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Table 8.5 Representative basic derivatives 9 and 10
Me
EtO
N
EtO
N
HN
Me
HN
C7
C7
N
N
N
N
N
N
Me
N
N
N
C5
N
C5
Et
Me
NH
NH
9
10
.
Criteria
9
10
PDE5 IC
50
(nM)
1.76
1.61
PDE6 selectivity fold
57
53
PDE11 selectivity fold
88
43
clog P
3.06
3.16
MW
411
423
LE (PDE5)
0.41
0.39
LLE (PDE5)
5.69
5.63
Caco-2 Papp A-B (
10
6
cm s
1
), eux ratio
19,
o
1
15, 1
TPSA
93
93
HBD, HBA
2, 9
2, 9
I
Kr
IC
50
(nM)
3562
10 600
hERG
25% @ 0.1 mM
39% @ 1 mM
The neutral amide 8 was profiled in more detail. Pharmacokinetic study was
undertaken (Table 8.6) and the projected human half-life of 8 was 12-36 h,
underpinned by the lower predicted clearance for the compound relative to
sildenafil. Unfortunately, detailed safety evaluation for 8 indicated significant
hERG I
Kr
ion channel activity (IC
50
ΒΌ
80 nM) and evidence of cardiac effects in
vivo, precluding any further development due to the low therapeutic index.
Leveraging the synthetic scope of the series, alternative series types were
explored. Firstly, the basic series typified by 4 was revisited and further rounds
of automated chemistry undertaken. Efforts focused on improving PDE5
selectivity and the cardiovascular safety window, whilst retaining permeability
and a long projected human half-life underpinned by a high volume of dis-
tribution. Compounds 9 and 10 were identified and featured alternative C5 and
C7 amine moieties (Table 8.5).
23
Both derivatives displayed high V
D
values in
rat but the bicyclopiperazine 10 projected to the largest cardiovascular safety
window and was selected for further progression. The projected human half-life
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