
O
O
OH
OH
CONHCH3
OH
HO
HO
HO
OH
OH
OH
CVT-3146 (Regadenoson)
R = H, CPA, R= Cl, CCPA
CVT-510 (Tecadenoson)
Figure 1. A1 and A2A adenosine receptor agonists.
O
HN
Cl
N
N
N
N
EtOH, Et3N
NH2NH2
RT
O
+
N
N
N
Cl
Heat
H2N
N
Cl
92%
O
O
85%
OAc
OAc
AcO
AcO
OAc
OAc
2
1
O
27 R1 = -Ph-4-CH3
O
HN
N
O
O
HN
N
28 R1 = -Ph-4-CF3
N
N
N
N
29 R1 = -2-pyridyl
30 R1 = -4-pyridyl
31 R1 = -2-quinolinyl
32 R1 = -2-pyrazinyl
33 R1 = -2-quinazolinyl
34 R1 = -2-pyridyl-4-COOH
N
H
H
N
R1
EtOH,Heat
N
N
NHNH2
O
O
75-80%
R1
OH
OH
HO
HO
OH
OH
3
Scheme 1.
ran in EtOH using triethylamine as a base afforded 2
in 85% yield. Direct substitution of 2 with hydrazine
and subsequent condensation of the resulting in 2-
hydrazinoadenosine derivative 3 with the appropriate
malonaldehyde in EtOH afforded the target com-
pounds in 75–80% yields. The 50-N-ethylcarboxamide
analogs 35–37 were prepared from the acid11 III
and ethylamine hydrochloride using standard amino
acid coupling (HBTu/HOBt) in DMF followed by
removal of the isopropylidene group in 80% AcOH/
H2O (Scheme 2). As outlined in Scheme 3 condensa-
tion of 2-hydrazino-N6-substituted adenosine deriva-
tive VI with ethyl 2,2-diformylacetate12 in EtOH
afforded the ester VII. Compounds 7, 8, 16, 17, 19,
20, and 26 were obtained by direct aminolysis of
the ester VII with ammonia, methylamine or ethyla-
mine. The pyrazole acid analogs 10, 18, and 23 were
obtained via hydrolysis of ester VII using 1 N NaOH/
MeOH. To enhance the solubility of the acid 6 in
organic solvents (resulting from hydrolysis of ester
4) the hydroxyl groups of 4 were protected with
TBDMS group (Scheme 4). Hydrolysis of ester 5
and coupling of the resulting acid 6 with the appro-
priate amines afforded the target compounds 9, 11,
and 13 after removal of the TBDMS group in 1 N
NH4F/MeOH.
Binding affinities of compounds 4–23 for the G-protein
coupled receptors (Ki-High, KiH) and uncoupled receptor
(Ki-Low, KiL) were evaluated in radioligand binding as-
says and the results are shown in Tables 2 and 3. For
the A1-AdoR, KiL was determined wherein GTPcS
was added to uncouple the G-protein from the
A1-AdoR while for the A2A, A3, and A2B-AdoRs KiH
were determined (in the absence of GTP). Agonists have
been demonstrated to have 3- to 10-folds higher affinity
for the G-protein coupled receptors than that for the
uncoupled receptors.13,14 For comparison purposes,
selected data for N6-methyl-2-pyrazolyl adenosine deriv-
atives are also listed (A–E, Table 1). The A1, A2A, and
A3-AdoRs binding affinities of these compounds were
previously reported.10 Replacement of the N6-methyl
substituent in compound A (Table 1) with R-THF group
as in 7 (Table 2) resulted in a significant enhancement in
the A1-AdoR binding affinity (KiL = 23 nM) and 9-fold
loss in A3-AdoR binding affinity relative to
A
(KiH = 710 nM). Increasing the length of the methyl-
carboxamide group in compound 7 to ethyl and propyl
groups has minimum effect on the A1-AdoR binding
affinity and at the same time resulted in enhancement
in the A3-AdoR binding affinity (8 and 9). Negatively
charged groups are known to diminish affinity at the
adenosine receptors and several carboxylate-bearing

E. Elzein et al. / Bioorg. Med. Chem. Lett. 17 (2007) 161–166
163
O
O
HN
HN
N
OMe
MeO
N
N
N
N
N
N
BAIB, TEMPO
MeCN/H2O 1:1
N
N
N
N
N
pTSOH, DMF, 60 0C
O
O
R1
O
R1
OH
HO
HO
O
OH
II
I
O
HN
N
O
O
HN
HN
N
N
N
N
N
N
N
N
N
80% AcOH/H2O
N
EtNH2, HBTu
DCM, DMAP
N
100 0C
N
N
N
N
O
N
N
O
O
O
O
HO
O
OH
R
R1
R1
O
EtHN
O
OH
35 R1 = -4-pyridyl
36 R1 = -Ph-4-CH3
37 R1 = -2-quinolinyl
EtHN
O
O
III
IV
Scheme 2.
R1
R1
N
HN
N
HN
N
Cl
N
N
N
N
N
N
R1
N
EtOH, Et3N
+
H2N
NH2NH2
RT
NHNH2
N
Cl
N
Cl
Heat
O
92%
O
O
85%
OH
OAc
OAc
HO
AcO
AcO
OH
VI
OAc
OAc
O
V
1
R1
N
R1
N
HN
N
HN
O
N
N
N
N
H
H
CO2Et
NH3, CH3NH2 OR EtNH2
65-85%
N
N
N
N
N
O
EtOH,Heat
75-80%
O
CONHR2
OH
OH
CO2Et
HO
HO
OH
OH
1N NaOH/MeOH
VII
R2 = H, Me or Et
R1 = THF, Cyclopentyl, Cyclohexyl or Norbornyl
R1
HN
N
N
10 R1 = THF
18 R1 = CP
23 R1 = norbornyl
N
N
N
N
O
OH
COOH
HO
OH
Scheme 3.
O
O
HN
N
N
HN
N
N
N
N
N
N
N
TBDMSCl, Imidazole
DMF, RT
O
N
N
N
O
OH
CO2Et
HO
OH
OTBDMS
CO2Et
HN
TBDMSO
4
OTBDMS
5
O
O
HN
9 R1 = propyl
11 R1 = Bn
12 R1 = Bn-4-F
13 R1 = Bn-4-Cl
N
N
N
N
N
1N NaOH/MeOH
1) HBTu, R1-NH2, DMF
2)1N NH4F/MeOH
N
N
N
N
N
N
N
O
O
OTBDMS
CONHR1
COOH
OH
TBDMSO
HO
OTBDMS
OH
6
Scheme 4.

164
E. Elzein et al. / Bioorg. Med. Chem. Lett. 17 (2007) 161–166
Table 1. A1 and A3-AdoRs binding affinities and selectivities of
compounds A–E10
A1-AdoR agonists have been reported to have affinities
about two orders of magnitude less than the correspond-
ing hydrogen-bearing derivatives.15 However, the acid
analog 10 displayed A1-AdoR binding affinity similar
to 7 (KiL = 24 nM) and at least 4-fold increased selectiv-
ity for the A1-AdoR over A3 and A2A-AdoRs relative to
7. Replacing the methylcarboxamide moiety in 7 with a
benzylamide group yielded at least 10-fold enhancement
in both A1- and A3-AdoRs binding affinity in compari-
son to 7 (11, KiL A1 = 2 nM, KiH A3 = 54 nM). Attempts
to improve the A1-AdoR selectivity of 11 over the
A3-AdoR by incorporating an electron-withdrawing
group in the p-position of the phenyl ring of 11 led to
a progressive enhancement in the A3-AdoR binding
affinity relative to 11 (12 and 13). Compound 15 that
contains a carboxylic acid group in the p-position of
the phenyl displayed high affinity (KiL = 8 nM) and
selectivity (>390-fold) for the A1-AdoR over the A3-
AdoR. Exchanging the R-THF moiety in 7 with a cyclo-
pentyl group as in 16 resulted in 11-fold improvement in
the A1-AdoR binding affinity (KiL = 2 nM) and at least
20-fold increased selectivity for the A1-AdoR over the
A3 and A2A-AdoRs relative to 7. Increasing the size of
the methylcarboxamide group in 16 to ethyl as in 17
R1
HN
N
N
N
N
N
N
O
R2
HO
OH
OH
b
c
Compounda
R1
R2
KiL A1
(nM)
KiH A3
(nM)
A
B
C
D
E
CH3
CH3
Et
CONHCH3
–Ph-4-OCH3
–Ph-4-OCH3
–2-Pyridyl
>6000
>4000
3700
73
15
41
2
CH3
Et
3800
1300
–2-Pyridyl
107
a 95% confidence limits were generally 15% of the mean value.
b Binding affinity for A1-AdoR was determined using DDT membranes
with [3H]-CPX as the radioligand, (Ki-Low).
c Binding affinity for A3-AdoR was determined using CHO-A3 cells
with [125I]-AB-MECA as the radioligand (Ki-High).
Table 2. A1, A3, A2B, and A2A-AdoRs binding affinities and selectivities
R1
HN
N
N
N
N
O
N
N
R2
HO
OH
OH
Compound
R1
R2
Kia (nM)
d
e
KiL (A1)b
KiH (A3)c
KiH (A2A
)
KiH (A2B
)
A3/A1
4
7
(R)-THF
(R)-THF
–COOCH2CH3
–CONHCH3
–CONHCH2CH3
–CONH(CH2)2CH3
–COOH
3
23
10
10
24
2
41
710
132
49
2410
726
>6000
>6000
>6000
>6000
>6000
>6000
>6000
>6000
>6000
>6000
>6000
>6000
>6000
>6000
>6000
>6000
>6000
>6000
>6000
>6000
>6000
13
30
13
5
8
(R)-THF
(R)-THF
1410
9
>5000
>4000
>5000
>5000
>5000
>5000
>5000
>5000
>5000
>5000
>5000
>5000
>5000
>5000
>5000
>5000
>5000
>5000
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
(R)-THF
(R)-THF
3210
54
133
27
–CONHBn
(R)-THF
(R)-THF
–CONHBn-4-F
–CONHBn-4-Cl
–CONHBn-4-CO2Et
–CONHBn-4-CO2H
–CONHCH3
–CONHCH2CH3
–COOH
43
27
6
15
0.34
0.15
15
4.0
(R)-THF
(R)-THF
92
8
3160
1420
20
395
710
20
Cyclopentyl
Cyclopentyl
Cyclopentyl
Cyclopentyl
Cyclopentyl
Cyclopentyl
Norbornyl
Norbornyl
Norbornyl
Cyclohexyl
Cyclohexyl
2
1
9
4120
380
19
468
633
21
–CONH2
–COOCH2CH3
H
0.6
0.9
34
3
105
250
>5000
1270
30
3
83
–COOCH2CH3
–COOH
1
>5000
3175
1
H
0.4
30
8
–COOCH2CH3
–CONHCH3
158
19
a 95% confidence limits were generally 15% of the mean value.
b Binding affinity for A1-AdoR was determined using DDT membranes with [3H]-CPX as the radioligand (Ki-Low).
c Binding affinity for A3-AdoR was determined using CHO-A3 cells with [125I]-AB-MECA as the radioligand (Ki-High).
d Binding affinity for A2A-AdoR was determined using HEK-A2A cells with [3H]-ZM241385 as the radioligand (Ki-High).
e Binding affinity for A2B-AdoR was determined using HEK-A2B cells with 3H-ZM241385 as the radioligand (Ki-High).

E. Elzein et al. / Bioorg. Med. Chem. Lett. 17 (2007) 161–166
165
Table 3. A1, A3, A2B, and A2A-AdoRs binding affinities and selectivities of compounds 27–37
O
HN
N
N
N
N
N
N
O
R2
R1
OH
OH
Compound
R1
R2
Kia (nM)
KiH (A2A
KiL (A1)b
KiH (A3)c
)
KiH (A2B
)
A3/A1
d
e
27
28
29
30
31
32
33
34
35
36
37
–Ph-4-CH3
–Ph-4-CF3
CH2OH
CH2OH
CH2OH
CH2OH
CH2OH
CH2OH
CH2OH
CH2OH
–CONHEt
–CONHEt
–CONHEt
74
31
94
15
3
2320
>5000
1180
1480
239
>6000
>6000
>6000
>6000
>6000
>6000
>6000
>6000
>6000
>6000
>6000
1
0.5
0.08
0.03
0.6
2
–2-Pyridyl
–4-Pyridyl
36
134
39
4
–2-Quinolinyl
–2-Pyrazinyl
–2-Quinazolinyl
–2-Pyridyl-4-COOH
–4-Pyridyl
26
36
63
77
NT
0.7
0.57
20
1170
357
160
64
0.4
1
>5000
NT
1060
121
89
–Ph-4-CH3
–2-Quinolinyl
>5000
>5000
0.005
0.006
NT, not tested.
a 95% confidence limits were generally 15% of the mean value.
b Binding affinity for A1-AdoR was determined using DDT membranes with [3H]-CPX as the radioligand (Ki-Low).
c Binding affinity for A3-AdoR was determined using CHO-A3 cells with [125I]-AB-MECA as the radioligand (Ki-High).
d Binding affinity for A2A-AdoR was determined using HEK-A2A cells with [3H]-ZM241385 as the radioligand (Ki-High).
e Binding affinity for A2B-AdoR was determined using HEK-A2B cells with 3H-ZM241385 as the radioligand (Ki-High).
resulted in 70-fold enhancement in A3-AdoR binding
affinity (KiH = 20 nM) relative to 16 while maintaining
the A1-AdoR binding affinity (KiL = 1 nM). This trend
is similar to the one that was observed when the same
structural changes were applied to compound 7.
Both the N6-R-THF carboxylic acid analog 10 (KiL
A1 = 24 nM, KiH A3 = 3120 nM) and the N6-cyclopen-
tyl carboxylic acid analog 18 (KiL A1 = 9 nM, KiH
A3 = 4120 nM) displayed comparable high binding
affinity and selectivity for the A1-AdoR. While the
cyclopentyl acid analog 18 showed comparable
A1-AdoR affinity and selectivity profile to the methyl
carboxamide analog 16, the THF acid analog 10 dis-
played slightly increased selectivity for the A1-AdoR
over both, the A3 and the A2A-AdoRs. However, the
N6-norbornyl acid analog 23 was the most selective
compound in this study and displayed low nanomolar
binding affinity for the A1-AdoR (KiL = 1 nM) and
>5000-fold selectivity for the A1-AdoR over the A3
and A2A-AdoRs. In addition, the N6-norbornyl unsub-
stituted pyrazole analog 24 exhibited subnanomolar
binding affinity (KiL = 0.4 nM) and substantial selec-
tivity for the A1-AdoR over both, the A3 and
A2A-AdoRs.
Taking into account the high A1-AdoR binding affinity
and selectivity of compound 7 relative to that of com-
pounds 8, 9, 11 and also the high A1-AdoR binding
affinity and selectivity of compound 16 relative to that
of 17, we hypothesize that within this class of com-
pounds steric factors at the 4-position of the pyrazole
ring may play a crucial role in determining the binding
affinity and selectivity for the A1 and A3-AdoRs. While
smaller substituents seem to be conducive to high
A1-AdoR binding affinity, larger substituents may show
preference in binding to the A3-AdoR and are detrimen-
tal to A1-AdoR binding affinity. To further test the
validity of this hypothesis, the carboxamide analog 19
was synthesized. Compound 19 indeed displayed sub-
nanomolar binding affinity (KiL = 0.6) and substantial
selectivity for the A1-AdoR over both, the A3 and
A2A-AdoRs providing additional support for the above
hypothesis.
Replacement of the N6-methyl group in compound D
(Table 1) with N6-R-THF resulted in 29 (KiH = 3 nM)
that displayed similar A3-AdoR binding affinity to D
and significant enhancement in the A1-AdoR binding
affinity (KiL = 36 nM) in comparison to D. In general,
compounds with aryl or heteroaryl in the 4-position of
the pyrazole ring showed similar affinity for both A1
and A3-AdoRs (27, 28, 31, 32, 34). However, introduc-
ing a carboxamide group (which is known to enhance
A3-AdoR binding affinity) in the 50-position of
Encouraged by the high binding affinity and selectivity
of the carboxylic acid analog 15, we opted to investi-
gate the effect of replacing the methylcarboxamide
group in compounds 7 and 16 with a carboxylic acid
functionality as in compounds 10 and 18, respectively.

166
E. Elzein et al. / Bioorg. Med. Chem. Lett. 17 (2007) 161–166
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Belardinelli, L. Curr. Top. Med. Chem. 2003, 3,
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3. Daly, J. W.; Padgett, W.; Thompson, R. D.;
Kusachi, S.; Bungi, R. A. Biochem. Pharmacol.
1986, 35, 2467.
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Nomoto, R.; Miyasaka, T.; Watanabe, Y.; Abiru, T. J.
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compounds 27 and 31 indeed led to significant increase
in the A3-AdoR binding affinity (36, 37, KiH = 0.7 and
0.5 nM, respectively).
Most of the compounds were evaluated for their relative
intrinsic activity in rat brain membranes.
The level of maximum stimulation of [35S]GTPcS bind-
ing to G protein induced by the full agonist CPA was
taken as 100%. The efficacy of all the tested compounds
was comparable to that of CPA and hence all the com-
pounds tested were considered to be full A1-AdoR ago-
nists (15 and 18 showed 100% [35S]GTPcS stimulation
relative to CPA).
In summary, we have discovered analogs with high
binding affinity and selectivity for the A1-AdoR. Com-
pound 23 that incorporated a carboxylic acid function-
ality in the 4-position of the pyrazole ring displayed
KiL value of 1 nM for the A1-AdoR and >5000-fold
selectivity over the A3 and A2A-AdoRs. In addition,
compound 19 that incorporated a carboxamide func-
tionality in the 4-position of the pyrazole ring displayed
subnanomolar affinity for the A1-AdoR (KiL = 0.6 nM)
and >600-fold selectivity over the A3 and A2A-AdoRs.
A1-AdoR agonists such as N6-cyclohexyladenosine
(CHA) have been shown to cause intense behavioral ef-
fects at low doses.16–19 The locomotor depression elicit-
ed by peripherally administrered A1-AdoR agonists is
usually interpreted as a CNS effect. Our new compounds
such as 23 contain a carboxylic acid group that would be
mostly charged at physiological pH and is expected to
diminish the diffusion of such compounds across the
blood–brain barrier by analogy of carboxylate xanthine
derivative BW-143320 and hence would serve as tools to
aid in further delineating the central and peripheral ef-
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of compounds may serve as leads to discover additional
potent and selective A1-AdoR agonists that may have
potential use as therapeutic agents.
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