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J. Kempson et al. / Bioorg. Med. Chem. Lett. 15 (2005) 1829–1833
Table 1.
PDE1 IC50 (lM)
(PDE1/PDE7)
PDE2 IC50 (lM)
(PDE2/PDE7)
PDE3 IC50 (lM)
(PDE3/PDE7)
PDE4 IC50 (lM)
(PDE4/PDE7)
PDE5 IC50 (lM)
(PDE5/PDE7)
PDE7
IC50 (lM)
Rolipram
Sidenafil
>10
>10
>10
>10
>10
0.74
4.6
>10
>10
>10
0.15
0.011
0.09
7.0
0.011
1a
1b
1c
0.22 (1.5)
0.95 (86)
50.0 (556)
1.7 (11)
0.95 (86)
(NT)
0.58 (3.8)
2.97 (270)
23.3 (259)
1.1 (7.3)
0.55 (50)
0.27 (3)
0.27 (1.8)
0.011 (1.0)
0.72 (8)
up-regulated in human B-lymphocytes.3 PDE7A3, a
splice variant of PDE7A1, is also reported to be up-reg-
ulated in activated CD4+ T cells.4 This expression profile
suggests inhibitors of PDE7A would have broad appli-
cation as immunosuppressants. It has recently been
shown that PDE7A deficient mice show no deficiencies
in T cell function, which calls the original hypothesis
into question.5 Identification of a small molecule inhib-
itor of PDE7, which could be evaluated in animal mod-
els could shed light on the current understanding of the
relevance of this target.
Cl
Me
O
X
N
N
EtO2C
S
N
H
N
Cl
Common Intermediate
X=CH2, CH2CH2, OCH2
R'
R
R'
R
N
N
N
N
Me
Me
O
N
N
N
N
N
EtO2C
EtO2C
n
N
S
S
N
H
N
H
Several groups have reported the preparation of potent
inhibitors of PDE7.6a–d We recently reported a focused
chemistry effort around our purine-based deck-hit 1a.6e
Variations around the purine core at C-6 demonstrated
that the potency and PDE selectivity could be improved
over the initial lead (e.g., Table 1, 1b). As part of a study
to investigate the selectivity (Table 1) and improve phys-
ical properties of this series, the regiochemistry around
the purine scaffold was used to examine the preferred
spatial orientation of the C-6 substituent (Fig. 1). In
general, these purine analogs displayed poor aqueous
solubility (<5 lg/mL @ pH 6.5) and were not sufficiently
permeable to membranes to permit gastrointestinal
absorption (PAMPA7 0–5 nm/s). This in turn impeded
their evaluation in vivo.
Ar
Ar
Figure 2.
treatment of 6 with POCl3. The olefin of 7 was oxidized
in a two step procedure using catalytic osmium tetroxide
to give the diol, which was subsequently cleaved using
sodium periodate to give a 78% yield of the aldehyde 8
in two steps. With the aldehyde in hand, the reductive
amination/cyclization step was performed with a variety
of amines to provide the tetrahydropyrrolopyrimidine
system 9. Diversity at C-6 was obtained by carrying
out the subsequent reaction in a microwave with a vari-
ety of amines to provide compounds of ring system 10.
Hence, our first objective was to identify a novel scaffold
with improved permeability as measured by PAMPA.
More specifically, we sought to explore systems other
than 1c in an effort to increase either solubility or perme-
ability. As part of this strategy, we needed a synthetic
route that would allow for diversity at the pyrimidine
4- and 6-positions of our target 2, to be installed at a late
stage in order to permit efficient analog preparation.
With this in mind, a synthetic route was devised to the
fused-pyrimidine systems 2, which relied upon a novel
reductive amination–cyclization protocol from a com-
mon aldehyde intermediate (Fig. 2).
Analogous [6,6]-fused systems were synthesized in a sim-
ilar manner using 13 and 14 as the coupling partners in
the condensation with guanidine 5. Scheme 2 illustrates
the synthesis of each of these coupling partners.
The structure–activity relationships for the inhibition of
PDE catalytic activity are summarized in Table 2.
A direct comparison between compounds 1c and 2a
shows a nearly fourfold loss in activity for the saturated
system. However, replacing the methylamine moiety at
C-6 with a piperazine group (compound 2b) improves
the PDE7 activity to 20 nM. A further improvement is
made in this first system by replacing the aryl portion
with trimethoxybenzylamine, a modification which also
improves the selectivity against PDE1–5. For the fused
six-membered compounds (2f–i), the same trend is ob-
served again, with the compound bearing the trimeth-
oxybenzylamine- and piperazine-residues possessing
the best PDE7 activity and selectivity. For the final
fused system, which incorporates an oxygen into the sat-
urated ring (2j,k), the same trend again holds, but this
time producing a compound with a far superior PDE
selectivity profile.
The synthetic pathway utilized in the preparation of the
tetrahydropyrrolopyrimidine system is outlined in
Scheme 1.
Thiazole guanidine 5 was prepared through the conden-
sation of 2-imino-4-thiobiuret 3 with 2-chloroacetoace-
tate 4 in the presence of pyridine. Guanidine 5 was
readily condensed with commercially available diethyl
allyl malonate under basic conditions in refluxing etha-
nol to give the desired pyrimidone 6 in 67% yield.
Dichloropyrimidine 7 was formed in 74% yield after
Kempson, James
