Chemistry Reference
In-Depth Information
8.4.3 Candidate Discovery
A range of basic amide derivatives of 5 were synthesised with an emphasis on
reduction of H-bond donor count and TPSA and included appending the basic
centre to the C3 amide group. Whilst good pharmacology could be maintained,
permeability remained poor. A more productive approach was based upon the
non-essential potency contribution made by the basic piperazine of 5. Given
that 5 was sub-nanomolar against PDE5, and a slight potency loss could be
tolerated, lower mass non-basic derivatives were explored as a means of
reducing H-bond donor count and TPSA. Potency was retained with ether,
heterocycle and neutral amide derivatives, as exemplified by compounds 6, 7
and 8 (Table 8.4),
28,29
which retained good LE and LLE. Whilst all three
options restored permeability in addition to retaining excellent potency and
selectivity, the amide derivative 8 appeared promising, lacking the human liver
microsome (HLM) metabolic liabilities of the other two classes and the I
Kr
potassium ion channel potency of the ether 6, indicative of the potential for
unfavourable cardiac activity.
Table 8.4 Profiles of representative neutral derivatives 6, 7 and 8
EtO
N
N
EtO
EtO
N
HN
Me
HN
Me
HN
Me
N
N
N
N
N
N
N
N
N
OMe
N
NHEt
N
NMe
2
N
N
O
Me
NHMe
N
OMe
N
6
N
7
8
.
Criteria
6
7
8
PDE5 IC
50
(nM)
0.83
0.80
0.84
PDE6 selectivity fold
82
169
116
PDE11 selectivity fold
104
155
54
clog P
2.8
2.1
2.8
MW
429
422
398
LE (PDE5)
0.40
0.40
0.43
LLE (PDE5)
6.28
7.00
6.28
Caco-2 Papp A-B (
10
6
cm s
1
), eux ratio
NA
NA
25,
o
2
TPSA
99
112
119
HBD, HBA
1, 10
1, 11
3, 10
I
Kr
IC
50
(nM)
526
410 000
2610
hERG IC
50
(nM)
-
-
80
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