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OMe
OMe
OMe
OMe
N
OMe
N
O
2
N
MeO
O
2
N
N
N
O
N
N
H
N
H
6-nitro-2,4-diaminoquinazoline related to 1 (See Figure X4)
PDE5 IC
50
137nM
cLogP 3.8, MWt 494
LE 0.27, LLE 3.05
1
PDE5 IC50 20nM
cLogP 5.4, MWt 545
LE 0.27, LLE 2.3
Figure 8.3
Representative 6-nitro-2,4-diaminoquinazoline HTS hit 1.
follow-up. The series displayed sub-100 nM level potency and was readily
amenable to parallel chemistry. The nitro derivative 1 was typical, displaying
20 nM level potency (Figure 8.3), but unattractive physicochemistry (clog
P
¼
5.4, MW
¼
545), resulting in LE and LLE values that fell short of the
corresponding figures for established PDE5 agents. The nitro group also
represented a potential toxicophore and gave us cause for concern with respect
to safety.
Additionally, we had binding site information from an X-ray co-crystal
structure that suggested significant scope for improvement (Figure 8.4a). In
particular, whilst the nitro group was maintaining a bidentate hydrogen bond
spanning two glutamine (GLN) residues (GLN817, GLN775) important to
activity, hydrophobic interactions appeared far from ecient and the sildenafil
''alkoxy'' pocket was unoccupied.
Using our structural knowledge of the requirements for PDE5 inhibi-
tion,
11,21,22
we set out to replace the nitro group using the diaminoquinazoline
core to target alternative interactions with GLN817. Additionally, we sought to
improve the eciency of the hydrophobic interactions. To this end, a library
based on sequential displacement of dichloroquinazoline templates was
designed and synthesised (Figure 8.5).
23
One of the products, compound 2,
featured an aminopyridine motif that represented a novel PDE5 pharmaco-
phore and retained potency despite the significantly modified structure. The
physicochemistry of 2 was vastly improved and reflected in a LE value that was
much more in accord with established PDE5 inhibitors. LLE also showed a
slight improvement.
With a more structurally desirable pharmacophore in hand, we designed a
second library (Figure 8.6). Objectives were to improve potency, identify
alternative diamino heterocycle templates that offered greater chemical scope
for lead optimisation and to incorporate ionisable functionality to aid
solubility, which in the case of a basic centre could also increase volume
of distribution to aid pharmacokinetics. Whilst several interesting structures
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