2-Substituted PI system derivatives of adenosine that are coronary vasodilators acting via the A2A adenosine receptor

Article abstract of DOI:10.1081/NCN-100002306

Compound 20 (CVT-3146 - a 2-[(N-1-(4-N-methylcarboxamidopyrazolyl)] adenosine derivative) and compound 31 (CVT-3033 - a 2-[(4-(1-N-pentyl-pyrazolyl)] adenosine derivative), were found to be short acting functionally selective coronary vasodilators (CV t

Full text of DOI:10.1081/NCN-100002306

This article was downloaded by: [UQ Library]
On: 24 November 2014, At: 01:14
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer
House, 37-41 Mortimer Street, London W1T 3JH, UK
Nucleosides, Nucleotides and Nucleic Acids
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/lncn20
2-SUBSTITUTED PI SYSTEM DERIVATIVES OF
ADENOSINE THAT ARE CORONARY VASODILATORS
ACTING VIA THE A2A ADENOSINE RECEPTOR
J. Zablocki , V. Palle , B. Blackburn , E. Elzein , G. Nudelman , S. Gothe a , Z. Gao , Z.
Li , S. Meyer & L. Belardinelli
a Tripos, Inc. , San Francisco, California, U.S.A.
Published online: 07 Feb 2007.
To cite this article: J. Zablocki , V. Palle , B. Blackburn , E. Elzein , G. Nudelman , S. Gothe , Z. Gao , Z. Li , S. Meyer
& L. Belardinelli (2001) 2-SUBSTITUTED PI SYSTEM DERIVATIVES OF ADENOSINE THAT ARE CORONARY VASODILATORS
ACTING VIA THE A2A ADENOSINE RECEPTOR, Nucleosides, Nucleotides and Nucleic Acids, 20:4-7, 343-360, DOI: 10.1081/
NCN-100002306
To link to this article: http://dx.doi.org/10.1081/NCN-100002306
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained
in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of
the Content. Any opinions and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied
upon and should be independently verified with primary sources of information. Taylor and Francis shall
not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other
liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or
arising out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any
form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://
www.tandfonline.com/page/terms-and-conditions

NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS, 20(4–7), 343–360 (2001)
2-SUBSTITUTED PI SYSTEM DERIVATIVES
OF ADENOSINE THAT ARE CORONARY
VASODILATORS ACTING VIA THE A2A
ADENOSINE RECEPTOR
J. Zablocki,1,∗ V. Palle,1 B. Blackburn,1,2 E. Elzein,1 G. Nudelman,1
S. Gothe,3 Z. Gao,2 Z. Li,2 S. Meyer,2 and L. Belardinelli2
1CV Therapeutics Dept. of Bioorganic Chemistry and
2CV Therapeutics Dept. of Pharmacological Science,
Palo Alto, California
3Tripos, Inc., San Francisco, California
ABSTRACT
Compound 20 (CVT-3146 - a 2-[(N-1-(4-N-methylcarboxamidopyrazolyl)]
adenosine derivative) and compound 31 (CVT-3033 - a 2-[(4-(1-N-pentyl-
pyrazolyl)] adenosine derivative), were found to be short acting functionally
selective coronary vasodilators ( CV t0.5 = 5.2 0.2 and 3.4 0.5 min, re-
spectively - rat isolated heart 50% reversal time) with good potency (EC50s =
6.4 1.2 nM and 67.9 16.7 nM, respectively), but they possess low affin-
ity for the ADO A2A receptor (Ki = 1122 323 nM and 2138 952 nM,
respectively; pig striatum).
INTRODUCTION
Initially, A2A adenosine (ADO) agonists, such as CGS-21680 and YT-146
(Compounds 1 and 2, respectively Fig. 1) were developed for there peripheral va-
sodilator effect for the treatment of hypertension (1–3). In the last decade, another
use for A2A ADO agonists is as coronary vasodilators in conjunction with radionu-
clide imaging of the heart or echocardiography to detect and provide prognostic
assessment of underperfused areas of myocardium. Currently, adenosine is used in
∗Corresponding author.
343
ꢀ
C
Copyright 2001 by Marcel Dekker, Inc.
www.dekker.com

ORDER
REPRINTS
344
ZABLOCKI ET AL.
Figure 1. Examples of compounds from the three classes of Ado A2A agonists that contain a
lipophilic 2-substituent, and their affinity for the rat brain (RB, forebrain) Ado A2A receptor: pi system
linker – compound 1 (YT-146) (2) and compound 3 (THENECA) (10) Panels A and C; heteroatom
linker – compound 2 (CGS-21680) (1) panel B; and pi system and heteroatom linker – compound 4
(WRC-470) (6) panel D. The Ki for THENECA is from reference 10.
“pharmacological stress” tests during myocardial imaging with excellent diagnostic
and prognostic value, however, a high percentage of patients that receive adenosine
experience a number of drug related side effects (4–5). We and others (6–9) have
hypothesized that a selective A2A Ado agonist may have fewer side effects than
adenosine itself. Therefore, our goal was to synthesize a coronary (not peripheral)
vasodilator that is functionally selective for the A2A Ado receptor, and test that it’s
effect is rapid in onset but short in duration.
There are three classes of Ado A2A agonists based on different 2-substituted
adenosine derivatives with illustrative examples shown in Figure 1. The first class
contains a pi system at the 2-position, exemplified by the acetylenic and trans double
bonds of YT-1462 and THENECA (10) respectively (Compounds 1 and 3), that are
used to extend a hydrophobic chain into a putative lipophilic pocket in the Ado A2A
receptor. A second class of A2A Ado agonists contain a 2-heteroatom alkyl linker to
a hydrophobic group that is exemplified by CGS-21680 (compound 2, Fig. 1) (1).
A third class of 2-substituted A2A adenosine agonists contains both a 2-heteroatom
linker and a pi system, and it is exemplified by WRC-0470 (compound 4, Fig. 1) (6).
All of the agonists shown in Figure 1 have high affinity for the A2A receptor, and pos-
sess low affinity for the A1 receptor (note: WRC-470, compound 4, has been shown
to be functionally selective for the ADO A2A receptor compared to A1 receptor (6)).

ORDER
REPRINTS
ADENOSINE DERIVATIVES AS CORONARY VASODILATORS
345
Our four classes of A2A Ado agonists that are 2-substituted pi system deriva-
tives of adenosine have design features related to those shown in Figure 1 where the
trajectory of the hydrophobic 2-substituent from the purine ring of adenosine ap-
proximates one of the three classes described above. The first class, a 2-propargyl
phenyl ether Ado derivatives, has the same linker as YT-146 (4), but a differ-
ent hydrophobic element than YT-146 (4) or (S)-PHPNECA (10) (5) shown in
Figure 2 (Panel A). The propargyl phenyl ether has only a hydrogen bond acceptor
in the ether oxygen, whereas the (S)-PHPNECA (5) has both a hydrogen bond
acceptor and a donor in the hydroxyl group. This structural difference may impart
different biological properties (see modeling section below). In class two (Panel B),
the 2,5-thienyl class of A2A Ado agonists has a hydrophobic group with a 164◦ tra-
jectory relative to the 180◦ trajectory of the acetylene linker (Fig. 2, Panel B).
Class three is a 2-[(4-(1-N-substituted pyrazolyl)] adenosine series (C-Pyrazole
class, Fig. 2, Panel C) that has the same 152◦ trajectory as that of the THENECA
(3) derivative shown in Figure 1. Similarly, the 2-[(N-1-(4-substituted pyrazolyl)]
adenosine series (N-pyrazole class 4) has a 152◦ trajectory, but also contains a
2-heteroatom linker and a pi system like WRC-470 (4). This class was designed by
envisioning a 5-membered pyrazole ring obtained through closing the hydrazone
as illustrated in Figure 2 (Panel D).
Figure 2. Our four classes of Ado A2A agonists that are 2-substituted pi system derivatives of
adenosine:propargylphenyletherclass1isrelatedto(S)-PHPNECA(Cristallietal(10));5-substituted
thiophene class 2 presents a lipophilic substituent at a 164o trajectory that is compared to the 180o
trajectory of the acetylene class 1; C-pyrazole class 3 has an identical trajectory to THENECA;
N-pyrazole class 4 can be viewed as a constrained hydrazone mimetic.

ORDER
REPRINTS
346
ZABLOCKI ET AL.
NH2
NH2
N
N
H
N
O
N
N
7
N
N
N
O
I
O
Cul
Pd(0)
O
HO
OH
OH
HO
OH
OH
6
8
Scheme 1.
CHEMISTRY
The synthesis of new compounds and intermediates from the 2-propargyl
phenyl ether, 2-thienyl, and 2-(1-N-pyrazolyl) adenosine series are illustrated in
Schemes 1–4. Members of the 2-(4-pyrazolyl) and 2-(N-1-pyrazolyl) adenosine
series are described elsewhere (8,9). The preparation of the propargyl phenyl ether
class utilizes a palladium mediated coupling reaction between the previously de-
scribed iodo derivative (11,12) 6 and the propargyl phenyl ether 7 as shown in
Scheme 1. The iodo derivative 6 is derived from guanosine in four steps involving
introduction of a 6-chloro group (POCl3), diazotization of the 2-amino group, and a
in situ radical trapping to introduce the 2-iodo group (11,12). The propargyl phenyl
ethers were all prepared in greater than 85% yield through the reaction of propargyl
bromide with the corresponding phenolic compounds in the presence of potassium
carbonate as base.
The 2-thienyl adenosine series was prepared through diazotization of the pre-
viously described 2-amino derivative (11,12) 9, and a in situ radical trapping to
introduce the 2-(5-methylthienyl) group of compound 10 as shown in Scheme 2
(13). Introductionofthe6-aminogroupanddeprotectionwasaccomplishedthrough
treatment with ammonia in methanol to yield compound 11. The 2-(5-iodothienyl)
and 2-(5-phenylthienyl) adenosine derivatives 14 and 16 respectively were pre-
pared from the previously described 2ꢁ, 3ꢁ, 5ꢁ-trisilylated 2-stannyl derivative (14)
12 through a palladium mediated Stille coupling involving 2,5-diiodothiophene as
Cl
N
NH2
48%
Cl
N
N
N
N
N
N
N
ONO
N
N
N
NH3
Me
Me
N
NH2
OAc
MeOH
S
CuO
S
O
O
O
OH
OAc
Me
OAc
OAc
OAc
OAc
OH
OH
S
9
10
11
Scheme 2.

ORDER
REPRINTS
ADENOSINE DERIVATIVES AS CORONARY VASODILATORS
347
I
S
NH2
NH2
N
NH2
I
N
N
N
N
N
N
N
N
N
NH4F
N
Bu3Sn
TBDMSO
N
Pd(0)
I
S
I
S
O
O
O
TBDMSO
HO
OTBDMS
OTBDMS
OH
OH
OTBDMS
OTBDMS
12
13
14
PhSn(n-bu)3
Pd(0)
NH2
NH2
N
N
N
N
N
NH4F
N
N
N
S
S
O
O
TBDMSO
HO
OTBDMS
OTBDMS
OH
OH
15
16
Scheme 3.
shown in Scheme 3. The 2-(5-iodothienyl) adenosine derivative 13 was converted
to the triol 14 by treatment with ammonium fluoride (15). A second Stille coupling
between 2-(5-iodothienyl) adenosine derivative 13 and commercially available trib-
utylphenyl stannane resulted in 2-(5-phenylthienyl) adenosine derivative 15 that
was deprotected by treatment with ammonium fluoride to yield compound 16.
The preparation of the new compounds of the 2-(N-1-pyrazolyl) adenosine
series is shown in Scheme 4. The 2-hydrazino adenosine derivative (16) 17 was
CO2Et
NH2
NH2
O
O
N
N
N
N
N
N
H
H
N
18
N
H2NHN
HO
N
N
EtO
O
O
O
HO
OH
OH
OH
OH
17
19
NH2
N
N
N
H
CH3NH2
N
N
N
O
N
O
HO
OH
OH
20
Scheme 4.

ORDER
REPRINTS
348
ZABLOCKI ET AL.
condensed with the known dialdehyde (17) 18 in a 1:1 mixture of acetic acid:
methanol at 80◦C to generate the ester 19. The ester was converted to various amides
by direct amine displacement or conversion to the acid and standard dehydrative
coupling (see experimental for details).
RESULTS AND DISCUSSION
Our goal was to obtain a short acting coronary vasodilator that is functionally
selective for the A2A Ado receptor. Four classes of 2-substituted pi system deriva-
tives of adenosine were evaluated for the affinity of individual members for both
pig brain (PB) and rat brain (RB) A2A Ado receptor, and their time to achieve 50%
reversal of coronary vasodilatation (CV t0.5) in isolated rat hearts (Tables 1–3).
The CV t0.5 was used as the principle screen for compound selection for further
characterization with respect to selective affinity (Table 4), and more importantly
functional selectivity for A2A Ado receptor mediated effects as opposed to A1 Ado
receptor mediated effects. The objective was to obtain a compound with a CV t0.5
that was two to three times longer than that of adenosine (CV t0.5 = 1.60 min)
with the purpose to have an agent to be administered as a bolus, and still produce a
coronary vasodilatation suitable for distribution and uptake of radionuclide agent
by the myocardium. Based on this criteria, compounds 20 and 31 were chosen for
further characterization with respect to selectivity (Tables 3 and 4, respectively).
A detailed discussion of the structure activity relationships (SAR) that led to this
choice follows.
The affinity of individual members of the 2-propargyl phenyl ether class for
the A2A Ado receptor, and their CV t0.5 are shown in Table 1. The unsubstituted
propargyl phenyl ether derivative 21 and the phenylmethylenedioxy derivative 22
Table 1. Affinity of Propargyl Ether Class 1 for Ado A2A
Rat
t0.5
Min
t0.9
Compd #
R1
R2
H
PB KiA2a nM
14
21
22
23
8
24
25
26
H
2
17.5 23.2
NT NT
16.7 25.6
NT NT
16.1 21.8
3,4-OCH2O-
4-CN
18
H
H
H
H
5-But
93 14
230 45
58 47
1030 145
>10,000
2-Ph
2-CH2Ph
4-Ph
3-But
NT
NT
NT
NT
PB stands for Pig Brain (striatum).

ORDER
REPRINTS
ADENOSINE DERIVATIVES AS CORONARY VASODILATORS
349
Table 2. Affinity for Ado A2A and Time for 50% Reversal of Coronary Vasodilation
(CV t0.5) in Isolated Rat Hearts
Cmpd #
R1
PB KiA2a nM
Rat t0.5
Min t0.9
27
11
14
16
H
5-Me
5-I
1000 175
692 102
>10,000
3.4 0.2
5.1 0.1
9.2 2.2
10.1 0.3
–
–
–
–
5-Ph
>10,000
PB stands for Pig Brain (striatum). The compounds were given as a bolus at approxi-
mately three times the EC50.
had the highest affinities for the A2A Ado receptor when compared to all of the
compounds tested with Ki’s of 14 2 nM and 18 nM, respectively (PB, Table 1).
A 2ꢁꢁ-phenyl compound 8 had four times the affinity of the 4ꢁꢁ-phenyl compound
25, and a 2ꢁꢁ-benzyl compound 24 had four times the affinity of compound 8. Thus,
it appears that a lipophilic substituent at the 2ꢁꢁ position was well tolerated. The
sterically demanding 3,5-ditert-butylphenyl derivative 26 was not well tolerated by
the A2A Ado receptor demonstrating a limit to the tolerance for large lipophilic
groups. Compounds 21, 23, and 24 had high affinities (<100 nM PB) for the A2A
Ado receptor, and their CV t0.5’s were greater than ten times that of adenosine.
The affinity of individual members of the 2-thienyl class for the A2A Ado
receptor, and their CV t0.5 are shown in Table 2. Both the unsubstituted 2-thienyl
Table 3. Affinity for Ado A2A and Time for 50% Reversal of Coronary Vasodilation
(CV t0.5) in Isolated Rat Hearts
nM
RB KiA2A
Rat Heart
t0.5
Cmpd #
R1
PB KiA2A
Min t0.9
–
19
20
28
29
30
32
CO2Et
60 29
1122 323
380 130
120 20
140 20
490 156
1280 430
290 10
60 10
50 20
50 10
14.8 3.6 15.0 1.6
5.2 3.6 11.5 2.7
–
–
–
–
–
CONHMe
CONHEt
CONHPr
CONHc-Pent
(Ph-4-Me)
–
–
–
–
–
–
190 50
14.2 2.8 19.3 4.6
PB stands for Pig Brain (striatum), and RB stands for Rat Brain (forebrain). The
compounds were given as a bolus at approximately three times the EC50.

ORDER
REPRINTS
350
ZABLOCKI ET AL.
Table 4. The Selective Affinity of Compounds 20 (CVT-3146) and 31 (CVT-3033) for Human Ado
Receptors Versus 2 (CGS-21680)
Cmpd
31
R1
HEK h-A2AnM
2895
A1/A2A
CHO h-A1nM
5836
2.0
20
2
1269
609
13.0
5.8
>16460
>3540
The affinity for human Ado receptor A2A was tested in human embryonic kidney cells (HEK) using
[3H]-ZM241385. The affinity for human Ado receptor A1 was tested in chinese hamster ovary cells
(CHO) using [3H]-CPX.
derivative 27 and the 2-(5-methylthienyl) derivative 11 had low affinity for the A2A
Ado receptor; however, their CV t0.5’s were approximately two to three times that
of adenosine. These compounds were not further evaluated, because compound 11
was positive in the Ames test. Suprisingly, the 2-(5-iodothienyl) compound 14 and
the 2-(5-phenylthienyl) compound 16 were not active at 10,000 nM (PB, Table 2).
This series requires further investigation to test the trajectory from the purine ring
of 162◦ with a more flexible lipophilic substituent, but the positive Ames test on a
related member precludes further exploration of this series for drug development
purposes.
The affinity of individual members of the 2-(N-1-pyrazolyl) adenosine class
for the A2A Ado receptor, and their CV t0.5 are shown in Table 3. Again, the high
affinity ester derivative 19 had a long CV t0.5 (>nine times adenosine). Conversion
of the ethyl ester of 19 to the N-methylamide of 20 resulted in a large decrease in
affinity, but a more favorable CV t0.5 (three times adenosine). A trend is develop-
ing wherein high affinity compounds took a longer time to achieve CV t0.5 than
low affinity compounds. We hypothesize that the lower affinity compounds may
have a more favorable off rate from the receptor leading to a shorter pharmaco-
dynamic effect in the heart. Compounds 28, 29, and 30 suggest that by replacing
the N-methylamide of 20 by amides containing a larger lipophilic group the affin-
ity for the A2A Ado receptor is returned to the level of ethyl ester 19 (RB data
Table 3). The importance of the nature of the heteroatoms within the 2-heterocyclic
substituent is made apparent in comparison of 4-methylphenyl derivative 32 and
2-(5-phenylthienyl) Ado derivative 16 (Table 2). Compound 16 has poor affinity
(>10,000 nM, Table 2), but the similarly substituted 2-(1-N-pyrazolyl) 32 has an
affinity of 490 156 nM (Table 3). We hypothesize that the 2-pyrazolyl nitrogen
may accept a hydrogen bond from the receptor, and orient the phenyl substituent in

ORDER
REPRINTS
ADENOSINE DERIVATIVES AS CORONARY VASODILATORS
351
the case of compound 32. This interaction would not be expected from the sulfur
of the thienyl group found in compound 16.
The SAR of the 2-(4-pyrazolyl) adenosine class for the A2A Ado receptor
has been previously described (8). The lead compound that has been further char-
acterized for selective affinity and functional selectivity is the 2-[(4-(1-N-pentyl
pyrazolyl)] adenosine derivative 31 (Table 4), and it’s affinity for the A2A Ado re-
ceptor is Ki = 2138 952 and Ki = 2590 320 (PB and RB, respectively). The
trend appears to hold, because the low affinity compound 31 had a CV t0.5 twice
that of adenosine (2.97 0.2 min).
The two lead compounds 20 and 31 were further evaluated for their selec-
tive affinity for the human A2A Ado receptor versus the human A1 Ado receptor
(Table 4). One well known side effect of the use of adenosine as a pharmacological
stress agent in patients is the negative dromotropic effects (AV block) of adenosine
that is mediated through activation of the A1 Ado receptor in the AV nodal cells
(4,5). Thus, afocuswasplacedonobtainingafunctionallyselectiveagentthatwould
induce coronary vasodilatation without negative dromotropic effects (i.e. prolonga-
tion of AV nodal conduction time). These pharmacological studies will be described
in complete detail elsewhere (18). The N-pyrazole compound 20 has a more favor-
able selectivity with respect to affinity A2A/A1 than the C-pyrazole compound 31
(Table 4), but both compounds were found to be functionally selective for coronary
vasodilatation in isolated rat hearts without any negative dromotropic effects ob-
served at high concentrations (500 × EC50 for vasodilatation) (18). In spite of their
relatively low affinity for the Ado A2A receptor, both compound 20 and compound
31 had favorable EC50’s relative to adenosine for coronary vasodilatation, EC50’s =
6.4 nM and 68 nM respectively (Ado EC50 = 59 nM). Previously, Belardinelli (19)
and Shryock have described in detail the high receptor reserve of the A2A receptor
mediated coronary vasodilatation. Further details regarding the exploitation of this
A
2A receptor reserve will be described in subsequent papers (18). Compound 20 was
further evaluated for it’s selectivity by testing the affinity against other human Ado
receptor subtypes, A2B (HEK cell membranes with [3H]-DPCPX) and A3 (CHO
cell membranes with [125I]ABMECA), where it demonstrated low affinity for these
subtypes (only 22% of the competitive ligand was displaced in both cases).
MOLECULAR MODELING
The design of the four series of compounds exploited similar vectors for
lipophilic substituents at the 2-position of the purine ring as the selective A2A
agonists described in Figure 1. The propargyl phenyl ether derivative 21 presents a
lipophilic group to the Ado A2A receptor in a different manner than (S)-PHPNECA
(10) as illustrated in Figure 3 panel A by the superimposition of the respective
compounds (Sybyl Fit algorithm). It is noteworthy that the propargyl phenyl ether
derivative 21 was found to have a 44 fold higher affinity for the A2A Ado receptor
when compared to the A1 Ado receptor, but the (S)-PHPNECA (10) was found to

ORDER
REPRINTS
352
ZABLOCKI ET AL.
Figure 3, Panel A. A superimposition of (S)-PHPNECA from Cristalli et al (10) and the unsub-
stituted propargyl phenyl ether 21 demonstrates an overlay of the oxygen hydrogen bond acceptor
regions, but a distinctly different presentation of the lipophilic phenyl groups to the receptor.
have similar affinity for both receptors. The difference in selectivity may be due to
the presence of a hydrogen bond donor in (S)-PHPNECA, a different presentation
of the lipophilic phenyl ring to the receptor, or both changes.
The 2-(N-1-pyrazolyl) adenosine class 4 (Fig. 2, Panel D) provides the same
152◦ trajectory as the THENECA (3) derivative, and the overlay of compound 29
from this class with THENECA is shown in Figure 3 Panel B (Sybyl Fit algorithm).
Both compounds have high affinity for the A2A Ado receptor, but it is apparent that
the trajectory of the lipophilic substituent alone does not solely dictate activity
based on the SAR in Table 3.
The 2-(N-1-pyrazolyl) adenosine series (class 4) was designed by envisioning
a 5-membered pyrazole ring obtained through closing the hydrazone group of com-
pound 4 (WRC-470) as illustrated in Figure 2, Panel D. Analysis of the H NMR
of compound 4 shows a mixture of the E and Z hydrazones with the E being the
predominant isomer (>5:1). Conformational searching of the E and Z hydrazones
resulted in two local minima for each isomer wherein the hydrazone pi system is
coplanar with the aromatic purine ring (Fig. 4, Panels A and B). A torsional search
demonstrated a very small barrier to rotation about the purine-2-nitrogen bond that
is attributed to a lack of ortho hydrogens on the purine ring. The 2-(N-1-pyrazolyl)
series SAR suggests that the 2-pyrazolyl nitrogen and the lipophilic group are key

ORDER
REPRINTS
ADENOSINE DERIVATIVES AS CORONARY VASODILATORS
353
Figure 3, Panel B. An overlay of compound 29 (Rat Brain Ado A2A Ki = 50 nM) and THENECA
(Rat Brain Ado A2A Ki = 1.6 nM) suggests a similar presentation of both lipophilic groups to the
receptor.
binding elements. Therefore, an attempt was made to superimpose the two nitrogens
of the pyrazole ring with the two nitrogens of the hydrazone plus achieve overlap
of the liophilic substituents. Only the lower energy Z hydrazone conformation of
compound 4 (Fig. 4 Panel B) and compound 20 would fit this requirement. Thus, the
2-[(N-1-(4-substituted pyrazolyl))] adenosine series may be a constrained mimetic
of the Z-hydrazone of compound 4.
SUMMARY
We accomplished our goal to obtain a short acting coronary vasodilator that is
functionally selective for the A2A Ado receptor with the discovery of two new com-
pounds: 20 (CVT-3146-a 2-[(N-1-(4-N-methylcarboxamidopyrazolyl)] adenosine
derivative) and compound 31 (CVT-3033 - a 2-[(4-(1-N-pentylpyrazolyl)] adeno-
sinederivative)withcoronaryvasodilatationCVt0.5’s=5.2 0.2and3.4 0.5min,
respectively - rat isolated heart 50% reversal time, with good potency - EC50s =
6.4 1.2 nM and 67.9 16.7 nM, respectively, but they possess low affinity for
the A2A ADO receptor (Ki = 1122 323 nM and 2138 952 nM, respectively;
pig striatum). We hypothesize that the low affinity compounds still produce the
desired coronary vasodilatation because of the high receptor reserve of the A2A

ORDER
REPRINTS
354
ZABLOCKI ET AL.
Figure 4, Panel A. Two local minima were found for the E hydrazone and superimposition was
done with compound 20; however, neither conformation affords an overlay of key binding elements
(i.e. lipophilic substituents and two nitrogens of pyrazole and hydrazone).
Ado receptor for this effect, and it (i.e. low affinity) may contribute to the short du-
ration of action through increasing their off rates from the receptor. Compounds 20
and 31 are currently being evaluated for their in vivo vasodilatation to further assess
their potential as pharmacological stress agents, and the results will be published
in due course.
EXPERIMENTAL
2-phenyl-1-prop-2-ynyloxybenzene (7). To a solution of propargyl bro-
mide (80% solution in toluene, 0.50 mL, 3.36 mmol) in acetone (15 mL) at 23◦C
was added 2-phenyl phenol (0.316 g, 1.86 mmol) and potassium carbonate (1.05 g,
7.61 mmol). After being stirred in a sealed reaction vial at 65◦C for 14 hours, the
reaction was concentrated in vacuo, and the residue purified by flash chromatog-
1
raphy (ethyl acetate: hexane: 9:1) to afford compound 7 in 95% yield. H NMR
(CDCl3) δ 2.45–2.55 (m, 1 H), 4.60–4.70 (m, 2 H), 6.90–7.43 (m, 9 H).
Synthesis of (4S,2R,3R,5R)-2-[6-amino-2-(3-phenoxyprop-1- ynyl)purin-
9-yl]-5-(hydroxymethyl)oxolane-3,4-diol (compound 8). To a solution of

ORDER
REPRINTS
ADENOSINE DERIVATIVES AS CORONARY VASODILATORS
355
Figure 4, Panel B. Two local minima were found for the Z hydrazone and superimposition was
done with compound 20. Only the lower energy conformation affords an overlay wherein the two
nitrogens of the pyrazole plus the two lipophilic substituents coincide.
(4S, 2R,3R,5R)-2-(6-amino-2-iodopurin-9-yl)-5-(hydroxymethyl)oxolane-3,4-diol
6 (0.05 g, 0.13 mmol) and 2-phenyl-1-prop-2-ynyloxybenzene 7 (0.03 mL,
0.16 mmol) in DMF (1 mL) and triethylamine (0.021 mL, 16.06 mmol) at 23◦C was
added copper iodide (0.005g, 0.026 mmol) and dichlorobis(triphenylphosphine)
palladium(II) (0.022 g, 0.031 mmol). After being stirred in a sealed reaction vial
at 80◦C for 6 hours, the reaction was concentrated in vacuo and the residue was
purified by preparatory thin layer chromatography (methylene chloride: methanol
9:1) to afford 9.6 mg of compound 8 ( 20% yield). 1H NMR (CDCl3:CD3OD 9:1)
δ 3.02–3.04 (m, 1 H), 3.07 (s, 1 H), 3.55, 3.74 (dd, 2 H), 4.02 (s, 1 H), 4.11–4.13
(m, 1 H), 4.48–4.52 (m, 1 H), 4.72 (s, 2 H), 5.65 (d, 1 H), 6.75–6.82 (m, 3 H),
7.08–7.12 (m, 2 H), 7.94 (s, 1 H).
(4S,2R,3R,5R)-2-[6-amino-2-(3-phenoxyprop-1-ynyl)purin-9-yl]-5-(hy-
droxymethyl)oxolane-3,4-diol (21). Compound 21 was prepared in a manner
similar to that employed in the synthesis of compound 8. 1H NMR (CDCl3:CD3OD
9:1) δ 3.02–3.04 (m, 1 H), 3.07 (s, 1 H), 3.55, 3.74 (dd, 2 H), 4.02 (s, 1 H), 4.11–
4.13 (m, 1 H), 4.48–4.52 (m, 1 H), 4.72 (s, 2 H), 5.65 (d, 1 H), 6.75–6.82 (m,
3 H), 7.08–7.12 (m, 2 H), 7.94 (s, 1 H). ), 4.48–4.52 (m, 1 H), 4.72 (s, 2 H), 5.65

ORDER
REPRINTS
356
ZABLOCKI ET AL.
(d, 1 H), 6.90–7.00 (m, 1 H), 7.10–7.15 (m, 1 H), 7.15–7.32 (m, 5 H), 7.35–7.45
(m, 2 H), 7.94 (s, 1 H).
4-(3-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-
aminopurin-2-yl} prop-2-ynyloxy)benzenecarbonitrile (23). Compound 23
was prepared in a manner similar to that employed in the synthesis of compound
8. 1H NMR (CDCl3:CD3OD 9:1) δ3.55 (d, 1 H), 3.70 (d, 1 H), 4.05–4.07 (m, 1 H),
4.10–4.12 (m, 1 H), 4.48 (dd, 1 H), 4.80 (s, 2 H), 5.65 (d, 1 H), 6.90 (d, 2 H), 7.45
(d, 2 H), 7.95 (s, 1 H).
(4S,2R,3R,5R)-2-{6-amino-2-[3-(4-phenylphenoxy)prop-1-ynyl]purin-9-
yl}-5-(hydroxymethyl)oxolane-3,4-diol (25). Compound 25 was prepared in a
manner similar to that employed in the synthesis of compound 8. 1H NMR (CDCl3:
CD3OD 9:1) δ3.02–3.04 (m, 1 H), 3.07 (s, 1 H), 3.55, 3.74 (dd, 2 H), 4.02 (s, 1 H),
4.11–4.13 (m, 1 H), 4.48–4.52 (m, 1 H), 4.72 (s, 2 H), 5.65 (d, 1 H), 6.90–7.00 (m,
1 H), 7.10–7.15 (m, 1 H), 7.15–7.32 (m, 5 H), 7.35–7.45 (m, 2 H), 7.94 (s, 1 H).
(4S,2R,3R,5R)-2-(6-amino-2-{3-[2-benzylphenoxy]prop-1-ynyl}purin-9-
yl)-5-(hydroxymethyl)oxolane-3,4-diol (24). Compound 24 was prepared in a
manner similar to that employed in the synthesis of compound 8. 1H NMR (CDCl3:
CD3OD 9:1) δ3.02–3.04 (m, 1 H), 3.07 (s, 1 H), 3.55, 3.74 (dd, 2 H), 3.92 (s, 2 H),
4.02 (s, 1 H), 4.11–4.13 (m, 1 H), 4.48–4.52 (m, 1 H), 4.72 (s, 2 H), 5.65 (d, 1 H),
6.80–6.88 (m, 1 H), 6.96–7.01 (m, 2 H), 7.15–7.22 (m, 6 H), 7.94 (s, 1 H).
(4S,2R,3R,5R)-2-(6-amino-2-{3-[2-benzylphenoxy]prop-1-ynyl}purin-9-
yl)-5-(hydroxymethyl)oxolane-3,4-diol (22). Compound 22 was prepared in a
manner similar to that employed in the synthesis of compound 8. 1H NMR (CDCl3:
CD3OD 9:1) δ3.02–3.04 (m, 1 H), 3.07 (s, 1 H), 3.55, 3.74 (dd, 2 H), 3.92 (s, 2 H),
4.02 (s, 1 H), 4.11–4.13 (m, 1 H), 4.48–4.52 (m, 1 H), 4.72 (s, 2 H), 5.65 (d, 1 H),
6.80–6.88 (m, 1 H), 6.96–7.01 (m, 2 H), 7.15–7.22 (m, 6 H), 7.94 (s, 1 H).
(4S,2R,3R,5R)-2-(6-amino-2-{3-[3,5-bis(tert-butyl)phenoxy]prop-1-ynyl}
purin-9-yl)-5-(hydroxymethyl)oxolane-3,4-diol (26). Compound 26 was pre-
1
pared in a manner similar to that employed in the synthesis of compound 8. H
NMR (CDCl3:CD3OD 9:1) δ1.22 (s, 9 H), 3.02–3.04 (m, 1 H), 3.07 (s, 1 H), 3.55,
3.74 (dd, 2 H), 4.02 (s, 1 H), 4.11–4.13 (m, 1 H), 4.48–4.52 (m, 1 H), 4.72 (s, 2 H),
5.65 (d, 1 H), 6.78 (s, 2 H), 6.99 (s, 1 H), 7.94 (s, 1 H).
{(2R,3R,4R,5R)-3,4-diacetyloxy-5-[6-chloro-2-(5-methyl(2-thienyl)) pur-
in-9-yl]oxolan-2-yl}methyl acetate (10). To a suspension of 2-Amino-6-
chloro-9-(2ꢁ,3ꢁ,5ꢁ-tri-O-acetyl)-D-ribofuranosyl-purine 9 (0.17 g, 0.40 mmol) in
2 mL 2-methylthiophene (20.0 mmol), was added isoamyl nitrite (0.25 mL,
1.80 mmol)), Cu (I) Oxide (0.060 g, 0.42 mmol)) and the mixture was allowed
to stir at 115◦C for 3 h. The reaction mixture was filtered, concentrated under
vacuo and the residue was purified using preparative thin layer chromatography

ORDER
REPRINTS
ADENOSINE DERIVATIVES AS CORONARY VASODILATORS
357
(EtOAc:Hexanes 1:1) to afford 10 in 51% yield. 1H NMR (CDCl3) δ2.0 (s, 3 H),
2.05 (s, 3 H), 2.1 (s, 3 H), 2.5 (s, 3 H), 4.30 (m, 1 H), 4.40–4.55 (m, 2 H), 5.90
(t, 1 H), 6.0 (t, 1 H), 6.1 (d, 1 H), 6.8 (d, 1 H), 7.85 (d, 1 H), 8.1 (s, 1 H).
(4S,2R,3R,5R)-2-[6-amino-2-(5-methyl(2-thienyl))purin-9-yl]-5-(hydro-
xymethyl)oxolane-3,4-diol (11). Compound 10 (0.05 g, 0.10 mmol) was dis-
solved in 5 mL methanolic ammonia (saturated at 0◦C), and the mixture was allowed
to stir at 40◦C for 24 h. After concentration in vacuo, the residue was purified using
preparative thin layer chromatography (10% MeOH/DCM) to afford 11 in 78%
yield. 1H NMR (CD3OD) δ2.5 (s, 3 H) 3.75 (d, 1 H), 3.85 (d, 1 H), 4.15 (d, 2 H)
4.45 (m, 1 H), 4.85 (m, 1 H), 6.0 (d, 1 H), 6.75 (d, 1 H), 7.7 (d, 1 H), 8.25 (s, 1 H).
(4S,3R,5R)-2-(6-amino-2-(2-thienyl)purin-9-yl)-5-(hydroxymethyl)oxo-
lane-3,4-diol (27). Compound 27 was synthesized in a manner similar to that
employed in the synthesis of 11 using thiophene instead of methylthiophene (81%
1
yield). H NMR (CD3OD) δ 3.75 (d, 1 H), 3.85 (d, 1 H), 4.15 (d, 2 H) 4.45
(m, 1 H), 4.85 (m, 1 H), 6.0 (d, 1 H), 7.10 (d, 1 H), 7.5 (d, 1 H), 7.9 (d, 1 H),
8.25 (s, 1 H).
9-{(2R,3R,4R,5R)-3,4-bis(1,1,2,2-tetramethyl-1-silapropoxy)-5-[(1,1,2,2-
tetramethyl-1-silapropoxy)methyl]oxolan-2-yl}-2-(5-iodo(2-thienyl))purine-
6-ylamine(13). Amixtureofcompound12(0.05g, 0.056mmol), 2,5-diiodopyra-
zole (0.05 g, 0.14 mmol), Pd(PPh3)4 (0.02 g, 15 mol %) and CuI (0.04 g, 0.2 mmol)
in DMF (1 mL) was stirred at 90◦C for 16 h. The reaction was concentrated in vacuo,
and the residue was purified by preparative thin layer chromatography (methylene
1
chloride: methanol 10:1) to afford compound 13: H NMR (CDCl3) δ 0.00 (s,
3 H), 0.01 (s, 3 H), 0.04 (s, 3 H), 0.07 (s, 3 H), 0.11 (s, 3 H), 0.14 (s, 3 H), 0.78
(s, 9 H), 0.83 (s, 9 H), 0.91 (s, 9 H), 3.80 (d, 1 H), 4.05 (d, 1 H), 4.11–4.12 (m, 1 H),
4.32–4.33 (m, 1 H), 4.80 (d, 1 H), 5.55 (bs, 2 H, D2O exchangeable), 5.95 (d, 1 H),
7.21 (d, 2 H), 7.50 (d, 2 H), 8.10 (s, 1 H).
(4S,2R,3R,5R)-2-[6-amino-2-(5-iodo(2-thienyl))purin-9-yl]-5-(hydroxy-
methyl)oxolane-3,4-diol(14). A solution of triTBDMS derivative 13 (0.015 g,
0.054 mmol) in 0.5 M solution of NH4F in methanol (5 mL) was refluxed for 16 h.
The reaction mixture was concentrated, and the residue was purified by preparative
TLC (methanol-dichloromethane 9:1) to afford 14; 1H NMR (CD3OD) δ 3.65 (d,
J = 11.2 Hz, 1 H), 3.81 (d, J = 11.2 Hz, 1 H), 4.15–4.16 (m, 1 H), 4.25–4.26
(m, 1 H), 4.78 (dd, 1 H), 5.72 (d, 1 H), 7.15 (s, 2 H), 7.45 (d, 2 H), 7.80 (s, 1 H).
9-{(2R,3R,4R,5R)-3,4-bis(1,1,2,2-tetramethyl-1-silapropoxy)-5-[(1,1,2,2-
tetramethyl-1-silapropoxy)methyl]oxolan-2-yl}-2-(5-phenyl(2-thienyl))pur-
ine-6-ylamine(15). A mixture of compound 13 (0.02 g, 0.056 mmol), tri n-butyl-
phenyltin (0.05 g), Pd(PPh3)4 (0.02 g, 15 mol %) and CuI (0.04 g, 0.2 mmol) in
DMF (1 mL) was stirred at 90 C for 16 h. The reaction was concentrated in vacuo,

ORDER
REPRINTS
358
ZABLOCKI ET AL.
and the residue was purified by preparative thin layer chromatography (methylene
1
chloride: methanol 10:1) to afford compound 15: H NMR (CDCl3) δ 0.00
(s, 3H), 0.01 (s, 3 H), 0.04 (s, 3 H), 0.07 (s, 3 H), 0.11 (s, 3 H), 0.14 (s, 3 H),
0.78 (s, 9 H), 0.83 (s, 9 H), 0.91 (s, 9 H), 3.80 (d, 1 H), 4.05 (d, 1 H), 4.11–4.12
(m, 1 H), 4.32–4.33 (m, 1 H), 4.80 (d, 1 H), 5.55 (bs, 2 H, D2O exchangeable), 5.95
(d, 1 H), 7.25–7.4 (m, 5 H), 7.65 (d, 2 H), 7.85 (d,1 H), 8.12 (s, 1 H).
(4S,2R,3R,5R)-2-[6-amino-2-(5-phenyl(2-thienyl))purin-9-yl]-5-(hydro-
xymethyl)oxolane-3,4-diol (16). A solution of triTBDMS derivative 15 (0.05 g)
in 0.5 M solution of NH4F in methanol (5 mL) was refluxed for 16 h. The Reaction
mixture was concentrated, and residue was purified by preparative TLC (methanol-
dichloromethane 9:1) to afford 16; 1H NMR (CD3OD) δ 3.65 (d, J = 11.2 Hz, 1 H),
3.81 (d, J = 11.2 Hz, 1 H), 4.15–4.16 (m, 1 H), 4.22–4.26 (m,1 H), 4.74 (dd, 1 H),
5.74 (d, 1 H), 7.10–7.25 (m, 5 H), 7.45 (d, 2 H), 7.74 (d, 2 H), 7.87 (s, 1 H).
Ethyl1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-
6-aminopurin-2-yl}pyrazole-4-carboxylate (19). To a suspension of 2-hydra-
zinoadenosine 17 (0.025 g, 0.08 mmol) in a 1:1 mixture of MeOH/AcOH was
added (ethoxycarbonyl)malondialdehyde (0.019 g, 0.12 mmol), and the mixture
was heated heart at 80◦C for 3 h. The precipitate formed was collected by filtration,
and washed with EtOH and ether to afford compound 19 in 91% yield. 1H NMR
(DMSO-d6) δ1.25 (t, 3 H), 3.5 (m, 1 H), 3.6 (m, 1 H), 3.8 (d, 1 H), 4.15 (d, 1 H),
4.55 (m, 1H), 5.0 (t, 1 H), 5.2 (d, 1 H), 5.5 (d, 1 H), 5.9 (d, 1H), 7.15-7.3 (m, 5 H),
7.8 (br s, 2 H), 8.1 (s, 1H), 8.4 (s, 1 H), 8.9 (s, 1H).
(1-{9-[(4S,2R,3R,5R)-3,4-Dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-
aminopurin-2-yl}pyrazol-4-yl)-N-methylcarboxamide (20). Compound 19
(0.05 mg, 0.12 mmol) was added to 4 mL methylamine (40%. sol. In water). The
mixture heated at 65◦C in for 24 h. After concentration in vacuo, the residue was
purified using prep. TLC (10% MeOH:DCM) to afford compound 20 75% yield.
1HNMR (CD3OD) δ2.90 (s, 3 H), 3.78 (m, 1 H), 3.91 (m, 1 H), 4.13 (d, 1 H), 4.34
(d, 1 H), 4.64 (m, 1 H), 6.06 (d, 1 H), 8.11 (s, 1 H), 8.38 (s, 1 H), 9.05 (s, 1 H).
(1-{9-[(4S,2R,3R,5R)-3,4-Dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-
aminopurin-2-yl}pyrazol-4-yl)-N-ethylcarboxamide (28). Compound 19
(0.10 g, 0.13 mmol) was suspended in 10 mL ethylamine, and the mixture was
heated at reflux in a sealed tube for 24 h. The solvent was evaporated and the
residue was dissolved in 1 mL MeOH and treated with 10 mL ethyl ether. The
precipitate formed was collected by filteration, and washed with ether to afford
1
compound 28 in 61% yield. MS 405.35 (M + 1). H NMR (CD3OD) δ 1.00 t,
3 H), 3.00 (m, 1 H), 3.41 (d, 1 H), 3.60 (d, 1 H), 3.80 (d, 2 H) 4.00 (m, 1 H),
4.25 (m, 1 H), 5.80 (d, 1 H), 7.95 (s, 1 H), 8.25 (s, 1 H), 8.80 (s, 1 H).

ORDER
REPRINTS
ADENOSINE DERIVATIVES AS CORONARY VASODILATORS
359
(1-{9-[(4S,2R,3R,5R)-3,4-Dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-
(30).
aminopurin-2-yl}pyrazol-4-yl)-N-(cyclopentylmethyl)carboxamide
Compound 19 (0.5) g, 1.2 mmol) was dissolved in dry DMF, TBDMSCl (1.5 g,
10 mmol) and imidazole (.068 g, 10 mmol) were added, and the mixture was heated
at 80◦C for 24 h. The solvent was evaporated, and the residue was purified by flash
column (20:1, DCM:MeOH) to afford the trisilyl protected form of compound 12
in 88% yield. MS 748.71 (M + 1).
The trisilyl derivative (0.8 g, 1 mmol) was suspended in 1 mL of water, and
treated with 4 mL 1N KOH/MeOH. The mixture was allowed to stirred at RT for 72.
The solvent was removed under reduced pressure, and the residue was suspended
in 5 mL of water and acidified to pH 5 with 1N HCl. The resulting precipitate was
filtered and washed with water and ethyl ether to afford the trisilyl acid 20.
The trisilyl derivative acid (0.14 g, 0.2 mmol) was then dissolved in 5 mL
dichloromethane. To the solution was added HBTU (0.19 g, 0.4 mmol), HOBt
(.076 g, 4 mmol), N-methylmorpholine (0.04 g, 0.4 mmol) and cat. DMAP. The
mixture was allowed to stir at RT for 24 h. The mixture was then washed with
10% citric acid, saturated NaHCO3, brine, and dried over MgSO4. The solvent was
removed, and the residue (without further purification) was treated with 5 mL 0.5 N
NH4F/MeOH. The solution was heated at reflux for 24 h. The solvent was evapo-
rated, and the residue was purified by preparative TLC (10 1, DCM:MeOH) to af-
ford compound 30 in 90% yield (one step). MS 445.26 (M + 1). 1H NMR (CD3OD)
δ 1.50–1.82 (m, 8 H), 3.40 (m, 1 H), 3.61 (d, 1 H), 3.85 (d, 1 H), 4.15 (d, 2 H) 4.45
(m, 1 H), 4.85 (m, 1 H), 5.95 (d, 1 H), 8.10 (s, 1 H), 8.25 (s, 1 H), 8.98 (s, 1 H).
REFERENCES
1. a) Hutchison, A. J.; Webb, R. L.; Oei, H. H.; Ghai, G. R.; Zimmerman, M. B.; Williams,
M. J. Pharmacol. Exp. Ther. 1989, 251, 47–55. b) Hutchison, A. J.; Williams, M. J.;
de Jesus, R.; Yokoyama, R.; Oei, H. H.; Ghai, G. R.; Webb, R. L.; Zoganas, H. C.;
Stone, G. A.; Jarvis, M. F. J. Med. Chem. 1990, 33, 1919–1924.
2. a). Abiru, T.; Yamaguchi, T.; Watanabe, Y.; Kogi, K.; Aihara, K.; Matsuda, A., Eur.
J Pharmacol. 1991, 196, 69–76. b) Kogi, K.; Uchibori, T.; Aihara, K.; Yamaguchi, T.;
Abiru T., Jpn J Pharmacol. 1991, 57, 153–65.
3. a) Chern, Y.; Lai, H. L.; Fong, J. C.; Liang, Y., Mol. Pharmacol. 1993, 44, 950–958.
b) Palmer, T. M.; Gettys, T. W.; Jacobson, K. A.; Stiles, G. L., Mol. Pharmacol., 1994,
45, 1082–94.
4. Verani, M. S. Cor. Art. Dis. 1992, 3, 1145–1151.
5. Verani, M. S.; Mahmonian, Y. Y. Am. J. Cardiol. Imaging 1994, 3, 223–230.
6. Glover, D. K.; Ruiz, M.; Yang, J. Y.; Koplan, B. A.; Allen, T. R.; Smith, W. H.; Watson,
D. D.; Barrett, R. J.; Beller, G. A. Circulation 1996, 94, 1726–1732.
7. Linden, J.; Sullivan, G. W.; Ross, S. C.; Kron, I. L.; McPherson, J. A.; Sarembock,
I. J.; Macdonald, T. L.; Okusa, M. D. Drug. Dev. Res., 2000, 50, 68 (Purine 2000
conference, abstract #078).

ORDER
REPRINTS
360
ZABLOCKI ET AL.
8. Palle, V. P.; Elzein, E. O.; Gothe, S. A.; Li. Z.; Gao, Z.; Meyer, S.; Blackburn, B.;
Belardinelli, L.; Zablocki, J. A. Drug. Dev. Res., 2000, 50, 64 (Purine 2000 conference,
abstract #062).
9. Elzein, E. O.; Palle, V. P.; Gothe, S. A.; Li. Z.; Gao, Z.; Meyer, S.; Blackburn, B.;
Belardinelli, L.; Zablocki, J. A. Drug. Dev. Res., 2000, 50, 64 (Purine 2000 conference,
abstract #061).
10. Cristalli, G.; Camaioni, E.; Di Francesco, E.; Vittori, S.; Volpini, R. Persp. In Receptor
Res. 1996, 165–180.
11. Miyashita, Y.; Abiru, T.; Watanabe, Y.; Yamaguchi, T.; Matsuda, A., US Patent 5,189,
027, 1993.
12. Nair, V.; Turner, G. A.; Buenger, G. S.; Chamberlain, S. D., J. Org. Chem. 1988, 53,
3051–3057.
13. Matsuda, A.; Satoh, K.; Tanaka, H.; Miyasaka, T. Synthesis, 1984, 963–965.
14. Kato, K.; Hayakawa, H.; Tanaka, H.; Kumamoto, H.; Miyasaka, T. Tetrahedron Lett.
1995, 36, 6507–6510.
15. Zhang, W.; Robins, M. J. Tetrahedron Lett. 1992, 33, 1177–1180.
16. Niiya, K.; Thompson, R. D.; Silvia, S. K.; Olsson, R. A., J. Med. Chem., 1992, 35,
4562–4566.
17. Bertz, S. H.; Dabbagh, G.; Cotte, P. J. Org. Chem. 1982, 47, 2216–2217.
18. Belardinelli, L.; Gao, Z.; Li, Z.; Zablocki, J.; Palle, V.; Elzein, E. Manuscript in
preparation.
19. Shryock, J. C.; Snowdy, S.; Baraldi, P. G.; Cacciari, B.; Spalluto, G.; Monopoli, A.;
Ongini, E.; Baker, S. P.; Belardinelli, L. Circulation 1998, 98, 711–718.

Request Permission or Order Reprints Instantly!
Interested in copying and sharing this article? In most cases, U.S. Copyright
Law requires that you get permission from the article’s rightsholder before
using copyrighted content.
All information and materials found in this article, including but not limited
to text, trademarks, patents, logos, graphics and images (the "Materials"), are
the copyrighted works and other forms of intellectual property of Marcel
Dekker, Inc., or its licensors. All rights not expressly granted are reserved.
Get permission to lawfully reproduce and distribute the Materials or order
reprints quickly and painlessly. Simply click on the "Request
Permission/Reprints Here" link below and follow the instructions. Visit the
U.S. Copyright Office for information on Fair Use limitations of U.S.
copyright law. Please refer to The Association of American Publishers’
(AAP) website for guidelines on Fair Use in the Classroom.
The Materials are for your personal use only and cannot be reformatted,
reposted, resold or distributed by electronic means or otherwise without
permission from Marcel Dekker, Inc. Marcel Dekker, Inc. grants you the
limited right to display the Materials only on your personal computer or
personal wireless device, and to copy and download single copies of such
Materials provided that any copyright, trademark or other notice appearing
on such Materials is also retained by, displayed, copied or downloaded as
part of the Materials and is not removed or obscured, and provided you do
not edit, modify, alter or enhance the Materials. Please refer to our Website
User Agreement for more details.
Order now!
Reprints of this article can also be ordered at
http://www.dekker.com/servlet/product/DOI/101081NCN100002306