3124
M. B. Tollefson et al. / Bioorg. Med. Chem. Lett. 20 (2010) 3120–3124
(36) showed a similar potency and selectivity profile indicating
that a basic nitrogen is not required for binding affinity (Table 3).
Unfortunately compound 36 metabolizes quickly (15% remaining
after 30 min). Piperidine methylalcohol 37 delivers excellent
PDE5 potency (70 pM) and good PDE6/11 selectivity (100Â/
120Â) but metabolizes quickly. 4-Amidopiperidines (38 and 39)
exhibit similarly good potencies and improved PDE6/11 selectivity
but metabolize extremely quick as well. The 3-amidopiperidine
(40) has excellent potency but now indicates a change in selectiv-
ity indicating the potential differences in the depth and width of
the PDE6 and PDE11 binding pockets.
We prepared carboxylic acid derivatives to further explore the
true nature of the binding pocket but to also alter the binding pro-
file to the hERG channel. This modification was also expected to
significantly decrease the volume of distribution and alter the PK
profile of these compounds. Compounds 41 and 42 both exhibit
excellent potencies (50 pM and 40 pM) while maintaining ade-
quate PDE6 selectivity and improved PDE11 selectivity (>400Â).
On a positive note, when compound 42 was incubated with human
liver microsomes, 87% of compound remained after 30 min.
Table 4 indicates additional profiling we performed on several
representative compounds. We initially used a competition assay
using radiolabeled dofetilide to determine the compound’s likeli-
hood to interact with the hERG channel. At a compound concentra-
These compounds were taken into an in vivo model of efficacy
(Table 4). We used spontaneously hypertensive rats (SHR) which
were monitored for compound levels and blood pressure. Encourag-
ingly pyrimidines 24, 31 and 42 all exhibited a lowering of blood
pressure after oral administration of compound. This is consistent
with low clearance and also the high solubility observed with com-
pounds from this series. Amines 24 and 31 show a maximum de-
crease in mean arterial blood pressure (MAP) of 10–15 mmHg at
1–2 h post dose. The MAP returned to basal levels in under 6 h as
indicatedby thehigherclearancesobservedin dogPK. Acid 42shows
a maximum reduction in MAP of 30 mmHg which is sustained for at
least 24 h. The measured free fraction of compound 42 at 24 h post
dose indicates blood levels 18-fold over the PDE5 IC50 levels.
We have presented an alternate to the trifluoroethoxyethyl
compounds that were previously reported. We successfully inden-
tified a number of potent and selective PDE5 inhibitors that that
exhibit promising PK profiles in the presence of the potentially
metabolizable ethoxyethyl substituent. In an efficacy model using
SHR we observed sustained lowering of blood pressure which
show promise as a long-acting therapeutic when the acid is incor-
porated. Compound 42 was taken forward into phase 1 clinical tri-
als for further evaluation.
References and notes
tion of 10 lM no molecule inhibited at a value greater than 70%.
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We followed up compounds with a value greater than 50% with a
hERG patch clamp assay. We found hERG values to be slight more
potent than what is predicted by the dofetilide assay. Based on a
ratio of hERG/PDE5 IC50 values of compound 24 (>3100Â) and
compound 42 (>27,000Â), we had few cardiac safety concerns
going forward with these compounds.
We examined the pharmacokinetic (PK) properties of these
molecules using dogs (Table 4).8 Methylpiperazine 20 has moder-
ately high clearance (30 mL/min/kg) and volume (11.4 L/kg). Amin-
opiperidine 31 had an even higher clearance (48 mL/min/kg) and
volume (50.4 mL). As previously stated we prepared the acids with
the hopes that it would alter the PK profile away from the high vol-
umes seen with the amines. This indeed was the case. Acid 42
showed an improved clearance (12.6 mL/min/kg) and reduced vol-
ume (3.8 L/kg) resulting in a half-life of 5.9 h.