Chemistry Reference
In-Depth Information
more closely and sought possible ways to eliminate or minimize this on-target
effect. Initially, we examined the effects of several TRPV1 antagonists repre-
sented by various chemotypes, including: cinnamides, ureas, amides, benzimi-
dazoles, and piperazine carboxamides on rat body temperature.
57
We found
that all chemotypes that we tested caused a 0.5-1.5 1C increase in body tem-
perature, suggesting that antagonist-induced hyperthermia was not chemotype
specific but rather occured because of TRPV1 blockade in vivo. Furthermore,
we also found that a TRPV1-selective antagonist did not cause hyperthermia in
TRPV1 knockout mice, demonstrating that the entire hyperthermic effect was
TRPV1 mediated.
57
We also took two approaches in attempts to eliminate or minimize the
hyperthermic response: (1) we examined the effect of peripherally restricted
TRPV1 antagonists,
66
and (2) we identified and evaluated compounds that
display differential pharmacologies (i.e., compounds that differentially mod-
ulate distinct modes of in vitro TRPV1 activation such as capsaicin, pH 5, and
heat) in vivo.
67
13.6.1 Peripherally Restricted TRPV1 Antagonists
68
Because the hypothalamus is the key area of the brain known to be involved in
thermoregulation,
69
we postulated that we may be able to separate the
analgesic effect of our TRPV1 antagonists from their hyperthermic effect if they
were excluded from the central nervous system (CNS). Unfortunately, all of the
initial derivatives of AMG 517 we had prepared and evaluated at that time had
significant brain penetration. For example, AMG 517 had exhibited significant
CNS penetration with a brain-to-plasma ratio (B/P) of 1. Therefore, to test our
hypothesis we needed to prepare and evaluate novel derivatives of AMG 517
that had low brain-to-plasma ratios while at the same time maintaining potent
TRPV1 activities.
Our approach to the discovery of peripherally restricted derivatives of AMG
517 was based on the premise that passive diffusion is the primary process for
translocation of these compounds from the bloodstream to the brain. CNS
permeability (and in general transcellular permeability) is a complex function of
the physicochemical properties of molecules such as size, lipophilicity, hydro-
gen-bonding potential, charge, and conformation.
70,71
In general, CNS-pene-
trant compounds are somewhat smaller than other biologically active molecules
(90% of them have molecular weights of less than 500). They also have any-
where from 2 to 7 hydrogen-bonding groups, while the range for non-CNS-
penetrant agents is 2-9. In addition, over 90% of the CNS-active drugs have 7
or fewer rotatable bonds, while this number is 10 for peripherally restricted
compounds. Finally, compounds that access the CNS are in general more
lipophilic (larger log P) than peripherally targeted compounds,
72,73
and they
generally have polar surface area (PSA) values less than 90.
74
Therefore, with
these guiding principles in mind, we sought to restrict the CNS penetration of
our TRPV1 antagonists by: (1) increasing molecular weight; (2) increasing the
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