Chemistry Reference
In-Depth Information
Table 8.6 Actual and projected human pharmacokinetic data for sildenafil, 8,
10 and 13.
Criteria
Sildenafil
8
10
13
Human clearance (mLmin
1
kg
1
)
0.1-0.3
a
2.3
a
0.2-0.3
b
6
Human V
D
(L kg
1
)
0.3
a
3-7
a
B
0.2
b
1.2
11-44
a
15-35
a
12-14
b
Human t
1/2
(h)
3-5
a
Projected human pharmacokinetics.
b
Derived from human oral data.
for 10 indicated the potential for once-daily dosing (Table 8.6). However, whilst
the hERG IC
20
of 600 nM indicated a substantial safety window against pri-
mary polypharmacology, further testing in vivo in a conscious dog indicated
threshold cardiovascular effects at 190 nM and progression was halted.
Alongside revisiting the basic series, the synthetic scope of the series was
further leveraged to explore acidic systems.
30
The co-crystal structure of the
amide 5 supported the belief that acidic moieties would be tolerated at the C3
position. Given that cardiovascular safety issues with acidic molecules are
extremely rare, presumably due to the negatively charged nature of the hERG
ion channel,
31
this new sub-class represented an attractive option. In terms of
retaining a long projected human half-life, ensuring low clearance would be
essential as an acid would likely have a low V
D
confined to blood plasma
volume.
Various C3 carboxylic acids were explored and the isopropyl(methyl)amino
derivative 11 emerged as a promising early lead (Table 8.7). Sub-nanomolar
PDE5 potency, good selectivity and good physical/ADME properties encour-
aged further profiling. The rat pharmacokinetics of 11 indicated low clearance,
but poor bioavailability was seen upon oral dosing. A portal-systemic rat study
was undertaken and indicated high levels of the glucuronide metabolite, con-
sistent with first-pass glucuronidation in the intestine.
Applying the rationale that acid isosteres would have a lower propensity for
glucuronidation, whilst still retaining appropriate features for activity, a range
of keto-oxadiazole and acylsulfonamide derivatives were made. Compounds 12
and 13 represented the best examples in each class (Table 8.7), displaying sub-
nanomolar level PDE5 potency, good PDE5 selectivity and physicochemical/
ADME properties that merited more detailed profiling. Whilst both com-
pounds displayed improved oral bioavailability in rat pharmacokinetic studies
relative to the carboxylic acid 11, the acylsulfonamide derivative 13 stood out
by virtue of very low clearance that resulted in a long 9.3 h half-life. Addi-
tionally, 13 displayed almost complete oral bioavailability. The resulting pro-
jected human pharmacokinetics for 13 pointed to a 410 h human half-life.
Blood pressure lowering was observed in a spontaneously hypertensive rat with
maximal effects at 5
the PDE5 in vitro IC
50
and the compound displayed an
excellent safety profile. No significant cross activity was seen upon wide ligand
profiling and the hERG signal was very weak (15% at 10 mM). Additionally, no
cardiovascular effects were observed up to 221
the ecacious concentration
Search WWH ::
Custom Search