Chemistry Reference
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Figure 9.7
Structures of leading CCR5 antagonists.
The story described here for maraviroc was typical for many other pro-
grammes. Internal high-throughput file screening identified leads that were
developed using conventional SAR with a concomitant realisation of the
potential for activity at the hERG ion channel, which was later reduced during
series development. Figure 9.7 shows a selection of disclosed small-molecule
antagonists that have reached clinical trials or represent the most advanced
agents disclosed by companies.
Merck's leading agent 42 (MrkA) showed high levels of antiviral potency
(EC
95
o
8 nM) and a good cross-species pharmacological profile (F440% rat,
dog, monkey), but was hepatotoxic in rat.
88
Compound 43 (aplaviroc, GSK)
showed high levels of antiviral activity (EC
50
ΒΌ
0.1-0.6 nM) across a range of
clinical isolates, oral bioavailability and a t
1/2
in man of
3h.
89
However, it
was withdrawn in 2006 during Ph 2b/c trials as a result of hepatotoxicity,
raising concerns for mechanism-based toxicity, which the later success of
maraviroc now tends to suggest is unlikely.
90
Compound 44 (NIBR-1282,
Novartis) was not designed as an anti-HIV agent, but to suppress kidney
rejection;
B
it showed a large window over the hERG ion channel and a
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