Chemistry Reference
In-Depth Information
small-molecule antagonists as a lipophilic pocket buried within the trans-
membrane region of the receptor, while interaction of gp120 with the receptor
occurs on the extracellular surface at the N-terminus of the receptor.
67,68
A strain of maraviroc-resistant HIV-1 was selected by the serial passage of a
primary viral isolate grown in peripheral blood lymphocytes in the presence of
sub-EC
50
levels of maraviroc.
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Sequencing studies showed that resistance was
associated with two amino acid mutations, A316T and I323V (confirmed by
reverse mutation), both in the V3 loop of gp120. Mutations in the V3 loop have
also been associated with virologic failure in the MOTIVATE clinical trials with
maraviroc. Plateaux in the maximal levels of inhibition were identified as a marker
of resistance, demonstrating the ability of resistant virus to use compound-bound
receptors to gain cell entry.
70
A second theoretical mechanism by which mar-
aviroc resistance can emerge is through tropism shifting from CCR5-tropic to
CXCX4-tropic or dual-tropic virus. Again, in the MOTIVATE trials, dual- or
mixed-tropic virus was observed among patients who experienced treatment
failure. Phylogenetic analysis of viral envelopes indicated that the emergent strains
represented an outgrowth (under the selective pressure of a CCR5 antagonist) of
virus which was initially present, but not detected, at initial screening.
71
From the in vitro data obtained to date, maraviroc-resistant strains retain
sensitivity to other CCR5 antagonists, indicating that not only do they still rely
on CCR5 for entry, but that their ability to gain access to antagonist-associated
receptor is limited to the compound used to select for them in the first
instance.
70,72
9.14 Identifying Back-up Agents
The identification of a compound that matches laboratory objectives, allows for
the prediction of an appropriate PK profile in man and has a demonstrable
safety window over toxic side-effects is a significant achievement for a drug
discovery team. However, attrition remains a significant risk before the drug
can reach the market; typically only 1 in 10 of compounds entering development
will reach the market.
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Ideally, feedback from the clinical programme would
drive the design of backup agents, but such information is rarely timely.
Consequently, assembled project teams will often attempt to identify further
compounds to address perceived risks with the prototype before expertise,
screening cascades and resources are disbanded. The greatest attrition risk is
from toxicity, and often a backup programme will attempt to maximise struc-
tural differentiation from the prototype to mitigate structure- or chemotype-
based toxicity. The CCR5 team devoted effort to identify additional agents
within the same chemotype and more widely to develop new structural classes.
Work within the same structural class led to the identification of 37 (PF-
232798; Table 9.7), which progressed into Phase 2 clinical trials in 2007.
74
This
agent retains the tropane core, shows a similar primary and selectivity/safety
profile to maraviroc, and with an improved PK profile allowing for once-daily
dosing.
75
Interestingly, despite its clear structural relationship to maraviroc, it
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