Chemistry Reference
In-Depth Information
number of hydrogen bond donors (HBD); (3) increasing the number of rota-
table bonds; (4) decreasing lipopholicity; and (5) increasing the polar surface
area.
75
As we modified the compounds in this series to minimize CNS penetration, it
was important to make specific structural changes that would maintain excel-
lent TRPV1 antagonism. Therefore, as a basis for the design of new periph-
erally restricted derivatives, we were guided by the results obtained from our
previous SAR investigations.
55,63,76
For example, we employed the 2-amino-
quinoxalinone ring system that had previously demonstrated superior TRPV1
antagonism (Table 13.2; ring system B). This heterocycle provided compounds
with higher PSA values and added two additional hydrogen-bond donors. Our
earlier studies also revealed that substituents at the 2-position of the central
pyrimidine ring (R
1
) were, in general, well tolerated for TRPV1 potency.
61
Additionally, we found that we could introduce substituents at the ortho-
position (R
2
) of the phenyl ring (X
¼
CH) or pyridine ring (X
¼
N) and
maintain good TRPV1 activities.
62
Therefore, we prepared a series of deriva-
tives with additional heteroatoms and polar groups at R
1
,R
2
, and X and
examined their effect on potency, CNS penetration,
77
ecacy (as determined by
inhibition of in vivo capsaicin-induced flinching), and body core temperature.
Modifying AMG 517 in this way led to the identification of five potent and
peripherally restricted TRPV1 antagonists (Table 13.2) that showed good on-
target in vivo ecacy in the capsaicin-induced flinch model (Figure 13.16A).
These derivatives were tested in a telemetry model to examine their effect on
body core temperature. Rats implanted with radiotelemetry probes were dosed
orally with a single dose of the TRPV1 antagonists; body core temperatures
were recorded 30min prior to drug administration and continued for 2 h post-
dose. Figure 13.16B shows the increase in body core temperature over control
animals at the 60-min time point, which usually corresponds with the maximum
increase in body core temperature. Unfortunately, all five TRPV1 antagonists
showed a significant increase in body core temperature (40.5 1C) compared to
vehicle control. These results suggested that peripheral restriction alone was not
sucient to eliminate TRPV1 antagonist-induced hyperthermia and the site of
action for the hyperthermic effect is predominantly outside of the blood-brain
barrier. From this study we concluded that minimizing brain penetration was
not sucient to separate the analgesic properties of TRPV1 antagonists from
the on-target hyperthermia observed in rodents.
13.6.2 TRPV1 Antagonists with Differential In vivo
Pharmacologies
The final approach we took to eliminate TRPV1-induced hyperthermia was to
evaluate compounds that display differential TRPV1 in vitro pharmacologies.
67
Until this point we had targeted compounds that blocked all modes of acti-
vation and had found that all compounds with this profile caused hyperther-
mia. However, since TRPV1 is a poly-modal sensor of lipids, protons, heat, and
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