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Table 8.7 Profile of acidic leads 11, 12 and 13
N
N
EtO
N
EtO
EtO
HN
Me
HN
Me
HN
Me
N
N
N
N
N
N
N
N
N
Et
Et
iPr
N
N
N
N
N
N
HO
2
C
O
Me
Me
Me
HN
NH
N
11
12
13
MeO
2
S
O
O
.
Criteria
11
12
13
PDE5 IC
50
(nM)
0.43
0.47
0.55
PDE6 selectivity fold
32
38
41
PDE11 selectivity fold
48
30
37
clog P
3.9
3.34
2.45
MW
413
439
476
LE (PDE5)
0.43
0.4
0.39
LLE (PDE5)
5.47
6.00
6.81
Caco-2 Papp A-B (
10
6
cm s
1
), e
ux ratio
12,
o
2
34,
o
2
25,
o
2
TPSA
118
140
144
HBD, HBA
2, 10
2, 12
2, 13
Rat clearance (mLmin
1
kg
1
)
1.8
10.9
0.54
Rat V
D
(L kg
1
)
0.3
1.3
0.48
Rat t
1/2
(h)
3.1
1.4
10.9
Rat F%
18 (variable)
30
82
in a dog haemodynamic study. The acylsulfonamide 13, PF-489791, was
nominated for development and is currently in Phase II clinical studies for
pulmonary arterial hypertension. Phase I first-in-man pharmacokinetic data
indicated a genuine once-daily oral dosing profile with a human half-life in the
12-14 h range (Table 8.6). The compound was well tolerated and dose-pro-
portional increases of cGMP were observed,
28
indicative of PDE5 inhibition.
8.5 Conclusions
In conclusion, a second-generation PDE5 agent has been discovered from an
HTS initiative. Key elements' in discovery were the focus on physicochemistry
and pharmacokinetics throughout the programme, together with the use of co-
crystal structure data to guide design and identification of a parallel chemistry
amenable, wide synthetic scope template. LE and LLE measurements served as
important indicators of ecient binding. These elements enabled rapid dis-
covery of a proprietary lead 3 with inherently good physicochemistry, a novel
aminopyridine pharmacophore and PDE6 selectivity. Further optimisation
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