Concise synthesis and CDK/GSK inhibitory activity of the missing 9-azapaullones

Article abstract of DOI:10.1016/j.bmcl.2010.06.024

A remarkably concise, chromatography-free route to the parent compound of the paullone family of cyclin-dependent kinase (CDK) inhibitors is reported. A similar strategy allowed the synthesis of the hitherto missing 9-azapaullone and its protonated, N-oxidised and N-alkylated derivatives. Screening studies identified an active and strongly selective inhibitor of CDK9/cyclin T.

Full text of DOI:10.1016/j.bmcl.2010.06.024

Bioorganic & Medicinal Chemistry Letters 20 (2010) 4940–4944
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Concise synthesis and CDK/GSK inhibitory activity of the missing 9-azapaullones
a,
a,
David P. Power a, Olivier Lozach b, Laurent Meijer b, , David H. Grayson , Stephen J. Connon
*
*
*
a Centre for Synthesis and Chemical Biology, School of Chemistry, University of Dublin, Trinity College, Dublin 2, Ireland
b CNRS, ‘Protein Phosphorylation & Human Disease’ group, Station Biologique, 29680 Roscoff, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A remarkably concise, chromatography-free route to the parent compound of the paullone family of
cyclin-dependent kinase (CDK) inhibitors is reported. A similar strategy allowed the synthesis of the hith-
erto missing 9-azapaullone and its protonated, N-oxidised and N-alkylated derivatives. Screening studies
identified an active and strongly selective inhibitor of CDK9/cyclin T.
Received 24 March 2010
Revised 2 June 2010
Accepted 4 June 2010
Available online 15 June 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
CDK
Inhibitor
Cancer
Cell cycle
Paullones
Synthesis
As our appreciation of the molecular mechanisms that control
the cell cycle matures, it is becoming clear that the molecules
which control the checkpoints dividing the cell-cycle phases are
interesting targets for the design of anti-cancer chemotherapeutic
agents.1,2 Cyclin-dependent kinases (CDKs) are a family of serine/
threonine kinases which, on binding to an appropriate regulatory
protein (cyclin), become catalytically competent and trigger key
switches during the cell cycle. When operating normally these
complex control mechanisms allow smooth passage between
cell-cycle phases and controlled proliferation.3,4 Mutations leading
to the misregulation of CDK-cyclin complexes are a characteristic
of most human tumour cells5 and thus the design of (selective)
CDK inhibitors is an attractive strategy to combat cancer in cells
where division is unregulated due to (for e.g.) either the overex-
pression of a cyclin component or the malfunctioning of a CDK
(or CDK-cyclin complex).6–8 In addition the inhibition of CDKs
has been identified as a potential strategy in a variety of other pro-
cesses in which cell proliferation plays an important role — such as
anti-viral and anti-bacterial chemotherapy, CNS disorders and car-
diovascular diseases.9,6
inhibitory activity of CDK1/cyclin B (IC50, 7.0
C-9 brominated analogue 2 (kenpaullone) proved a potent inhibi-
tor with an activity IC50 of 0.4 M. Subsequent SAR-type studies re-
sulted in the identification of the corresponding C-9 nitro
compound (alsterpaullone, 3) as a powerful CDK inhibitor at close
to nanomolar concentrations.12 Further optimisation led to the dis-
covery of the 2-cyanoethyl substituted compound 4 which is active
at picomolar concentrations.13 It is noteworthy that both 3 and 4
are also highly active inhibitors of glycogen synthase kinase-3
lM), however, the
l
(GSK-3a and b) — an enzyme with roles in a number of biological
processes such as glucose metabolism, the regulation of microtu-
bule stability and cell-cycle control (inter alia).14–16
Seminal studies on these compounds by Kunick et al. repeatedly
demonstrated that the fused tetracyclic unit incorporating three
aromatic rings and an e-lactam component (including the methy-
lene group), the indole proton and a strongly electron withdrawing
group at C-9 (preferably one with at least one lone pair of electrons
capable of accepting a hydrogen bond) are all prerequisites for
strong CDK1/cyclin B (and GSK 3a
/b-inhibitory activity.10–12
A diverse array of these compounds have been synthesised
(including azapaullone 5a and 12-azapaullone derivative 5b17—a
potent and selective inhibitor of GSK-3),10–12 however, we were in-
trigued by the absence of the azapaullone derivative 6 from all
screened libraries. 9-Azapaullone (6) would be a compound of con-
siderable interest — the pyridine ring nitrogen renders the aro-
matic ring electron deficient in a similar manner to the nitro
group of alsterpaullone (3), and as such is an interesting target
for its potential potency/specificity alone, however it could also
be either alkylated or most importantly (given the SAR identified
Paullones (Fig. 1) are fused tetracyclic compounds identified
from analysis of data from an anti-cancer drug screen of the Na-
tional Cancer Institute’s tumour cell lines using the COMPARE algo-
rithm to identify similarities (in terms of mode of action) between
screened library compounds and the known CDK inhibitor flavopir-
idol.10 The parent compound 111 (paullone) possessed moderate
* Corresponding author.
E-mail address: connons@tcd.ie (S.J. Connon).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.06.024

D. P. Power et al. / Bioorg. Med. Chem. Lett. 20 (2010) 4940–4944
4941
O
O
O
NH
NH
NH
Y
O N
2
R
R
N
N
H
N
X
H
H
NC
O
1 R = H
2 R = Br
4
5a R = H, X = N, Y = CH
5b R = CN, X = CH, Y = N
3 R = NO
2
O
O
X
NH
NH
NH
O
N
N
N
N
H
N
H
N
H
7b
7a
6
Figure 1. Selected paullone derivatives and aza-paullone 6.
by Kunick) oxidised to afford compounds such as 7a–b, respec-
tively. These, together with 6, would be potentially useful in fur-
ther exploring chemical space around 3 and in particular offer
new opportunities for the facile modification of the C-9 substituent
while remaining firmly within the orbit of the pharmacophore. For
example, Lemcke et al.12b constructed a 3D-QSAR picture of 3
bound to the ATP-binding site of CDK1 and identified regions of
space where steric bulk (blue), negative charge (black) and positive
charge (red) lead to increased inhibitory activity (Fig. 2). We were
thus intrigued as to the potential activity of compounds such as
7a,b — which are structurally quite distinct from 1–4 and possess
(due to the innate modifiability of the pyridine ring at the nitrogen
atom) functionality in these key areas predicted to be consistent
with efficient binding.
Speculating that the absence of 6 from the literature was related
to a synthetic challenge, we therefore set out to develop a new, con-
cise and readily modifiable route to the paullone core and then to
utilise this to prepare and evaluate the potency of 9-azapaullone.
The route to the basic paullone structure originally developed by
Kunick et al. (Scheme 1) involves a three step conversion of anthra-
nilic acid ethyl ester (8) into lactam 9 after an acylation, Dieckmann
condensation and hydrolysis/decarboxylation sequence. A Fischer
indole synthesis with phenylhydrazine (10) then affords the
product. This route has proven satisfactory for the synthesis of a
wide range of paullone derivatives, however in the case of the arche-
typal paullone 1 it requires the use of an anthranilic acid derivative
(a DEA list 1 restricted chemical) and it also involves a Fischer indole
synthesis18 in the final reaction step — a reaction of wide general
O
H
10
NHNH
N
NH
2
3 steps
2
1
H
CO Et
2
R
O
8
9
Scheme 1. Original Kunick paullone synthesis.
scope but which is notorious for variable product yields and harsh
conditions.
In developing a new route to 1, our choice of disconnections
were guided by a desire to (a) start the synthesis with a Fischer in-
dole synthesis product rather than end with it, (b) take advantage
of the inherent reactivity of indoles towards electrophiles at the
C-3 position and (c) close the lactam ring as late as possible in
the synthesis, in order to exploit the rigidity afforded by the two
aromatic rings to facilitate ring closure.
Our route to 1 is outlined in Scheme 2. Starting from the known
indole 11 (readily available on multigram scale19 from the Fischer
indole synthesis involving o-nitroacetophenone and phenylhydr-
azine), reaction with oxalyl chloride20 in ether produced the
Friedel-Crafts acid halide product, which then underwent alcohol-
ysis in ethanol. The product precipitated from solution in pure
form during both operations. Protection of the ketone moiety as
the corresponding dithiolane by acid catalysed reaction with 1,2-
ethanedithiol gave 12 in 78% overall yield.21
Treatment of 12 with Raney nickel followed by heating in diox-
ane in the presence of acetic acid allowed (without purification)
the reduction of the nitro functionality, hydrogenolysis of the
dithiolane to a methylene group22 and cyclisation via attack of
the in situ formed aniline on the ester to afford paullone 1 in
54% yield.23 Analysis of this reaction as it progressed revealed that
the cyclisation is the final step (i.e., ring closure of 12a24). The route
is concise and efficient: it utilises a readily available starting mate-
rial, it takes advantage of multiple reaction steps in one pot and re-
quires no chromatography.25 In addition, since the Fischer indole
synthesis is relocated to the beginning of the route, this strategy
offers (in our view) a greater degree of certainty regarding versatil-
ity. One can synthesise the indole with the required substitution
pattern on both aromatic rings at the beginning of the sequence
areas where positive charge
is predicted to improve activity
O
NH
O
areas where steric
bulk is predicted to
improve activity
N
O
NH
areas where negative charge
is predicted to improve activity
and then form the e-lactam (which is essential for activity) via a
novel, short, two-pot sequence, instead of necessitating that
potential modifications to the paullone core be compatible with
Figure 2. Pictorial representation of the CoMSIA contour map for steric and
electrostatic fields reported by Lemcke et al. for the binding of 3 to CDK1 (indole
section only).

4942
D. P. Power et al. / Bioorg. Med. Chem. Lett. 20 (2010) 4940–4944
1. (COCl)
O
2
S
Et O, rt, 3.5 h
2
S
1. Raney Ni, dioxane
2. Filter
OEt
H (3 atm.), rt, 48 h
2
3. EtOH, rt, 16 h
Ar
4. Filter
N
N
2. AcOH (2.0 equiv.)
dioxane, 80 °C, 48 h
H
H
5. HSCH CH SH
2
2
O N
2
HCl
60 °C, 24 h
(g)
11 Ar = 2-NO -C H
12 78%
2
6
4
O
O
NH
OEt
N
H
N
H
H N
2
12a
1 54%
Scheme 2. A new concise route to 1 involving a one-pot reduction, hydrogenolysis and lactamisation sequence.
Fischer
Indole
synthesis
NHNH
N
O
2
O N
2
N
no reaction
NO
N
2
H
13
14
15
Scheme 3. Failure of the Fischer indole synthesis strategy.
the often harsh conditions associated with Fischer indole synthesis
in the final step.
theses utilising 13 have been reported, in our hands this reaction
failed repeatedly, despite considerable experimentation.
We were next keen to apply this route to the synthesis of the
missing azapaullone 6. Here the prudence of the above sequence be-
came clear: the preparation of 6 requires a Fischer indole synthesis
using pyridylhydrazine 13 and acetophenone 14 and in our hands
this reaction would not proceed under a variety of different condi-
tions (either thermal or microwave assisted) in the presence of
either Brønstedor Lewis acids (Scheme 3). WhilstFischer indole syn-
Thus, it was clear that in order to synthesise 6 using the same
general strategy outlined in Scheme 2 an alternative route to the
azaindole 15 was required. We therefore developed a straightfor-
ward route (Scheme 4) to the azapaullone precursor based on the
known protected iodopyridine 16,26 which could be coupled with
the commercially available terminal alkyne 17 under Sonogashira
conditions to give internal alkyne 18. Fluoride ion-mediated
TIPS
17
(1.2 equiv.)
PdCl (PPh ) (2 mol%)
NHBoc
NHBoc
TIPS
Bu N F (1.1 equiv.)
NHBoc
4
I
2
3 2
CH Cl (0.2 M),
2
2
CuI (6 mol%), PPh (8 mol%)
3
rt, 1 h
N
N
N
NEt (0.2 M), 55 °C, 24 h
3
16
18 94%
19 89%
I
20
NO
2
O N
2
NHBoc
(1.2 equiv.)
PdCl (PPh ) (2 mol%)
CuI (10 mol%)
DBU (10 mol%)
N
NO
2
3 2
2
N
CuI (6 mol%), NEt (0.2 M)
DMF, 50 °C, 16 h
3
Boc
N
PPh (8 mol%), 55 °C, 24 h
22 82%
3
21 84%
O N
2
TFA/CH Cl
2
2
rt, 16 h
N
N
H
15 88%
Scheme 4. Synthesis of azaindole precursor 15.

D. P. Power et al. / Bioorg. Med. Chem. Lett. 20 (2010) 4940–4944
4943
O
O
O
S
O
O
S
(15 equiv.)
HSCH CH SH
2
2
OEt
OEt
CH Cl /TFA
23
Cl
OEt
2
2
N
N
15
AlCl (15 equiv.)
60 °C, 48 h
3
N
N
CH Cl /MeNO (9:1 v/v)
H
2
2
2
H
O N
2
O N
2
rt, 24 h
24 (not isolated)
25 63%
O
1. Raney Ni, dioxane
H (3 atm.), rt, 48 h
2
NH
CF CO H
3
2
N
2. AcOH (2.0 equiv.)
dioxane, 80 °C, 48 h
N
H
3. CH Cl /TFA, rt, 1 h
2
2
6 TFA 17%
Scheme 5. Synthesis of 9-azapaullone (6ÁTFA).
deprotection of 18 afforded 19, which participated in a second
Sonogashira reaction with iodonitrobenzene 20 to afford the
cyclisation precursor 21. After extensive investigation it was found
that 21 would undergo a base-catalysed smooth 5-endo-dig cycli-
sation reaction under relatively mild conditions in the presence of
DBU if CuI was added as a co-catalyst.27 Removal of the Boc-
protecting group then furnished 15 in good overall yield.
With azaindole 15 in hand attention now turned to the 9-aza-
paullone synthesis (Scheme 5). Due to the attenuating properties
of the azaindole nitrogen atom on the heterocycle’s affinity for
electrophiles, more forcing conditions for the Friedel-Crafts reac-
tion than those used to prepare 12 were required. With the assis-
tance of AlCl3, 15 could be converted to 24 (in addition to the
corresponding diethylketal if ethanol was used to quench the reac-
tion) in the presence of excess acid chloride 23. Protection of the
ketone moiety as its dithiolane derivative 25 (in good overall yield
from 15) then allowed the same reduction, hydrogenolysis and
cyclisation sequence as that used to prepare 1 to give the desired
azapaullone 6, which was isolated as its TFA salt due to the poor
solubility of the free base in organic solvents.
alkylation of 6ÁTFA with benzyl bromide in the presence of base
afforded the N-alkyl salt 7a.
The biological activity of paullones 1, 2, 6 and 7a, b was
then evaluated on a small panel of standard relevant kinases
(Table 1).
The results of this screening study confirm the potency of paull-
ones as CDK and GSK-3 inhibitors. As expected, paullone (1)
possessed modest activity, however, the performance of 9-azapaul-
lone (6) is of interest: it exhibits broadly similar activity to 1, with
the exception that 6 is a considerably more efficient inhibitor of
CDK9/cyclin T (entry 4), although neither are as powerful an inhibi-
tor of this kinase/cyclin complex as kenpaullone (2).
The evaluation of azapaullone derivatives 7a and 7b furnished
the most intriguing (and gratifying) results. The N-benzyl salt 7a
was inactive in the presence of almost all the kinases. The neutral
N-oxide 7b, however, possesses the most promising activity profile
of the compounds evaluated in this study — it exhibits 0.24 lM
activity as an inhibitor of CDK9/cyclin T. While it should be pointed
out that 7b is ca. four times less active than 2 towards this com-
plex, unlike 2 (which inhibits CDK9/cyclin T and GSK-3 with almost
equal potency — entries 4 and 9), 7b is remarkably selective and is
more than an order of magnitude less effective an inhibitor of GSK
than CDK9/cyclin T. In addition, it is either essentially inactive or
very weakly active against all other kinases utilised in the screen.
Thus, while the inhibitory activity of 7b towards CDK9/cyclin T is
respectable but not comparable to that associated with benchmark
compounds in the literature, this N-oxide does appear to possess
the ability to effectively distinguish CDK9/cyclin T from a range
Derivatisation of 6ÁTFA was carried out as shown in Scheme 6.
After considerable experimentation, conditions were identified un-
der which the azapaullone salt could be N-oxidised in aqueous
media. Treatment of the azapaullone with mCPBA in aqueous diox-
ane under basic conditions led to the isolation of N-oxide 7b, while
O
mCPBA (4.5 equiv.)
Na CO (5.0 equiv.)
NH
2
3
O
6 TFA
N
Table 1
Protein kinase inhibitory activity of compounds 1, 2, 6, 7a, 7b
dioxane/H O (3:2)
2
N
50 °C, 48 h
H
Entry
Target
IC50
(l
M)a
1
2
6
7a
7b
7b 19%
1
2
3
4
5
6
7
8
9
CDK1/cyclin B
CDK2/cyclin A
CDK5/p25
CDK9/cyclin T
CK1
CLK1
DYRK1A
GSK-3
PfGSK-3
3.0
2.7
4.2
0.81
>10
>10
>10
1.1
0.5
0.78
1.0
0.064
>10
>10
>10
0.078
>10
2.1
2.1
3.0
0.22
>10
>10
>10
0.81
>10
>10
>10
>10
7.4
>10
>10
>10
>10
>10
5.7
6.2
7.3
0.24
>10
>10
>10
3.4
O
BnBr (2.0 equiv.)
Br
NH
Bu N OH (1.0 equiv.)
4
6 TFA
N
MeCN, 80 °C, 48 h
N
>10
>10
H
a
Compounds were tested at various concentrations on nine purified kinases as
described in Ref. 28. IC50 values, calculated from the dose–response curves, are
reported in M.
7a 25%
l
Scheme 6. Synthesis of oxidised and alkylated 9-azapaullone derivatives.

4944
D. P. Power et al. / Bioorg. Med. Chem. Lett. 20 (2010) 4940–4944
19. MacPhillamy, H. B.; Dziemian, R. L.; Lucas, R. A.; Kuehne, M. E. J. Am. Chem. Soc.
1958, 80, 2172.
20. Han, Q.; Dominguez, C.; Stouten, P. F. W.; Park, J. M.; Duffy, D. E.; Galemmo, R.
A.; Rossi, K. A.; Alexander, R. S.; Smallwood, A. M.; Wong, P. C.; Wright, M. M.;
Luetten, J. M.; Knabb, R. M.; Wexler, R. R. J. Med. Chem. 2000, 43, 4398.
of related proteins/protein complexes — in particular the challeng-
ing case of GSK-3.
In summary, we have developed an efficient, easily modified
and concise route to paullone 1 from simple starting materials. A
variant of this synthetic strategy was then used to prepare the
hitherto unreported 9-azapaullone (6), in addition to its N-benzyl
salt 7a and N-oxide derivative 7b. A study to evaluate the inhibi-
tory activity of these compounds against a range of kinases inden-
tified 7b as a selective inhibitor of CDK9/cyclin T. The potential
significance of the function of CDK9/cyclin T in a range of medici-
nally relevant domains such as cell-cycle/transcription regula-
tion,4,8,29 HIV-1 replication30 and cardiovascular disease31 is only
beginning to be understood, thus the development of highly selec-
tive inhibitors of this complex is a goal of considerable interest.
Studies aimed at increasing the potency of 7b and improving its
ability to distinguish between CDK9/cyclin T and other kinases
are underway.
21. Dithiolane 12: In
a three-necked round bottomed flask, oxalyl chloride
(1.28 mL, 15.11 mmol) was added to anhydrous diethyl ether (16 mL) under
an atmosphere of argon. The solution was cooled to 0 °C and indole 11 (1.64 g,
5.87 mmol) was added. The resulting suspension was stirred at ambient
temperature for 3.5 h. The resulting pale yellow precipitate was removed by
filtration, suspended in ethanol and stirred at ambient temperature for 24 h.
The resulting solid was removed by filtration, washed with a mixture of
ethanol and diethyl ether (ca. 1:1) yielding 1.89 g of crude ethyl ester which
was used without further purification. The ethyl ester was then suspended in
ethanol (85 mL) and the suspension saturated with HCl gas. Ethane dithiol
(0.59 mL, 7.04 mmol) was added. The solution was heated overnight at 60 °C
under an argon atmosphere. The resulting (spectroscopically pure) orange
precipitate (1.84 g, 78%) was removed by filtration and used without further
purification. mp 228–230 °C. 1H NMR (DMSO-d6, 400 MHz) d = 0.98 (t, J 7.1 Hz,
3H), 3.30 (m, 4H) 3.74 (q, J 7.1 Hz, 2H), 7.06 (app. t, 1H), 7.16 (app. t, 1H), 7.33
(d, J 8.0 Hz, 1H), 7.57 (d, J 7.3 Hz, 1H), 7.75 (m, 2H), 7.82 (app. t, 1H), 8.21 (d, J
8.0 Hz, 1H), 11.51 (br s, 1H). 13C NMR (DMSO-d6, 100 MHz) 13.4, 39.7, 61.6,
67.7, 108.7, 111.3, 118.9, 120.2, 121.3, 124.4, 126.5, 128.2, 130.4, 131.4, 132.9,
133.7, 135.7, 148.5, 170.0. IR (solid)
m
3265, 1688, 1498, 980 cm-1. HRMS (ESI)
calcd for [C20H18N2O4 + Na]+ requires 437.0613. Found 437.0606.
22. Melhado, L. L.; Brodsky, J. L. J. Org. Chem. 1988, 53, 3852.
Acknowledgments
23. Paullone (1): Dithiolane (0.580 g, 1.40 mmol) was dissolved in dioxane (58 mL),
Raney Nickel (wet) was added and the resulting suspension was shaken under
at atmosphere of hydrogen (3 atm) for 24 h. When reduction of both the
dithiolane and nitro functional groups was adjudged to be complete by 1H
NMR spectroscopic analysis, the Raney Nickel was removed by filtration
through celite. The filtrate was then concentrated to approximately 10 mL in
vacuo. Acetic acid (1.60 mL, 28.0 mmol) was added and the solution heated at
60 °C for 48 h. The solvent was then removed under reduced pressure, and the
residue triturated with ethyl acetate/hexane (1:1) to give a white solid which
was isolated by filtration to afford pure 1 (0.189 g, 54%). The spectroscopic data
associated with 1 was identical to those in the literature.24 mp >300 °C (lit.24
>280 °C). 1H NMR (DMSO-d6, 400 MHz) d = 3.50 (s, 2H), 7.08 (app. t, 1H), 7.18
(app. t, 1H), 7.26 (m, 2H), 7.38 (app. t, 1H), 7.44 (d, J 8.4 Hz, 1H), 7.66 (d, J
7.9 Hz, 1H), 7.74 (d, 1H, J 7.7 Hz), 10.11 (s, 1H), 11.61 (s, 1H). 13C NMR (DMSO-
d6, 100 MHz) d = 31.6, 107.5, 111.4, 117.9, 119.1, 122.1, 122.2, 122.8, 123.6,
126.5, 126.8, 127.9, 132.4, 135.4, 137.4, 171.6.
We thank Trinity College Dublin and the HEA PRTLI Cycle 3 for
generous financial support. This research was supported by grants
from the ‘Cancéropole Grand-Ouest’ grant (LM), the ‘Association
France-Alzheimer Finistère’ (LM), ‘Association pour la Recherche
sur le Cancer’ (ARC-1092) (LM) and the ‘Ligue Nationale contre le
Cancer’ (LM).
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24. Our cyclisation conditions are based on those originally developed by Opatz,
who reported a similar cyclisation strategy via the ring closure of in situ
generated 12a. In the Opatz synthesis the generation of 12a via a 5-exo-trig
cyclisation reaction involving a deprotonated
a-aminonitrile requires more
steps and furnishes 1 in lower yield: Opatz, T.; Ferenc, D. Synthesis 2008, 3941.
25
25. For alternative strategies for the synthesis of paullone see Ref.
and: (a)
Baudoin, O.; Cesario, M.; Guenard, D.; Gueritte, F. J. Org. Chem 2002, 67, 1199;
(b) Joucla, L.; Popowycz, F.; Lozach, O.; Meijer, L.; Joseph, B. Helv. Chim. Acta
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Becker, M.; Davis, R.; Spada, A.; Liang, G.; Chu, V.; Brown, K.; Collussi, D.;
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Maignan, S.; Guilloteau, J. –P.; Mikol, V. J. Med. Chem. 2003, 46, 681.
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