Chemistry Reference
In-Depth Information
O
O
O
N
O
HN
O
HN
N
O
HN
N
N
N
N
N
N
N
O
S
O
S
O
S
N
N
NH
O
O
N
O
N
N
O
Vardenafil
Sildenafil
Udenafil
Cl
O
O
O
N
N
O
HN
HN
N
N
NC
N
N
O
N
H
O
O
S
N
N
O
O
N
Eisai
Tadalafil
UK-371800
N
Figure 8.1
Structures of marketed and advanced PDE5 inhibitors.
sildenafil, this would require free drug levels below the corresponding PDEX
IC
50
at all times. We believed that this profile could be best achieved by a long-
duration compound with low peak-to-trough concentrations.
8.2 X-Ray Crystallography and Structure-based Drug
Design
Although not available at the time of the design of the first-generation PDE5
inhibitors, an in-house effort yielded a crystal structure of a truncated form of
the enzyme complexed with sildenafil.
11
An independent study
12
also solved the
structures of the catalytic domain of PDE5 complexed to sildenafil, vardenafil
and tadalafil. We were also able to obtain bound structures of compounds
from our sildenafil follow-on effort, including UK-371800,
13,14
as well as those
for literature compounds (e.g. a close analogue of E-4010),
15
which we felt
would provide additional insights into the promiscuity of the PDE5 active site
(Figure 8.2). The availability of structural information enabled us to rationalise
the structure-activity relationships (SAR) we had observed in our earlier syn-
thetic efforts and thus direct further effort into regions of the active site we felt
would yield more optimal interactions.
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